Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances.

Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may disrupt a range of cellular processes, such as impaired protein quality control pathways, ion channel dysfunction, mitochondrial dysfunction, transcriptional dysregulation, DNA damage, loss of nuclear integrity, and ultimately, impairment of neuronal function and integrity which causes diseases. Many disease-modifying therapies, such as gene editing technology, RNA interference, antisense oligonucleotides, stem cell technology, and pharmacological therapies are currently under clinical trials. However, the development of curative approaches for genetic diseases remains a global challenge, beset by technical, ethical, and other challenges. Therefore, the study of the pathogenesis of spinocerebellar ataxia is of great importance for the sustained development of disease-modifying molecular therapies.

Antifungal bioactivity of Sarcococca hookeriana var. digyna Franch. against fluconazole-resistant Candida albicans in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Sarcococca hookeriana var. digyna Franch. has been widely utilized in folk medicine by the Miao people in the southwestern region of China for treating skin sores which may be associated with microbial infection. AIM OF THE STUDY: To investigate the antifungal bioactivity of S. hookeriana var. digyna against fluconazole-resistant Candida albicans in vitro and in vivo, as well as its underlying mechanism and the key bioactive component. MATERIALS AND METHODS: The antifungal bioactivity of 80% ethanol extract of S. hookeriana var. digyna (SHE80) was investigated in vitro using the broth microdilution method, time-growth curve, and time-kill assay. Its key functional component and antifungal mechanism were explored with combined approaches including UPLC-Q-TOF-MS, network pharmacology and metabolomics. The antifungal pathway was further supported via microscopic observation of fungal cell morphology and examination of its effects on fungal biofilm and cell membranes using fluorescent staining reagents. In vivo assessment of antifungal bioactivity was conducted using a mouse model infected with C. albicans on the skin. RESULTS: S. hookeriana var. digyna suppressed fluconazole-resistant C. albicans efficiently (MIC = 16 µg/mL, MFC = 64 µg/mL). It removed fungal biofilm, increased cell membrane permeability, induced protein leakage, reduced membrane fluidity, disrupted mitochondrial membrane potential, induced the release of reactive oxygen species, promoted cell apoptosis, and inhibited the transformation of fungi from the yeast state to the hyphal state significantly. In terms of mechanism, it affected sphingolipid metabolism and signaling pathway. Moreover, the predicted bioactive component, sarcovagine D, was supported by antifungal bioactivity evaluation in vitro (MIC = 4 µg/mL, MFC = 16 µg/mL). Furthermore, S. hookeriana var. digyna promoted wound healing, reduced the number of colony-forming units, and reduced inflammation effectively in vivo. CONCLUSIONS: The traditional use of S. hookeriana var. digyna for fungal skin infections was supported by antifungal bioactivity investigated in vitro and in vivo. Its mechanism and bioactive component were predicted and confirmed by experiments, which also provided a new antifungal agent for future research.

Novel insights into the glucose metabolic alterations of freshwater snails: a pathway to molluscicide innovation and snail control strategies.

As ecosystem disruptors and intermediate hosts for various parasites, freshwater snails have significant socioeconomic impacts on human health, livestock production, and aquaculture. Although traditional molluscicides have been widely used to mitigate these effects, their environmental impact has encouraged research into alternative, biologically based strategies to create safer, more effective molluscicides and diminish the susceptibility of snails to parasites. This review focuses on alterations in glucose metabolism in snails under the multifaceted stressors of parasitic infections, drug exposure, and environmental changes and proposes a novel approach for snail management. Key enzymes within the glycolytic pathway, such as hexokinase and pyruvate kinase; tricarboxylic acid (TCA) cycle; and electron transport chains, such as succinate dehydrogenase and cytochrome c oxidase, are innovative targets for molluscicide development. These targets can affect both snails and parasites and provide an important direction for parasitic disease prevention research. For the first time, this review summarises the reverse TCA cycle and alternative oxidase pathway, which are unique metabolic bypasses in invertebrates that have emerged as suitable targets for the formulation of low-toxicity molluscicides. Additionally, it highlights the importance of other metabolic pathways, including lactate, alanine, glycogenolysis, and pentose phosphate pathways, in snail energy supply, antioxidant stress responses, and drug evasion mechanisms. By analysing the alterations in key metabolic enzymes and their products in stressed snails, this review deepens our understanding of glucose metabolic alterations in snails and provides valuable insights for identifying new pharmacological targets.

A fast and high precision multi-robot environment modeling based on M-BFSI: Bidirectional filtering and scene identification method.

This article designs and implements a fast and high-precision multi-robot environment modeling method based on bidirectional filtering and scene identification. To solve the problem of feature tracking failure caused by large angle rotation, a bidirectional filtering mechanism is introduced to improve the error-matching elimination algorithm. A global key frame database for multiple robots is proposed based on a pretraining dictionary to convert images into a bag of words vectors. The images captured by different sub-robots are compared with the database for similarity score calculation, so as to realize fast identification and search of similar scenes. The coordinate transformation from local map to global map and the cooperative SLAM exploration of multiple robots is completed by the best matching image and the transformation matrix. The experimental results show that the proposed algorithm can effectively close the predicted trajectory of the sub-robot, thus achieving high-precision collaborative environment modeling.

[Toxic effect and mechanism of Tripterygium glycosides on ovarian germline stem cells of mice in vitro by Notch signaling pathway].

The ovarian germline stem cells(OGSCs) cultured in the optimized culture system were used as the research object to observe the effect of Tripterygium glycosides(TG) on OGSCs and explore the mechanism of reproductive toxicity by the Notch signaling pathway. Cell counting kit-8(CCK-8) was used to observe the viability level of OGSCs in mice cultured in vitro by TG of 3.75, 7.5, and 15 µg·mL~(-1). Immunofluorescence technology and reverse transcription-polymerase chain reaction(RT-PCR) were used to detect the protein and gene expression level of OGSCs marker mouse vasa homologue(MVH) and octamer-binding transcription factor 4(Oct4) by TG of 3.75 µg·mL~(-1). RT-PCR detected the gene expression of neurogenic locus Notch homolog protein 1(Notch1), Hes family BHLH transcription factor 1(Hes1), and jagged canonical Notch ligand 1(Jagged1). The RNA was extracted for transcriptome analysis to analyze the mechanism of action of TG intervention on OGSCs. 3.75 µg·mL~(-1) of TG was combined with 40 ng·mL~(-1) Notch signaling pathway γ-secretagocin agonist jagged canonical notch ligand(Jagged) for administration. CCK-8 was used to detect the viability level of OGSCs. Double immunofluorescence technology was used to detect the protein co-expression of MVH with Hes1, Notch1, and Jagged1. The results showed that compared with the blank group, the TG administration group significantly inhibited the activity of OGSCs(P<0.01 or P<0.001). It could reduce the protein and gene expression of OGSC markers, namely MVH and Oct4(P<0.05, P<0.01, or P<0.001). It could significantly inhibit the gene expression of Notch1, Hes1, and Jagged1(P<0.001). Transcriptomic analysis showed that TG affected the growth and proliferation of OGSCs by intervening Jagged1, a ligand associated with the Notch signaling pathway. The experimental results showed that the combination of Notch signaling pathway γ-secretagorein agonist Jagged could significantly alleviate the decrease in OGSC viability induced by TG(P<0.001) and significantly increased the OGSC viability compared with the TG group(P<0.001). It also could significantly increase the co-expression of MVH/Jagged1, MVH/Hes1, and MVH/Notch1 proteins(P<0.01 or P<0.001). It suggested that TG play the role of γ-secretagorease inhibitors by downregulating the OGSC markers including MVH and Oct4 and Notch signaling pathway molecules such as Notch1, Hes1, and Jagged1, participate in the OGSC pathway, and mediate reproductive toxicity caused by the Notch signaling pathway.

Construction of a clinical prediction model for the impact of acupuncture on pregnancy outcomes in poor ovarian response (POR) patients based on a patient registry research platform. / åŸºäºŽç— ä¾‹æ³¨å†Œç™»è®°ç ”ç©¶å¹³å°æž„å»ºé’ˆç¸å¯¹åµå·¢ä½Žååº”æ‚£è€ å¦Šå¨ ç»“å±€çš„ä¸´åºŠé¢„æµ‹æ¨¡åž‹.

OBJECTIVES: To construct a clinical prediction model for the impact of acupuncture on pregnancy outcomes in poor ovarian response (POR) patients, providing insights and methods for predicting pregnancy outcomes in POR patients undergoing acupuncture treatment. METHODS: Clinical data of 268 POR patients (2 cases were eliminated) primarily treated with "thirteen needle acupuncture for Tiaojing Cuyun (regulating menstruation and promoting pregnancy)" was collected from the international patient registry platform of acupuncture moxibustion (IPRPAM) from September 19, 2017 to April 30, 2023, involving 24 clinical centers including Acupuncture-Moxibustion Hospital of China Academy of Chinese Medical Sciences. LASSO and univariate Cox regression were used to screen factors influencing pregnancy outcomes, and a multivariate Cox regression model was established based on the screening results. The best model was selected using the Akaike information criterion (AIC), and a nomogram for clinical pregnancy prediction was constructed. The prediction model was evaluated using receiver operating characteristic (ROC) curves and calibration curves, and internal validation was performed using the Bootstrap method. RESULTS: (1) Age, level of anti-Müllerian hormone (AMH), and total treatment numbers of acupuncture were independent predictors of pregnancy outcomes in POR patients receiving acupuncture (P<0.05). (2) The AIC value of the best subset-Cox multivariate model (560.6) was the smallest, indicating it as the optimal model. (3) The areas under curve (AUCs) of the clinical prediction model after 6, 12, 24, and 36 months treatment were 0.627, 0.719, 0.770, and 0.766, respectively, and in the validation group, they were 0.620, 0.704, 0.759, and 0.765, indicating good discrimination and repeatability of the prediction model. (4) The calibration curve showed that the prediction curve of the clinical prediction model was close to the ideal model's prediction curve, indicating good calibration of the prediction model. CONCLUSIONS: The clinical prediction model for the impact of acupuncture on pregnancy outcomes in POR patients based on the IPRPAM platform has good clinical application value and provides insights into predicting pregnancy outcomes in POR patients undergoing acupuncture treatment.

Influence of Cordyceps militaris-fermented grain substrate extracts on alleviating food allergy in mice.

Background: Cordyceps militaris is recognized as a tonic in traditional Chinese medicine, and there have been documented findings on the anti-allergic properties of its extract derived from the fruiting body. Due to the limited availability of wild C. militaris, a specialized grain substrate has been devised for the solid-state fermentation of its fruiting bodies. However, the fermented grain substrate is considered waste and usually used as feeds for animals. To achieve the sustainable development goals, C. militaris-fermented grain substrate (CFGS) was collected to prepare CFGS extracts. Further, the anti-allergic properties of these extracts were assessed with the aim of exploring novel applications. Methods: The water extract and ethanol extract of CFGS were prepared, and their potential in alleviating allergic enteritis was assessed in mice with food allergy. Assessment of immunomodulatory effects included the measurement of serum antibodies and splenic cytokines. Additionally, influence of extracts on gut microbiota composition was examined through sequencing analysis of 16S rRNA gene from freshly collected feces of the mice. Results: Daily administration of the water and ethanol extracts, at doses of 50 or 250 mg/kg body weight, demonstrated a notable alleviation of allergic diarrhea and enteritis. This was accompanied by a decrease in mast cell infiltration in the duodenum and a reduction in allergen-specific IgE production in the serum. Both extracts led to a significant decrease in IL-4 secretion. Conversely, there was an increase in IFN-γ, IL-10, and TGF-ß secretion from splenocytes. Remarkably, allergic mice exhibited a distinct fecal microbiota profile compared to that of normal mice. Intriguingly, the administration of these extracts had varying effects on the fecal microbiota. Conclusion: Taken together, these findings collectively indicate the potential of CFGS extracts as promising candidates for functional foods. These extracts show promise in managing allergic enteritis and modulating gut microbiota.

Association between a maternal vegetarian diet during pregnancy and the occurrence of atopic dermatitis in children.

BACKGROUND: Atopic dermatitis (AD) is rising globally, with genetics and environmental factors both playing crucial roles. Dietary habits during pregnancy are linked to children's allergic disease risk. However, limited studies have explored the association between maternal vegetarian diets during pregnancy and child AD. Therefore, this study aimed to examine the relationship between maternal vegetarian diets during pregnancy and the occurrence of AD in children. METHODS: In this study, the Taiwan Birth Cohort Study (TBCS) database was used, comprising a representative national birth cohort of infants born in Taiwan in 2005. Of 24,200 mother-child pairs in the database, 20,172 completed face-to-face interviews at 6 and 18 months. Employing a 1:10 matching strategy based on maternal age, education level, and child sex, 408 mothers who followed a vegetarian diet during pregnancy were matched with 4080 nonvegetarian mothers. This resulted in a final dataset of 4488 subjects. Logistic regression was used to explore the association between maternal vegetarian diets during pregnancy and the occurrence of AD in children. RESULTS: Among the TBCS participants, there were 292 (1.8%) mothers who adhered to lacto-ovo vegetarianism and 116 (0.7%) mothers who adhered to veganism, totaling 408 (2.4%) vegetarians during pregnancy. Compared to children of nonvegetarian mothers, children of mothers who followed a vegetarian diet during pregnancy showed a lower risk of developing AD before 18 months of age (OR = 0.65, 95% CI = 0.45-0.93, p = 0.018). CONCLUSION: This study suggests that a vegetarian diet during pregnancy may lower the risk of AD in children. It is essential to carry out long-term follow-up to fully understand the impact of a mother's diet on allergic conditions.

Single-cell transcriptome and metagenome profiling reveals the genetic basis of rumen functions and convergent developmental patterns in ruminants.

The rumen undergoes developmental changes during maturation. To characterize this understudied dynamic process, we profiled single-cell transcriptomes of about 308,000 cells from the rumen tissues of sheep and goats at 17 time points. We built comprehensive transcriptome and metagenome atlases from early embryonic to rumination stages, and recapitulated histomorphometric and transcriptional features of the rumen, revealing key transitional signatures associated with the development of ruminal cells, microbiota, and core transcriptional regulatory networks. In addition, we identified and validated potential cross-talk between host cells and microbiomes and revealed their roles in modulating the spatiotemporal expression of key genes in ruminal cells. Cross-species analyses revealed convergent developmental patterns of cellular heterogeneity, gene expression, and cell-cell and microbiome-cell interactions. Finally, we uncovered how the interactions can act upon the symbiotic rumen system to modify the processes of fermentation, fiber digestion, and immune defense. These results significantly enhance understanding of the genetic basis of the unique roles of rumen.

Preparation and evaluation of Cordyceps militaris polysaccharide- and sesame oil-loaded nanoemulsion for the treatment of candidal vaginitis in mice.

BACKGROUND: Candida albicans is the most prevalent fungal pathogen, affecting over 75% of women who have experienced candidal vaginitis. Given the identification of drug-resistant C. albicans strains, there is an urgent need to develop therapeutic methods for treating vaginal Candida infection. Polysaccharide is the major bioactive component of Cordyceps militaris, known to modulate immune responses and alleviate inflammation. Sesame oil is known with anti-microbial and anti-inflammatory activities. METHODS: C. militaris polysaccharide was prepared and formulated with sesame oil to prepare emulsion and nanoemulsion, which are ideal mucosal delivery systems for both hydrophobic and hydrophilic compounds concurrently. The physical property and storage stability of these formulations were illustrated, and their effects on ameliorating vaginitis were investigated in a murine model of vaginal Candida infection. RESULTS: C. militaris polysaccharide-containing nanoemulsion showed smaller particle size, lower polydispersity index, higher zeta-potential and better stability than emulsion. Intravaginal administration of C. militaris polysaccharide-containing nanoemulsion significantly attenuated C. militaris colonization and vaginitis. Notably, these formulations exerted distinct effects on modulating cell infiltration and splenic cytokine production. Moreover, different profile of vaginal microflora was observed among the treatment groups, revealing the potential action mechanisms of these formulations to mitigate vaginal Candida infection. CONCLUSION: C. militaris polysaccharide- and sesame oil-containing nanoemulsion is potential to be developed as intravaginal therapeutic strategy for C. albicans-induced vaginitis.

Mechanical properties of multilayer combined gradient cellular structure and its application in the WLL.

In order to improve the buffering performance of a walkable lunar lander (WLL), an optimization method of multi-layer combined gradient cellular structure (MCGCS) is proposed. The impact load, impact action time, impact overload, and deformation amount are analyzed. The buffering performance of the material is evaluated and verified effectively with the simulation data. The overload acceleration of the WLL, the volume, and mass of the buffer material were set as the space-time solution to the optimal buffer problem, and the complex relationship between the material structure parameters and the buffer energy absorption (EA) parameters was established based on the sensitivity analysis method, and the buffer structure parameters were automatically optimized. The buffer energy absorption characteristics of the MCGCS are like the simulation results, and it has a good buffering effect, which provides a new research perspective for the excellent landing buffering mechanical properties of the WLL and a new idea for the application of engineering materials.

A bibliometric analysis of traditional Chinese non-pharmacological therapies in the treatment of knee osteoarthritis from 2012 to 2022.

Objective: The benefits of traditional Chinese non-pharmacological therapies in the treatment of Knee osteoarthritis (KOA) are receiving increasing attention. Therefore, this study aims to systematically analyze the global research on the treatment of KOA by Chinese traditional non-pharmacological therapies using bibliometric analysis and present the results with a knowledge map form. Methods: Literature related to traditional Chinese non-pharmacological therapies used in the treatment of KOA from 2012 to 2022 was searched from the Web of Science core database and PubMed database. CiteSpace, SCImago Graphica and VOSviewer were used to extract nations, institutions, journals, authors, references, keywords, as well as the most widely used acupoints, therapies and evaluation indexes. Results: A total of 375 literature have been included. 32 countries around the world have participated in the research. China, the United States, and Europe were at the center of the global cooperation network. The most prolific institutions and authors were from China represented by Cun-zhi Liu and Jian-feng Tu of Beijing University of Chinese Medicine, the institution with the highest cited frequency was University of York, and "Osteoarthritis Cartilage" was the most frequently cited journal. The most frequently cited literature was "OARSI guidelines for the non-surgical management of knee, hip, and poly articular osteoarthritis." 22 kinds of Chinese non-pharmacological therapies were used to treat KOA, among which acupuncture was the most commonly used one, and ST36 (Zusanli) and WOMAC were the most commonly selected acupoint and evaluation index. Conclusion: In the past decade, the value of Chinese non-pharmacological therapies in the treatment of KOA has received widespread attention. It was a common concern of global researchers to relieve the pain of KOA patients and restore the quality of life. Under the background that acupuncture accounts for a relatively high proportion, the next step may consider how to make the balanced development of a variety of Chinese non-pharmacological therapies. In addition, the problem of how to eliminate the placebo effect maybe the direction of future research.

Optimisation of the Extraction Process of Naringin and Its Effect on Reducing Blood Lipid Levels In Vitro.

The naringin extraction process was optimised using response surface methodology (RSM). A central component design was adopted, which included four parameters: extraction temperature (X1), material-liquid ratio (X2), extraction time (X3), and ultrasonic frequency (X4) of 74.79 °C, 1.58 h, 1:56.51 g/mL, and 28.05 KHz, respectively. Based on these optimal extraction conditions, naringin was tested to verify the model's accuracy. Naringin yield was 36.2502 mg/g, which was equivalent to the predicted yield of 36.0124 mg/g. DM101 macroporous adsorption resin was used to purify naringin. The effects of loading concentration, loading flow rate, and sample pH on the adsorption rate of naringin and the effect of ethanol concentration on the desorption rate of naringin were investigated. The optimum conditions for naringin purification using macroporous resins were determined. The optimal loading concentration, sample solution pH, and loading flow rate were 0.075 mg/mL, 3.5, and 1.5 mL/min, respectively. Three parallel tests were conducted under these conditions, and the average naringin yield was 77.5643%. Naringin's structure was identified using infrared spectroscopy and nuclear magnetic resonance. In vitro determination of the lipid-lowering activity of naringin was also conducted. These results showed that naringin has potential applications as a functional food for lowering blood lipid levels.

Associations between residential proximity to agricultural land use as pesticides exposure and birth outcomes.

Pesticides are widely used globally. Due to their widespread use, exposure to pesticides is of concern. In addition to occupational exposure, residential exposure during pesticide application is a concern for those living in or near agricultural areas. The objective of this study was to analyze the association between residential proximity to agricultural pesticide use and birth outcomes. The association between residential proximity to agricultural land use as pesticide exposure and birth outcomes was explored in a birth cohort including 283 pregnant women from a medical center in Hualien during 2013-2016. In the third trimester, we collected demographic information and the residential addresses of pregnant women via structured questionnaires. After delivery, newborn birth weight, gestational age, and head circumference were collected from medical records. Maternal residential address during pregnancy was collected for geospatial mapping. The percentages of farmland area within circular buffers of different sizes were applied to estimate pesticide exposure. Associations between residential proximity to agricultural land use as pesticide exposure and birth outcomes were analyzed by multiple linear regression analyses. A significantly smaller head circumference was associated with agricultural farmland located within 400 m (ß = - 0.51 [95% CI, - 0.99, - 0.03], P = 0.037) and 500 m (ß = - 0.67 [95% CI, - 1.14, - 0.19], P = 0.006) radii of residences in the tertile 2 group. A significantly smaller head circumference was also associated with dry farming area within 400 m (ß = - 0.70 [95% CI, - 1.17, - 0.24], P = 0.003) and 500 m (ß = - 0.81 [95% CI, - 1.27, - 0.34], P = 0.001) radii of residences in the tertile 2 group. The multivariate linear regression analyses did not show any significant association between residential farmland area and birth weight or gestational age. In conclusion, residential proximity to agricultural land use as pesticide exposure was associated with negative infant birth outcomes, especially a small head circumference. In the future, agricultural land use information could be combined with biological samples to more accurately assess exposure in pregnant women.

Construction of a clinical prediction model for the impact of acupuncture on pregnancy outcomes in poor ovarian response (POR) patients based on a patient registry research platform / 中国针灸

OBJECTIVES@#To construct a clinical prediction model for the impact of acupuncture on pregnancy outcomes in poor ovarian response (POR) patients, providing insights and methods for predicting pregnancy outcomes in POR patients undergoing acupuncture treatment.@*METHODS@#Clinical data of 268 POR patients (2 cases were eliminated) primarily treated with "thirteen needle acupuncture for Tiaojing Cuyun (regulating menstruation and promoting pregnancy)" was collected from the international patient registry platform of acupuncture moxibustion (IPRPAM) from September 19, 2017 to April 30, 2023, involving 24 clinical centers including Acupuncture-Moxibustion Hospital of China Academy of Chinese Medical Sciences. LASSO and univariate Cox regression were used to screen factors influencing pregnancy outcomes, and a multivariate Cox regression model was established based on the screening results. The best model was selected using the Akaike information criterion (AIC), and a nomogram for clinical pregnancy prediction was constructed. The prediction model was evaluated using receiver operating characteristic (ROC) curves and calibration curves, and internal validation was performed using the Bootstrap method.@*RESULTS@#(1) Age, level of anti-Müllerian hormone (AMH), and total treatment numbers of acupuncture were independent predictors of pregnancy outcomes in POR patients receiving acupuncture (P<0.05). (2) The AIC value of the best subset-Cox multivariate model (560.6) was the smallest, indicating it as the optimal model. (3) The areas under curve (AUCs) of the clinical prediction model after 6, 12, 24, and 36 months treatment were 0.627, 0.719, 0.770, and 0.766, respectively, and in the validation group, they were 0.620, 0.704, 0.759, and 0.765, indicating good discrimination and repeatability of the prediction model. (4) The calibration curve showed that the prediction curve of the clinical prediction model was close to the ideal model's prediction curve, indicating good calibration of the prediction model.@*CONCLUSIONS@#The clinical prediction model for the impact of acupuncture on pregnancy outcomes in POR patients based on the IPRPAM platform has good clinical application value and provides insights into predicting pregnancy outcomes in POR patients undergoing acupuncture treatment.

A Novel Cuprotosis-Related Gene FDX1 Signature for Overall Survival Prediction in Clear Cell Renal Cell Carcinoma Patients.

Background: Ferredoxin 1 (FDX1) is a newly discovered gene regulating cuprotosis. However, the effect of FDX1 expression on clear renal cell carcinoma (ccRCC) is unknown. Methods: Gene expression profiles and clinical data of ccRCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. The differences in FDX1 expression between ccRCC and nonneoplastic tissues adjacent to cancer were analyzed by R software. The results were validated by GEO data, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB), and immunohistochemistry (IHC). Chi-square test was used to analyze the clinical pathological parameters. Kaplan-Meier survival analysis and Cox proportional hazard regression model selection were used to evaluate the effect of FDX1 expression on overall survival. Protein interaction networks were used to analyze other proteins that interact with FDX1. Signal pathway analysis was performed for possible FDX1 enrichment using GSEA and ssGSEA algorithms. Pan-cancer analysis of FDX1 was carried out through TCGA database. Results: The FDX1 expression in nontumor tissues was significantly higher than that in ccRCC, and the expression difference was verified by GEO data, qRT-PCR, WB, and IHC. The high expression of FDX1 was significantly related to the well overall survival rate (P < 0.05). The chi-square test showed that the high expression of FDX1 was related to gender, TNM stage, T stage, lymph node metastasis, and pathological grade. Additionally, the FDX1 expression level was different in groups classified based on pathological grade, gender, TNM stage, T stage, lymph node metastasis, and distant metastasis (P < 0.05). The multivariate analysis revealed the high expression of FDX1 as an important independent predictor for overall survival. STRING database results showed that LIAS and LIPT1 may interact with FDX1 in the PPI network, which are also involved in the regulation of cuprotosis. The GSEA and ssGSEA results showed that the FDX1 was enriched in the anticancer pathway. The FDX1 high expression is associated with better prognosis in many cancers, as revealed by pan-cancer analysis. Conclusion: FDX1 may play a role in the progression of ccRCC as a tumor suppressor gene. It can be used as a potential prognostic indicator and therapeutic target of ccRCC. However, the cuprotosis regulatory role in the development of ccRCC needs to be further verified.

B-DP: Dynamic Collection and Publishing of Continuous Check-In Data with Best-Effort Differential Privacy.

Differential privacy (DP) has become a de facto standard to achieve data privacy. However, the utility of DP solutions with the premise of privacy priority is often unacceptable in real-world applications. In this paper, we propose the best-effort differential privacy (B-DP) to promise the preference for utility first and design two new metrics including the point belief degree and the regional average belief degree to evaluate its privacy from a new perspective of preference for privacy. Therein, the preference for privacy and utility is referred to as expected privacy protection (EPP) and expected data utility (EDU), respectively. We also investigate how to realize B-DP with an existing DP mechanism (KRR) and a newly constructed mechanism (EXPQ) in the dynamic check-in data collection and publishing. Extensive experiments on two real-world check-in datasets verify the effectiveness of the concept of B-DP. Our newly constructed EXPQ can also satisfy a better B-DP than KRR to provide a good trade-off between privacy and utility.

A Statistical Prediction Model for Survival After Kidney Transplantation from Deceased Donors.

BACKGROUND In an environment of limited kidney donation resources, patient recovery and survival after kidney transplantation (KT) are highly important. We used pre-operative data of kidney recipients to build a statistical model for predicting survivability after kidney transplantation. MATERIAL AND METHODS A dataset was constructed from a pool of patients who received a first KT in our hospital. For allogeneic transplantation, all donated kidneys were collected from deceased donors. Logistic regression analysis was used to change continuous variables into dichotomous ones through the creation of appropriate cut-off values. A regression model based on the least absolute shrinkage and selection operator (LASSO) algorithm was used for dimensionality reduction, feature selection, and survivability prediction. We used receiver operating characteristic (ROC) analysis, calibration, and decision curve analysis (DCA) to evaluate the performance and clinical impact of the proposed model. Finally, a 10-fold cross-validation scheme was implemented to verify the model robustness. RESULTS We identified 22 potential variables from which 30 features were selected as survivability predictors. The model established based on the LASSO regression algorithm had shown discrimination with an area under curve (AUC) value of 0.690 (95% confidence interval: 0.557-0.823) and good calibration result. DCA demonstrated clinical applicability of the prognostic model when the intervention progressed to the possibility threshold of 2%. An average AUC value of 0.691 was obtained on the validation data. CONCLUSIONS Our results suggest that the proposed model can predict the mortality risk for patients after kidney transplants and could help kidney specialists choose kidney recipients with better prognosis.

Hypoglycemic Effect of the N-Butanol Fraction of Torreya grandis Leaves on Type 2 Diabetes Mellitus in Rats through the Amelioration of Oxidative Stress and Enhancement of ß-Cell Function.

Materials and Methods: Sprague-Dawley rats were randomly divided into six groups: control, T2DM, metformin, high-dose BFTL (800 mg/kg), middle-dose BFTL (400 mg/kg), and low-dose BFTL (200 mg/kg). After 4 weeks of BFTL treatment, the correlations of serum indicators with protein expression in tissue were determined, and pathological changes in the liver, kidneys, and pancreas were analyzed. Results: Compared with the results in the T2DM group, serum fasting blood glucose, triglyceride, total cholesterol, malondialdehyde, alanine aminotransferase, and aspartate aminotransferase levels were significantly decreased (p < 0.05), whereas superoxide dismutase and glutathione peroxidase levels were significantly increased (p < 0.05) in the high-, middle-, and low-dose BFTL groups. The treatment also improved oral glucose tolerance. In addition, the pathological changes of the liver, kidney, and pancreas were improved by BFTL treatment. Cytochrome and caspase-3 expression in pancreatic was significantly decreased (p < 0.05) by BFTL treatment, whereas the Bcl-2/Bax ratio was significantly increased (p < 0.05). Discussion and Conclusion. BFTL exerted significant hypoglycemic effect on T2DM model rats, and its mechanism involved the suppression of blood glucose levels and oxidative stress by improving the metabolism of blood lipids and antioxidant capacity, boosting ß-cell function, and inhibiting ß-cell apoptosis.

Wnt7a / β-catenin / autoimmune regulator signaling pathway involved in the occurrence of type 1 diabetes / 解剖学报

[Abstract] Objective To investigate the relationship between the expression of Wnt signaling pathway, autoimmune regulator (AIRE) and type 1 diabetes (T1D) tissue specific antigen (TSAs) insulin 2(Ins2) and glutamic acid decarboxybase(GAD67) in thymus and the occurrence of T1D in NOD/ Ltj mice with spontaneous type 1 diabetes (T1D). Methods Sixty female NOD/ Ltj mice were divided into three groups: 3 weeks group, 16 weeks non-onset group and 16 weeks onset group. Two consecutive non-fasting blood glucose levels ≥ 11. 1 mmol/ L were considered as the occurrence of T1D. Pancreatic HE staining was used to observe the occurrence of islet inflammation. Anti-Ins and CD45 immunohistochemical staining showed islet cells or infiltrating inflammatory cells. The protein levels and mRNA expressions of Wnt7a, -catenin, AIRE, Ins and GAD67 in thymus were detected by Western blotting and Real-time PCR. The proportion of T cells in thymus was analyzed by flow cytometry. Results 1. With the occurrence of T1D, the islet structure was destroyed, a large number of lymphocytes infiltrated, and the remaining islet cells were reduced. A large number of CD45