VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.

Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, which is regulated by factor BECN1 (beclin 1). UFMylation is a novel ubiquitin-like modification that has been demonstrated to modulate several cellular activities. However, the role of UFMylation in regulating autophagy has not been fully elucidated. Here, we found that VCP/p97 is UFMylated on K109 by the E3 UFL1 (UFM1 specific ligase 1) and this modification promotes BECN1 stabilization and assembly of the PtdIns3K complex, suggesting a role for VCP/p97 UFMylation in autophagy initiation. Mechanistically, VCP/p97 UFMylation stabilizes BECN1 through ATXN3 (ataxin 3)-mediated deubiquitination. As a key component of the PtdIns3K complex, stabilized BECN1 facilitates assembly of this complex. Re-expression of VCP/p97, but not the UFMylation-defective mutant, rescued the VCP/p97 depletion-induced increase in MAP1LC3B/LC3B protein expression. We also showed that several pathogenic VCP/p97 mutations identified in a variety of neurological disorders and cancers were associated with reduced UFMylation, thus implicating VCP/p97 UFMylation as a potential therapeutic target for these diseases. Abbreviation: ATG14:autophagy related 14; Baf A1:bafilomycin A1;CMT2Y: Charcot-Marie-Toothdisease, axonal, 2Y; CYB5R3: cytochromeb5 reductase 3; DDRGK1: DDRGK domain containing 1; DMEM:Dulbecco'smodified Eagle's medium;ER:endoplasmic reticulum; FBS:fetalbovine serum;FTDALS6:frontotemporaldementia and/or amyotrophic lateral sclerosis 6; IBMPFD1:inclusion bodymyopathy with early-onset Paget disease with or withoutfrontotemporal dementia 1; LC-MS/MS:liquid chromatography tandem mass spectrometry; MAP1LC3B/LC3B:microtubule associated protein 1 light chain 3 beta; MS: massspectrometry; NPLOC4: NPL4 homolog, ubiquitin recognition factor;PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3;PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K:phosphatidylinositol 3-kinase; RPL26: ribosomal protein L26; RPN1:ribophorin I; SQSTM1/p62: sequestosome 1; UBA5: ubiquitin likemodifier activating enzyme 5; UFC1: ubiquitin-fold modifierconjugating enzyme 1; UFD1: ubiquitin recognition factor in ERassociated degradation 1; UFL1: UFM1 specific ligase 1; UFM1:ubiquitin fold modifier 1; UFSP2: UFM1 specific peptidase 2; UVRAG:UV radiation resistance associated; VCP/p97: valosin containingprotein; WT: wild-type.

Psychological factors enhanced heterogeneous learning interactive graph knowledge tracing for understanding the learning process.

Introduction: With the rapid expansion of online education, there is a burgeoning interest within the EdTech space to offer tailored learning experiences that cater to individual student's abilities and needs. Within this framework, knowledge tracing tasks have garnered considerable attention. The primary objective of knowledge tracing is to develop a model that assesses a student's proficiency in a particular skill based on their historical performance in exercises, enabling predictions regarding the likelihood of correct responses in future exercises. While existing knowledge tracing models often incorporate information such as students' exercise answering history and skill mastery level, they frequently overlook the students' mental states during the learning process. Methods: This paper addresses this gap by introducing a novel psychological factors-enhanced heterogeneous learning interactive graph knowledge tracing model (Psy-KT). This model delineates the interactions among students, exercises, and skills through a heterogeneous graph, supplementing it with four psychological factors that capture students' mental states during the learning process: frustration level, confusion level, concentration level, and boredom level. In the modeling of students' learning processes, we incorporate the forgetting curve and construct relevant cognitive parameters from the features. Additionally, we employ the Item Response Theory (IRT) model to predict students' performance in answering exercises at the subsequent time step. This model not only delves into the psychological aspects of students during the learning process but also integrates the simulation of forgetting, a natural phenomenon in the learning journey. The inclusion of cognitive parameters enhances the description of changes in students' abilities throughout the learning process. This dual focus allows for a more comprehensive understanding of students' learning behaviors while providing a high level of interpretability for the model. Results and discussion: Empirical validation of the Psy-KT model is conducted using four publicly available datasets, demonstrating its superior performance in predicting students' future performance. Through rigorous experimentation, the integration of psychological and forgetting factors in the Psy-KT model not only improves predictive accuracy but also enables educators to offer more targeted tutoring and advice, enhancing the overall efficacy of the learning experience.

Ultra-Highly Stiff and Tough Shape Memory Polyurea with Unprecedented Energy Density by Precise Slight Cross-Linking.

Shape memory polymers (SMPs) have attracted significant attention and hold vast potential for diverse applications. Nevertheless, conventional SMPs suffer from notable shortcomings in terms of mechanical properties, environmental stability, and energy density, significantly constraining their practical utility. Here, inspired by the structure of muscle fibers, an innovative approach that involves the precise incorporation of subtle, permanent cross-linking within a hierarchical hydrogen bonding supramolecular network is reported. This novel strategy has culminated in the development of covalent and supramolecular shape memory polyurea, which exhibits exceptional mechanical properties, including high stiffness (1347 MPa), strength (82.4 MPa), and toughness (312.7 MJ m-3), ensuring its suitability for a wide range of applications. Furthermore, it boasts remarkable recyclability and repairability, along with excellent resistance to moisture, heat, and solvents. Moreover, the polymer demonstrates outstanding shape memory effects characterized by a high energy density (24.5 MJ m-3), facilitated by the formation of strain-induced oriented nanostructures that can store substantial amounts of entropic energy. Simultaneously, it maintains a remarkable 96% shape fixity and 99% shape recovery. This delicate interplay of covalent and supramolecular bonds opens up a promising pathway to the creation of high-performance SMPs, expanding their applicability across various domains.

A spatiotemporal atlas of cholestatic injury and repair in mice.

Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFß in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.

A spatiotemporal atlas of mouse liver homeostasis and regeneration.

The mechanism by which mammalian liver cell responses are coordinated during tissue homeostasis and perturbation is poorly understood, representing a major obstacle in our understanding of many diseases. This knowledge gap is caused by the difficulty involved with studying multiple cell types in different states and locations, particularly when these are transient. We have combined Stereo-seq (spatiotemporal enhanced resolution omics-sequencing) with single-cell transcriptomic profiling of 473,290 cells to generate a high-definition spatiotemporal atlas of mouse liver homeostasis and regeneration at the whole-lobe scale. Our integrative study dissects in detail the molecular gradients controlling liver cell function, systematically defining how gene networks are dynamically modulated through intercellular communication to promote regeneration. Among other important regulators, we identified the transcriptional cofactor TBL1XR1 as a rheostat linking inflammation to Wnt/ß-catenin signaling for facilitating hepatocyte proliferation. Our data and analytical pipelines lay the foundation for future high-definition tissue-scale atlases of organ physiology and malfunction.

PARP1 UFMylation ensures the stability of stalled replication forks.

The S-phase checkpoint involving CHK1 is essential for fork stability in response to fork stalling. PARP1 acts as a sensor of replication stress and is required for CHK1 activation. However, it is unclear how the activity of PARP1 is regulated. Here, we found that UFMylation is required for the efficient activation of CHK1 by UFMylating PARP1 at K548 during replication stress. Inactivation of UFL1, the E3 enzyme essential for UFMylation, delayed CHK1 activation and inhibits nascent DNA degradation during replication blockage as seen in PARP1-deficient cells. An in vitro study indicated that PARP1 is UFMylated at K548, which enhances its catalytic activity. Correspondingly, a PARP1 UFMylation-deficient mutant (K548R) and pathogenic mutant (F553L) compromised CHK1 activation, the restart of stalled replication forks following replication blockage, and chromosome stability. Defective PARP1 UFMylation also resulted in excessive nascent DNA degradation at stalled replication forks. Finally, we observed that PARP1 UFMylation-deficient knock-in mice exhibited increased sensitivity to replication stress caused by anticancer treatments. Thus, we demonstrate that PARP1 UFMylation promotes CHK1 activation and replication fork stability during replication stress, thus safeguarding genome integrity.

Clinical application of reserved gastric tube in neuroendoscopic endonasal surgery for pituitary tumor.

BACKGROUND: The neuroendoscopic approach has the advantages of a clear operative field, convenient tumor removal, and less damage, and is the development direction of modern neurosurgery. At present, transnasal surgery for sphenoidal pituitary tumor is widely used. But it has been found in clinical practice that some patients with this type of surgery may experience post-operative nausea and vomiting and other discomforts. AIM: To explore the effect of reserved gastric tube application in the neuroendoscopic endonasal resection of pituitary tumors. METHODS: A total of 60 patients who underwent pituitary adenoma resection via the endoscopic endonasal approach were selected and randomly divided into the experimental and control groups, with 30 in each group. Experimental group: After anesthesia, a gastric tube was placed through the mouth under direct vision using a visual laryngoscope, and the fluid accumulated in the oropharynx was suctioned intermittently with low negative pressure throughout the whole process after nasal disinfection, during the operation, and when the patient recovered from anesthesia. Control group: Given the routine intraoperative care, no gastric tube was left. The number of cases of nausea/vomiting/aspiration within 24 h post-operation was counted and compared between the two groups; the scores of pharyngalgia after waking up, 6 h post-operation, and 24 h post-operation. The frequency of postoperative cerebrospinal fluid leakage and intracranial infection were compared. The hospitalization days of the two groups were statistically compared. RESULTS: The times of postoperative nausea and vomiting in the experimental group were lower than that in the control group, and the difference in the incidence of nausea was statistically significant (P < 0.05). After the patient woke up, the scores of sore throat 6 h after the operation and 24 h after operation were lower than those in the control group, and the difference was statistically significant (P < 0.05). The number of cases of postoperative cerebrospinal fluid leakage and intracranial infection was higher than that of the control group, but there was no statistically significant difference from the control group (P > 0.05). The hospitalization days of the experimental group was lower than that of the control group, and the difference was statistically significant (P < 0.05). CONCLUSION: Reserving a gastric tube in the endoscopic endonasal resection of pituitary tumors, combined with intraoperative and postoperative gastrointestinal decompression, can effectively reduce the incidence of nausea, reduce the number of vomiting and aspiration in patients, and reduce the complications of sore throat The incidence rate shortened the hospitalization days of the patients.

Cuproptosis in stroke: focusing on pathogenesis and treatment.

Annually, more than 15 million people worldwide suffer from stroke, a condition linked to high mortality and disability rates. This disease significantly affects daily life, impairing everyday functioning, executive function, and cognition. Moreover, stroke severely restricts patients' ability to perform daily activities, diminishing their overall quality of life. Recent scientific studies have identified cuproptosis, a newly discovered form of cell death, as a key factor in stroke development. However, the role of cuproptosis in stroke remains unclear to researchers. Therefore, it is crucial to investigate the mechanisms of cuproptosis in stroke's pathogenesis. This review examines the physiological role of copper, the characteristics and mechanisms of cuproptosis, the differences and similarities between cuproptosis and other cell death types, and the pathophysiology of cuproptosis in stroke, focusing on mitochondrial dysfunction and immune infiltration. Further research is necessary to understand the relationship between previous strokes and cuproptosis and to clarify the mechanisms behind these associations.

Porous High-Entropy Oxide Anode Materials for Li-Ion Batteries: Preparation, Characterization, and Applications.

High-entropy oxides (HEOs), as a new type of single-phase solid solution with a multi-component design, have shown great potential when they are used as anodes in lithium-ion batteries due to four kinds of effects (thermodynamic high-entropy effect, the structural lattice distortion effect, the kinetic slow diffusion effect, and the electrochemical "cocktail effect"), leading to excellent cycling stability. Although the number of articles on the study of HEO materials has increased significantly, the latest research progress in porous HEO materials in the lithium-ion battery field has not been systematically summarized. This review outlines the progress made in recent years in the design, synthesis, and characterization of porous HEOs and focuses on phase transitions during the cycling process, the role of individual elements, and the lithium storage mechanisms disclosed through some advanced characterization techniques. Finally, the future outlook of HEOs in the energy storage field is presented, providing some guidance for researchers to further improve the design of porous HEOs.

Comparison of the efficacy of neuronavigation-assisted intracerebral hematoma puncture and drainage with neuroendoscopic hematoma removal in treatment of hypertensive cerebral hemorrhage.

OBJECTIVE: To compare neuronavigation-assisted intracerebral hematoma puncture and drainage with neuroendoscopic hematoma removal for treatment of hypertensive cerebral hemorrhage. METHOD: Ninety-one patients with hypertensive cerebral hemorrhage admitted to our neurosurgery department from June 2022 to May 2023 were selected: 47 patients who underwent endoscopic hematoma removal with the aid of neuronavigation in observation Group A and 44 who underwent intracerebral hematoma puncture and drainage in control Group B. The duration of surgery, intraoperative bleeding, hematoma clearance rate, pre- and postoperative GCS score, National Institutes of Health Stroke Scale (NIHSS) score, mRS score and postoperative complications were compared between the two groups. RESULTS: The duration of surgery, intraoperative bleeding and hematoma clearance were significantly lower in Group B than in Group A (p < 0.05). Conversely, no significant differences in the preoperative, 7-day postoperative, 14-day postoperative or 1-month postoperative GCS or NIHSS scores or the posthealing mRS score were observed between Groups A and B. However, the incidence of postoperative complications was significantly greater in Group B than in Group A (p < 0.05), with the most significant difference in incidence of intracranial infection (p < 0.05). CONCLUSION: Both neuronavigation-assisted intracerebral hematoma puncture and drainage and neuroendoscopic hematoma removal are effective at improving the outcome of patients with hypertensive cerebral hemorrhage. The disadvantage of neuronavigation is that the incidence of complications is significantly greater than that of other methods; postoperative care and prevention of complications should be strengthened in clinical practice.

Combined vertical and external rotational force in plantarflexion position produces posterior pilon fracture: A preliminary cadaveric study.

BACKGROUND: Posterior pilon fracture is speculated to occur by a combination of rotation and axial load, which makes it different from rotational posterior malleolar fracture or pilon fracture, but is not validated in vitro. The aim of the current study is to investigate the injury mechanisms of posterior pilon fracture on cadaveric specimens. METHODS: Eighteen cadaveric specimens were mounted to a loading device to undergo solitary vertical loading, solitary external rotational loading, and combined vertical and external rotational loading until failure, in initial position of plantarflexion with or without varus. The fracture characteristics were documented for each specimen. RESULTS: Vertical loading force combined with external rotation force diversified the fracture types resulting in pilon fracture, tibial spiral fracture, rotational malleolar fracture, talar fracture or calcaneal fracture. Vertical violence combined with external rotational loading in position of 45° of plantarflexion and 0° of varus produced posterior pilon fracture in specimens No. 13 and 14. CONCLUSION: Combination of vertical and external rotational force in plantarflexion position on cadaveric specimens produce posterior pilon fracture.

Clinical efficacy analysis of 5-aminolevulinic acid photodynamic therapy for vulvar lichen sclerosus.

OBJECTIVE: The purpose of this study is to analyze the efficacy of photodynamic therapy in the treatment of vulvar lichen sclerosus who do not respond to topical glucocorticoid therapy, analyze whether there are factors that affect the efficacy, and identify adverse reactions to the treatment. METHOD: This retrospective study included 42 patients with vulval lichen sclerosis treated with ALA-PDT. Basic data of all patients were collected, and the clinical symptoms and signs of the patients before treatment were evaluated. After one year of treatment, the clinical efficacy was evaluated and analyzed whether there were any factors that affected the treatment effect. RESULT: One year after the ALA-PDT treatment, the clinical effective rate was 64.29 % (27/42), the general effective rate was 19.05 % (8/42), the ineffective rate was 4.76 % (2/42), and the recurrence rate was 11.90 % (5/42). There was no correlation between menopause, number of births given, body mass index, duration of disease, treatment times and treatment effect. For patients with severe itching and atrophy, PDT was less effective. Adverse effects were minimal and no structural complications were reported. CONCLUSION: ALA-PDT can obviously alleviate itching in VLS patients, improve skin elasticity, skin color and reduce lesion area. ALA-PDT for VLS has a low recurrence rate and few side effects.

Application of deep learning in predicting suspended sediment concentration: A case study in Jiaozhou Bay, China.

Previous research methodologies for quantifying Suspended Sediment Concentration (SSC) have encompassed in-situ observations, numerical simulations, and analyses of remote sensing datasets, each with inherent constraints. In this study, we have harnessed Convolutional Neural Networks (CNNs) to create a deep learning model, which has been applied to the remote sensing data procured from the Geostationary Ocean Color Imager (GOCI) spanning April 2011 to March 2021. Our research indicates that on a small time scale, wind and hydrodynamic forces both have a significant impact on the prediction results of CNNs model. Considering both wind and hydrodynamic forces can effectively improve the model's prediction efficiency for SSC. Moreover, we have employed CNNs to interpolate absent values within the remote sensing datasets, yielding enhancements superior to those attained via linear or multivariate regression techniques. Finally, the correlation coefficient between CNN-derived SSC estimates for Jiaozhou Bay (JZB) and its corresponding remote sensing data is 0.72. Correlation coefficient and root mean square error differ in different regions. In the shallow water of JZB, due to water level changes, there is limited data, and the correlation coefficient in this area is about 0.5-0.6. In the central region of JZB with sufficient data, the correlation coefficient is generally higher than 0.75. Therefore, we believe that this CNNs model can be used to predict the hourly variation of SSC. When juxtaposed with alternative methodologies, the CNN approach is found to economize computational resources and enhance processing efficiency.

Isobavachalcone exhibits antifungal and antibiofilm effects against C. albicans by disrupting cell wall/membrane integrity and inducing apoptosis and autophagy.

Isobavachalcone (IBC) is a natural flavonoid with multiple pharmacological properties. This study aimed to evaluate the efficacy of IBC against planktonic growth and biofilms of Candida albicans (C. albicans) and the mechanisms underlying its antifungal action. The cell membrane integrity, cell metabolic viability, and cell morphology of C. albicans treated with IBC were evaluated using CLSM and FESEM analyses. Crystal violet staining, CLSM, and FESEM were used to assess the inhibition of biofilm formation, as well as dispersal and killing effects of IBC on mature biofilms. RNA-seq combined with apoptosis and autophagy assays was used to examine the mechanisms underlying the antifungal action of IBC. IBC exhibited excellent antifungal activity with 8 µg/mL of MIC for C. albicans. IBC disrupted the cell membrane integrity, and inhibited biofilm formation. IBC dispersed mature biofilms and damaged biofilm cells of C. albicans at 32 µg/mL. Moreover, IBC induced apoptosis and autophagy-associated cell death of C. albicans. The RNA-seq analysis revealed upregulation or downregulation of key genes involved in cell wall synthesis (Wsc1 and Fks1), ergosterol biosynthesis (Erg3, and Erg11), apoptisis (Hsp90 and Aif1), as well as autophagy pathways (Atg8, Atg13, and Atg17), and so forth, in response to IBC, as evidenced by the experiment-based phenotypic analysis. These results suggest that IBC inhibits C. albicans growth by disrupting the cell wall/membrane, caused by the altered expression of genes associated with ß-1,3-glucan and ergosterol biosynthesis. IBC induces apoptosis and autophagy-associated cell death by upregulating the expression of Hsp90, and altering autophagy-related genes involved in the formation of the Atg1 complex and the pre-autophagosomal structure. Together, our findings provide important insights into the potential multifunctional mechanism of action of IBC.

Uncovering the Bronchoalveolar Single-Cell Landscape of Patients With Pulmonary Tuberculosis With Human Immunodeficiency Virus Type 1 Coinfection.

BACKGROUND: Coinfection of human immunodeficiency virus type 1 (HIV-1) is the most significant risk factor for tuberculosis (TB). The immune responses of the lung are essential to restrict the growth of Mycobacterium tuberculosis and avoid the emergence of the disease. Nevertheless, there is still limited knowledge about the local immune response in people with HIV-1-TB coinfection. METHODS: We employed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid from 9 individuals with HIV-1-TB coinfection and 10 with pulmonary TB. RESULTS: A total of 19 058 cells were grouped into 4 major cell types: myeloid cells, T/natural killer (NK) cells, B cells, and epithelial cells. The myeloid cells and T/NK cells were further divided into 10 and 11 subsets, respectively. The proportions of dendritic cell subsets, CD4+ T cells, and NK cells were lower in the HIV-1-TB coinfection group compared to the TB group, while the frequency of CD8+ T cells was higher. Additionally, we identified numerous differentially expressed genes between the CD4+ and CD8+ T-cell subsets between the 2 groups. CONCLUSIONS: HIV-1 infection not only affects the abundance of immune cells in the lungs but also alters their functions in patients with pulmonary TB.

Apical papilla stem cell-derived exosomes regulate lipid metabolism and alleviate inflammation in the MCD-induced mouse NASH model.

Stem cells from the apical papilla(SCAPs) exhibit remarkable tissue repair capabilities, demonstrate anti-inflammatory and pro-angiogenic effects, positioning them as promising assets in the realm of regenerative medicine. Recently, the focus has shifted towards exosomes derived from stem cells, perceived as safer alternatives while retaining comparable physiological functions. This study delves into the therapeutic implications of exosomes derived from SCAPs in the methionine-choline-deficient (MCD) diet-induced mice non-alcoholic steatohepatitis (NASH) model. We extracted exosomes from SCAPs. During the last two weeks of the MCD diet, mice were intravenously administered SCAPs-derived exosomes at two distinct concentrations (50 µg/mouse and 100 µg/mouse) biweekly. Thorough examinations of physiological and biochemical indicators were performed to meticulously evaluate the impact of exosomes derived from SCAPs on the advancement of NASH in mice induced by MCD diet. This findings revealed significant reductions in body weight loss and liver damage induced by the MCD diet following exosomes treatment. Moreover, hepatic fat accumulation was notably alleviated. Mechanistically, the treatment with exosomes led to an upregulation of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) levels in the liver, enhancing hepatic fatty acid oxidation and transporter gene expression while inhibiting genes associated with fatty acid synthesis. Additionally, exosomes treatment increased the transcription levels of key liver mitochondrial marker proteins and the essential mitochondrial biogenesis factor. Furthermore, the levels of serum inflammatory factors and hepatic tissue inflammatory factor mRNA expression were significantly reduced, likely due to the anti-inflammatory phenotype induced by exosomes in macrophages. The above conclusion suggests that SCAPs-exosomes can improve NASH.

Combination of biopsy forceps excision and ALA-PDT for the treatment of cervical condylomata acuminata.

BACKGROUND: Human papilloma virus (HPV) infection and cervical condyloma acuminatum (CA) often co-exist. Although there are many methods to treat cervical CA, high recurrence rate and cervical scars are still troublesome. Biopsy forceps excision combined with 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a feasible approach for cervical CA, but its efficacy and limitation need to be evaluated. METHODS: This retrospective study consisted of 49 patients aged 18-50 years with a histologically or colposcopic confirmed cervical CA and with HPV infection. Patients were treated with biopsy forceps excision and ALA-PDT. The efficacy was evaluated through HPV typing and colposcopy directed biopsy. RESULTS: Three months after the combination treatment the total lesion remission rate was 93.88 % (46/49) and the HPV clearance rate was 83.67 % (41/49). One patients showed some residual lesions and two patients showed new lesions. Recurrence rate was 4.34 % at 6 months follow-up. There was no significant difference in HPV clearance rate at 3 and 6 months follow-up. Univariate analysis showed that the combination treatment was less effective for patients who had size of visible lesion > 1.5 cm2. Adverse effects were minimal and no structural complications were reported. The main side effects were abdominal pain and increased vaginal secretions. CONCLUSION: Combination of biopsy forceps excision and ALA-PDT is safe and effective for eliminating cervical condylomata lesion and eradicating HPV infection. Colposcopic evaluation is recommended before and after treatment.

GLP-1RAs inhibit the activation of the NLRP3 inflammasome signaling pathway to regulate mouse renal podocyte pyroptosis.

OBJECTIVE: Podocytes are closely related to renal function as an important part of the glomerulus. The reduction and damage of podocytes lead to further decline of renal function and aggravate the progression of DKD. Glucagon-like peptide-1 receptor agonists (GLP-1RAS) have recently attracted great attention in improving podocyte dysfunction, but the specific mechanism remains uncertain. METHODS: We used mouse kidney podocyte MPC5 to construct a high-glucose injury model. Cell viability was detected by the MTT method; RT-qPCR and western blotting were used to detect the expressions of NF-κB p65, NLRP3, GSDMD, N-GSDMD, caspase-1 and cleaved-caspase-1, and we used ELISA to detect the expressions of inflammatory factors IL-1ß and IL-18. RESULTS: Our results showed that high glucose decreased podocyte survival, while liraglutide and semaglutide increased podocyte survival under high glucose. Liraglutide and semaglutide can inhibit the expression of pyroptosis-related genes and proteins and also inhibit the expression of inflammatory factors IL-1ß, IL-18 increase. CONCLUSION: The protective effect of liraglutide and semaglutide on podocytes may be achieved by regulating the NLRP3 inflammasome pathway and inhibiting pyroptosis, and there were no significant differences between the two GLP-1RAs (liraglutide and semaglutide) in inhibiting podocyte pyroptosis.

Bacteroides methylmalonyl-CoA mutase produces propionate that promotes intestinal goblet cell differentiation and homeostasis.

Propionate is a short-chain fatty acid that is generated upon microbiome-mediated fiber fermentation in the intestine. By modulating immune and metabolic pathways, propionate exerts many health benefits. Key bacterial species, such as Bacteroides thetaiotaomicron, generate propionate, but the biochemical pathways and specific functions remain undetermined. We identified a gene operon-encoding methylmalonyl-CoA mutase (MCM) that contributes to propionate biosynthesis in B. thetaiotaomicron. Colonization of germ-free mice with wild-type or MCM-deficient strains as well as in vitro examination demonstrated that MCM-mediated propionate production promotes goblet cell differentiation and mucus-related gene expression. Intestinal organoids lacking the propionate receptor, GPR41, showed reduced goblet cell differentiation upon MCM-mediated propionate production. Furthermore, although wild-type B. thetaiotaomicron alleviated DSS-induced intestinal inflammation, this effect was abolished in mice receiving the MCM-deficient strain but restored upon propionate supplementation. These data emphasize the critical role of MCM-mediated propionate biosynthesis in goblet cell differentiation, offering potential pathways to ameliorate colitis.

Knowledge relation rank enhanced heterogeneous learning interaction modeling for neural graph forgetting knowledge tracing.

Knowledge tracing models have gained prominence in educational data mining, with applications like the Self-Attention Knowledge Tracing model, which captures the exercise-knowledge relationship. However, conventional knowledge tracing models focus solely on static question-knowledge and knowledge-knowledge relationships, treating them with equal significance. This simplistic approach often succumbs to subjective labeling bias and lacks the depth to capture nuanced exercise-knowledge connections. In this study, we propose a novel knowledge tracing model called Knowledge Relation Rank Enhanced Heterogeneous Learning Interaction Modeling for Neural Graph Forgetting Knowledge Tracing. Our model mitigates the impact of subjective labeling by fine-tuning the skill relation matrix and Q-matrix. Additionally, we employ Graph Convolutional Networks (GCNs) to capture intricate interactions between students, exercises, and skills. Specifically, the Knowledge Relation Importance Rank Calibration method is employed to generate the skill relation matrix and Q-matrix. These calibrated matrices, alongside heterogeneous interactions, serve as input for the GCN to compute exercise and skill embeddings. Subsequently, exercise embeddings, skill embeddings, item difficulty, and contingency tables collectively contribute to an exercise relation matrix, which is then fed into an attention mechanism for predictions. Experimental evaluations on two publicly available educational datasets demonstrate the superiority of our proposed model over baseline models, evidenced by enhanced performance across three evaluation metrics.