Impacted spike frequency adaptation associated with reduction of KCNQ2/3 exacerbates seizure activity in temporal lobe epilepsy.

Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.

Performance Test of a Well-Trained Model for Meningioma Segmentation in Health Care Centers: Secondary Analysis Based on Four Retrospective Multicenter Data Sets.

BACKGROUND: Convolutional neural networks (CNNs) have produced state-of-the-art results in meningioma segmentation on magnetic resonance imaging (MRI). However, images obtained from different institutions, protocols, or scanners may show significant domain shift, leading to performance degradation and challenging model deployment in real clinical scenarios. OBJECTIVE: This research aims to investigate the realistic performance of a well-trained meningioma segmentation model when deployed across different health care centers and verify the methods to enhance its generalization. METHODS: This study was performed in four centers. A total of 606 patients with 606 MRIs were enrolled between January 2015 and December 2021. Manual segmentations, determined through consensus readings by neuroradiologists, were used as the ground truth mask. The model was previously trained using a standard supervised CNN called Deeplab V3+ and was deployed and tested separately in four health care centers. To determine the appropriate approach to mitigating the observed performance degradation, two methods were used: unsupervised domain adaptation and supervised retraining. RESULTS: The trained model showed a state-of-the-art performance in tumor segmentation in two health care institutions, with a Dice ratio of 0.887 (SD 0.108, 95% CI 0.903-0.925) in center A and a Dice ratio of 0.874 (SD 0.800, 95% CI 0.854-0.894) in center B. Whereas in the other health care institutions, the performance declined, with Dice ratios of 0.631 (SD 0.157, 95% CI 0.556-0.707) in center C and 0.649 (SD 0.187, 95% CI 0.566-0.732) in center D, as they obtained the MRI using different scanning protocols. The unsupervised domain adaptation showed a significant improvement in performance scores, with Dice ratios of 0.842 (SD 0.073, 95% CI 0.820-0.864) in center C and 0.855 (SD 0.097, 95% CI 0.826-0.886) in center D. Nonetheless, it did not overperform the supervised retraining, which achieved Dice ratios of 0.899 (SD 0.026, 95% CI 0.889-0.906) in center C and 0.886 (SD 0.046, 95% CI 0.870-0.903) in center D. CONCLUSIONS: Deploying the trained CNN model in different health care institutions may show significant performance degradation due to the domain shift of MRIs. Under this circumstance, the use of unsupervised domain adaptation or supervised retraining should be considered, taking into account the balance between clinical requirements, model performance, and the size of the available data.

Multi-walled Carbon Nanotubes Remediate the Phytotoxicity of Quinclorac to Tomato.

In order to remediate the phytotoxicity of quinclorac to tomato by multi-walled carbon nanotubes (MWCNTs), the adsorption of quinclorac to MWCNTs was monitored and the effect of MWCNTs on the phytotoxicity of quinclorac to tomato in soil were studied. The results showed that the Linear equation and Freundlich equation can well fit the adsorption isotherm of quinclorac in the soil containing MWCNTs. The adsorption of quinclorac in soil was significantly enhanced by the addition of MWCNTs; the Kd of soil (1% MWCNTs) was 28.7 times of pure soil. The quinclorac had an obvious inhibitory effect on the growth of tomatoes; serious phytotoxicity was also induced even at the lowest concentration of 0.025 mg/kg. With the MWCNTs content in soil increased to 0.5% and 1%, the phytotoxicity of quinclorac to tomatoes decreased significantly, and the height and fresh weight of tomatoes were even higher than those of the control group, indicating that MWCNTs can promote the growth of tomato. These results provide a reference for resolving the problem of phytotoxicity induced by residual herbicides in farmland.

SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1.

Faithful inheritance of DNA methylation across cell division requires DNMT1 and its accessory factor UHRF1. However, how this axis is regulated to ensure DNA methylation homeostasis remains poorly understood. Here we show that SET8, a cell-cycle-regulated protein methyltransferase, controls protein stability of both UHRF1 and DNMT1 through methylation-mediated, ubiquitin-dependent degradation and consequently prevents excessive DNA methylation. SET8 methylates UHRF1 at lysine 385 and this modification leads to ubiquitination and degradation of UHRF1. In contrast, LSD1 stabilizes both UHRF1 and DNMT1 by demethylation. Importantly, SET8 and LSD1 oppositely regulate global DNA methylation and do so most likely through regulating the level of UHRF1 than DNMT1. Finally, we show that UHRF1 downregulation in G2/M by SET8 has a role in suppressing DNMT1-mediated methylation on post-replicated DNA. Altogether, our study reveals a novel role of SET8 in promoting DNA methylation homeostasis and identifies UHRF1 as the hub for tuning DNA methylation through dynamic protein methylation.

Selenium-doped calcium phosphate biomineral reverses multidrug resistance to enhance bone tumor chemotherapy.

The construction of a functional drug delivery system to reverse the multidrug resistance (MDR) of bone tumors in cases of failed chemotherapy remains a challenge. Herein, we demonstrate a selenium-doped calcium phosphate (Se-CaP) biomineral with high biocompatibility, biodegradability and pH-sensitive drug release properties. Se-CaP may not only serve as an effective drug-carrier to enhance the uptake of doxorubicin (DOX), but may also synchronously induce caspases-mediated apoptosis of osteosarcoma by generating intracellular reactive oxygen species (ROS). Furthermore, in vitro and in vivo studies obviously demonstrate that Se-CaP can reverse the MDR of osteosarcoma by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (ABCB1 and ABCC1). Finally, DOX-loaded Se-CaP can significantly inhibit DOX-resistant MG63 (MG63/DXR) tumor growth in nude mice. Considering its biomimetic chemical properties, the Se-CaP biomineral, with the multiple functions mentioned above, could be a promising candidate for treating bone tumors with MDR characteristics.

Effects of pH and gallic acid on the adsorption of two ionizable organic contaminants to rice straw-derived biochar-amended soils.

The existing form of ionizable organic contaminants (IOCs) could affect their adsorption characteristics to soil and biochar. In this study, 2 IOCs, namely, sulfadiazine and imazalil, were selected to study their adsorption by rice straw-derived biochar-amended soils, as well as the effect of pH and gallic acid on their adsorption. The results showed that the soil adsorption isotherms of the two ionizable organic contaminants could be fitted well by a linear equation and the Freundlich equation, and r2 was more than 0.80. The adsorption coefficient (Kd) in the three kinds of soil ranged from 0.262 to 4.07 L kg-1 for sulfadiazine and from 3.11 to 96.5 L kg-1 for imazalil. After the addition of biochar, the adsorption of sulfadiazine and imazalil in the soil increased. The adsorption of sulfadiazine by biochar gradually decreased with the increase in pH; the adsorption of imazalil increased when the pH increased from 2 to 5 and then gradually decreased with increasing pH. Gallic acid enhanced the adsorption of the two IOCs to pure soil and biochar-amended soil.

[Early complications after robot-assisted laparoscopic radical cystectomy and their risk factors].

OBJECTIVE: To identify risk factors for early complications in patients after robot-assisted laparoscopic radical cystectomy (RARC) and a standardized reporting model to predict complications precisely and recommend reasonable prophylaxis.
 Methods: A total of 90 patients with bladder cancer, who underwent RARC in the Second Xiangya Hospital and the Third Xiangya Hospital of Central South University from January 2016 to January 2018, were enrolled for this study. Their clinical information, preoperative examination and follow-up data within 90 d after RARC were collected. Univariable and multivariable logistic regressions were performed to identify risk factors for early complications after RARC.
 Results: The overall incidence of complications within 90 d after RARC was 48.9% (44/90), including 9 cases of Clavien grade 1, 17 cases of Clavien grade 2, 4 cases of Clavien grade 3, 12 cases of Clavien grade 4, and 2 cases of Clavien grade 5. Acute renal injury (22.2%), intestinal obstruction (16.7%), urinary tract infection (14.4%) and lymphatic leakage (10.0%) were the most common complications within 90 d after the operation. Two patients (2.2%) died within 90 d after the operation. Preoperative BMI (OR=1.16, 95% CI 1.02 to 1.32), postoperative instant (≤30 min) serum creatinine (OR=1.02, 95% CI 1.00 to 1.03), and pT stage (OR=1.67, 95% CI 1.05 to 2.68) were the risk factors for early complications after RARC. 
 Conclusion: The incidence of early complications after RARC is high. Preoperative hemodialysis, correction of anemia, intraoperative protection of renal function, and early recovery after surgery are helpful to prevent early complications after RARC.

Exploration of the antioxidant system and photosynthetic system of a marine algicidal Bacillus and its effect on four harmful algal bloom species.

A novel marine bacterium, strain B1, initially showed 96.4% algicidal activity against Phaeocystis globosa. Under this situation, 3 other harmful algal species (Skeletonema costatum, Heterosigma akashiwo, and Prorocentrum donghaiense) were chosen to study the algicidal effects of strain B1, and the algicidal activities were 91.4%, 90.7%, and 90.6%, respectively. To explore the algicidal mechanism of strain B1 on these 4 harmful algal species, the characteristics of the antioxidant system and photosynthetic system were studied. Sensitivity to strain B1 supernatant, enzyme activity, and gene expression varied with algal species, while the algicidal patterns were similar. Strain B1 supernatant increased malondialdehyde contents; decreased chlorophyll a contents; changed total antioxidant and superoxide dismutase activity; and restrained psbA, psbD, and rbcL genes expression, which eventually resulted in the algal cells death. The algicidal procedure was observed using field emission scanning electron microscopy, which indicated that algal cells were lysed and cellular substances were released. These findings suggested that the antioxidant and photosynthetic system of these 4 algal species was destroyed under strain B1 supernatant stress. This is the first report to explore and compare the mechanism of a marine Bacillus against harmful algal bloom species of covered 4 phyla.

A novel trauma induced urethral stricture in rat model.

Urethral stricture (US) is a longstanding disease, while there has not existed a suitable animal model to mimic the condition. We aimed to establish a trauma-induced US animal model to simulate this clinical scenario. A total of 30 rats were equally distributed into two groups, sham and US group. All rats were anesthetized with isoflurane and undergone cystostomy. In the US group, a 2 mm incision was made in the urethra and sutured to induce US. The sham group only make a skin incision on the ventral side of the anterior urethra. 4 weeks later, ultrasound and cystourethrography were performed to evaluate the degree of urethral stricture, pathological examinations were carried out to evaluate the degree of fibrosis. Urodynamic evaluation and mechanical tissue testing were performed to evaluate the bladder function and urethral tissue stiffness. The results showed that the urethral mucosa was disrupted and urethral lumen was stenosed in the US group. Additionally, the US group showed elevated bladder pressure, prolonged micturition intervals and increased tissue stiffness. In conclusion, the rat urethral stricture model induced by trauma provides a closer representation of the real clinical scenario. This model will significantly contribute to advancing research on the mechanisms underlying traumatic urethral stricture.

Mitochondria-Targeted Nanoadjuvants Induced Multi-Functional Immune-Microenvironment Remodeling to Sensitize Tumor Radio-Immunotherapy.

It is newly revealed that collagen works as a physical barrier to tumor immune infiltration, oxygen perfusion, and immune depressor in solid tumors. Meanwhile, after radiotherapy (RT), the programmed death ligand-1 (PD-L1) overexpression and transforming growth factor-ß (TGF-ß) excessive secretion would accelerate DNA damage repair and trigger T cell exclusion to limit RT efficacy. However, existing drugs or nanoparticles can hardly address these obstacles of highly effective RT simultaneously, effectively, and easily. In this study, it is revealed that inducing mitochondria dysfunction by using oxidative phosphorylation inhibitors like Lonidamine (LND) can serve as a highly effective multi-immune pathway regulation strategy through PD-L1, collagen, and TGF-ß co-depression. Then, IR-LND is prepared by combining the mitochondria-targeted molecule IR-68 with LND, which then is loaded with liposomes (Lip) to create IR-LND@Lip nanoadjuvants. By doing this, IR-LND@Lip more effectively sensitizes RT by generating more DNA damage and transforming cold tumors into hot ones through immune activation by PD-L1, collagen, and TGF-ß co-inhibition. In conclusion, the combined treatment of RT and IR-LND@Lip ultimately almost completely suppressed the growth of bladder tumors and breast tumors.

The human microbiome and benign prostatic hyperplasia: Current understandings and clinical implications.

The research of the human microbiome in the preceding decade has yielded novel perspectives on human health and diseases. Benign prostatic hyperplasia (BPH) is a common disease in middle-aged and elderly males, which negatively affects the life quality. Existing evidence has indicated that the human microbiome, including urinary, intra-prostate, gut, oral and blood microbiome may exert a significant impact on the natural progression of BPH. The dysbiosis of the microbiome may induce inflammation at either a local or systemic level, thereby affecting the BPH. Moreover, metabolic syndrome (MetS) caused by the microbiome can also be involved in the development of BPH. Additionally, alterations in the microbiome composition during the senility process may serve as another cause of the BPH. Here, we summarize the influence of human microbiome on BPH and explore how the microbiome is linked to BPH through inflammation, MetS, and senility. In addition, we propose promising areas of investigation and discuss the implications for advancing therapeutic approaches.

Inorganic Pyrophosphate at Serum Concentration May Not Be Able to Inhibit Mineralization: A Study in Aqueous Solutions and Serum.

The constituent ions of calcium phosphate in body fluids are in the supersaturated state and tend to form minerals physiologically or pathologically. Inorganic pyrophosphate (PPi) has been considered as one of the most important inhibitors against the formation of calcium phosphate minerals. However, serum PPi concentrations in humans are maintained at a level of several µmol/L, and its effectiveness and mechanism for mineralization inhibition remain ambiguous. Therefore, this work studied the mineralization process in an aqueous solution, explored the effective inhibitory concentration of PPi by titration, and characterized the species during the reactions. We find that PPi at a normal serum concentration does not inhibit mineralization significantly. Such a conclusion was further confirmed in the PPi-added serum. This work indicates that PPi may not be a major direct inhibitor of mineralization in serum and possibly functions via alternative mechanisms.

Association of TRMT2B gene variants with juvenile amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, and it demonstrates high clinical heterogeneity and complex genetic architecture. A variation within TRMT2B (c.1356G>T; p.K452N) was identified to be associated with ALS in a family comprising two patients with juvenile ALS (JALS). Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS, and three more variants were identified in a public ALS database including 3317 patients with ALS. A decreased number of mitochondria, swollen mitochondria, lower expression of ND1, decreased mitochondrial complex I activities, lower mitochondrial aerobic respiration, and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells. Further, TRMT2B variations overexpression cells also displayed decreased ND1. In conclusion, a novel JALS-associated gene called TRMT2B was identified, thus broadening the clinical and genetic spectrum of ALS.

Rehabilitation exercise-driven symbiotic electrical stimulation system accelerating bone regeneration.

Electrical stimulation can effectively accelerate bone healing. However, the substantial size and weight of electrical stimulation devices result in reduced patient benefits and compliance. It remains a challenge to establish a flexible and lightweight implantable microelectronic stimulator for bone regeneration. Here, we use self-powered technology to develop an electric pulse stimulator without circuits and batteries, which removes the problems of weight, volume, and necessary rigid packaging. The fully implantable bone defect electrical stimulation (BD-ES) system combines a hybrid tribo/piezoelectric nanogenerator to provide biphasic electric pulses in response to rehabilitation exercise with a conductive bioactive hydrogel. BD-ES can enhance multiple osteogenesis-related biological processes, including calcium ion import and osteogenic differentiation. In a rat model of critical-sized femoral defects, the bone defect was reversed by electrical stimulation therapy with BD-ES and subsequent bone mineralization, and the femur completely healed within 6 weeks. This work is expected to advance the development of symbiotic electrical stimulation therapy devices without batteries and circuits.

Amorphous 1-D nanowires of calcium phosphate/pyrophosphate: A demonstration of oriented self-growth of amorphous minerals.

Amorphous inorganic solids are traditionally isotropic, thus, it is believed that they only grow in a non-preferential way without the assistance of regulators, leading to the morphologies of nanospheres or irregular aggregates of nanoparticles. However, in the presence of (ortho)phosphate (Pi) and pyrophosphate ions (PPi) which have synergistic roles in biomineralization, the highly elongated amorphous nanowires (denoted ACPPNs) form in a regulator-free aqueous solution (without templates, additives, organics, etc). Based on thorough characterization and tracking of the formation process (e.g., Cryo-TEM, spherical aberration correction high resolution TEM, solid state NMR, high energy resolution monochromated STEM-EELS), the microstructure and its preferential growth behavior are elucidated. In ACPPNs, amorphous calcium orthophosphate and amorphous calcium pyrophosphate are distributed at separated but close sites. The ACPPNs grow via either the preferential attachment of ∼2 nm nanoclusters in a 1-dimension way, or the transformation of bigger nanoparticles, indicating an inherent driving force-governed process. We propose that the anisotropy of ACPPNs microstructure, which is corroborated experimentally, causes their oriented growth. This study proves that, unlike the conventional view, amorphous minerals can form via oriented growth without external regulation, demonstrating a novel insight into the structures and growth behaviors of amorphous minerals.

Quercetin-3-O-glc-1-3-rham-1-6-glucoside decreases Aß production, inhibits Aß aggregation and neurotoxicity, and prohibits the production of inflammatory cytokines.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the hallmark of aggregation of beta-amyloid (Aß) into extracellular fibrillar deposition. Accumulating evidence suggests that soluble toxic Aß oligomers exert diverse roles in neuronal cell death, oxidative stress, neuroinflammation, and the eventual pathogenesis of AD. Aß is derived from the sequential cleavage of amyloid-ß precursor protein (APP) by ß-secretase (BACE1) and γ-secretase. The current effect of single targeting is not ideal for the treatment of AD. Therefore, developing multipotent agents with multiple properties, including anti-Aß generation and anti-Aß aggregation, is attracting more attention for AD treatment. Previous studies indicated that Quercetin was able to attenuate the effects of several pathogenetic factors in AD. Here, we showed that naturally synthesized Quercetin-3-O-glc-1-3-rham-1-6-glucoside (YCC31) could inhibit Aß production by reducing ß-secretase activity. Further investigations indicated that YCC31 could suppress toxic Aß oligomer formation by directly binding to Aß. Moreover, YCC31 could attenuate Aß-mediated neuronal death, ROS and NO production, and pro-inflammatory cytokines release. Taken together, YCC31 targeting multiple pathogenetic factors deserves further investigation for drug development of AD.

Epigenetic-related gene-based prognostic model construction and validation in prostate adenocarcinoma.

Prostate adenocarcinoma (PRAD), driven by both genetic and epigenetic factors, is a common malignancy that affects men worldwide. We aimed to identify and characterize differentially expressed epigenetic-related genes (ERGs) in PRAD and investigate their potential roles in disease progression and prognosis. We used PRAD samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to identify prognosis-associated ERGs. Thirteen ERGs with two distinct expression profiles were identified through consensus clustering. Gene set variation analysis highlighted differences in pathway activities, particularly in the Hedgehog and Notch pathways. Higher epigenetic scores correlated with favorable prognosis and improved immunotherapeutic response. Experimental validation underscored the importance of CBX3 and KAT2A, suggesting their pivotal roles in PRAD. This study provides crucial insights into the epigenetic scoring approach and presents a promising prognostic tool, with CBX3 and KAT2A as key players. These findings pave the way for targeted and personalized interventions for the treatment of PRAD.

Combination of hsa_circ_0004674 and lncRNA OIP5­AS1 as a novel clinical biomarker used to predict prognosis in patients with osteosarcoma.

Osteosarcoma is a malignant tumor that predominantly occurs in children or adolescents under the age of 20 years old. Metastasis and chemotherapy resistance are two problems in the treatment of osteosarcoma, and the lack of definite biomarkers impairs the course of treatment. In recent years, non-coding RNA, as a biomarker of osteosarcoma, has become an area of research focus. The role of long non-coding RNAs (lncRNAs), such as lncRNA OIP5-AS1, and circular RNAs, such as hsa_circ_0004674, in osteosarcoma have previously been revealed, and the present study investigated their clinical significance. A total of 20 samples were collected from patients with osteosarcoma. The expression levels of lncRNA OIP5-AS1 and hsa_circ_0004674 were analyzed in tumor tissues and patient serum, and their associations with chemotherapy sensitivity, lung metastasis and prognosis were assessed. The results revealed that these two non-coding RNAs were significantly upregulated in the osteosarcoma tissues of patients compared with those in the adjacent tumor tissues. In addition, the expression levels of the two non-coding RNAs were increased in the serum of patients with osteosarcoma compared with those in patients with bone fractures (P<0.01). In patients with lung metastasis or chemotherapy resistance (tumor necrosis rate <90%), the expression levels of the two non-coding RNAs were similarly increased. By plotting the receiver operating characteristic curve, it was revealed that the combination of hsa_circ_0004674 and lncRNA OIP5-AS1 was better than ALP or either non-coding RNA alone in predicting chemotherapy sensitivity and metastasis. Kaplan-Meier survival analysis showed that, in patients with osteosarcoma, higher expression of both non-coding RNAs was associated with worse survival time (log-rank test P=0.006). In conclusion, the combination of hsa_circ_0004674 and lncRNA OIP5-AS1 may be used as a better biomarker than traditional biomarkers, such as ALP, in a clinical setting.

Extracellular matrix stiffness aggravates urethral stricture through Igfbp3/Smad pathway.

Urethral stricture refers to the narrowing of the urethral lumen. While previous studies have hinted at inflammation as the initial driver of this condition, the reasons and mechanisms behind its progression remain largely unknown. By Atomic force microscope (AFM), researchers measured the matrix stiffness of urethra to be 5.23 ± 0.37 kPa for normal tissue and 41.59 ± 2.48 kPa for stricture urethral scar. Similar results were observed in rat urethral stricture models, where the matrix stiffness of normal urethra was 4.29 ± 0.82 kPa, while 32.94 ± 7.12 kPa for urethral stricture scar. Notably, the matrix stiffness increased in rat models over time. To further investigate, polyacrylamide hydrogels were employed to mimic different levels of stiffness for normal and stricture condition. Interestingly, higher matrix stiffness led to an increased fibroblast-to-myofibroblast transition (FMT) in rat urethral fibroblasts, indicated by enhanced expression of α-SMA and Collagen I, as well as changing in the morphology of fibroblast. RNA-seq analysis suggested that Igfbp3/Smads might regulate the progressive FMT in urethral stricture. In the experiment where the expression of Igfbp3 was inhibited, increasing matrix stiffness lose the potential to stimulate FMT progression and the expression of p-Smad2/3 decreased. On the contrary, overexpression of Igfbp3 promoted the process of FMT in urethral fibroblasts. In conclusion, Igfbp3/Smad pathway appeared to be involved in the progression of urethral fibrosis. This finding suggested that Igfbp3/Smad might be an promising target for future research and treatment in this filed.