Model-agnostic counterfactual reasoning for identifying and mitigating answer bias in knowledge tracing.

Knowledge tracing (KT) aims to monitor students' evolving knowledge states through their learning interactions with concept-related questions, and can be indirectly evaluated by predicting how students will perform on future questions. In this paper, we observe that there is a common phenomenon of answer bias, i.e., a highly unbalanced distribution of correct and incorrect answers for each question. Existing models tend to memorize the answer bias as a shortcut for achieving high prediction performance in KT, thereby failing to fully understand students' knowledge states. To address this issue, we approach the KT task from a causality perspective. A causal graph of KT is first established, from which we identify that the impact of answer bias lies in the direct causal effect of questions on students' responses. A novel COunterfactual REasoning (CORE) framework for KT is further proposed, which separately captures the total causal effect and direct causal effect during training, and mitigates answer bias by subtracting the latter from the former in testing. The CORE framework is applicable to various existing KT models, and we implement it based on the prevailing DKT, DKVMN, and AKT models, respectively. Extensive experiments on three benchmark datasets demonstrate the effectiveness of CORE in making the debiased inference for KT. We have released our code at https://github.com/lucky7-code/CORE.

Concurrent Crystalline Light-Chain Proximal Tubulopathy and Membranous Nephropathy: A Case Report and Literature Review.

Light-chain proximal tubulopathy (LCPT) is typically characterized by the intracytoplasmic deposition of light chains within the proximal tubular epithelial cells, which is usually classified into crystalline and noncrystalline subgroups. Membranous nephropathy (MN) is a common glomerular disease characterized by diffused subepithelial electron-dense deposits along the capillary loop accompanied by the effacement and microvillus transformation of the foot process. Here, we report a biopsy-confirmed case of a concurrence of LCPT with crystals (κ light chains restricted) and antigen-undetermined MN in a male patient. The patient presented with low-molecular-weight proteinuria, increased serum creatinine levels, and incomplete Fanconi syndrome. To our knowledge, this is the first report of a concurrence of LCPT and independent MN of unknown target antigens, which may enrich our recognition of monoclonal gammopathy of renal significance with synchronous MN.

Establishment of a graphene oxide-assisted nucleic acid chromatography strip detection technology for Prorocentrum minimum.

In recent decades, the harmful algal blooms (HABs) caused by Prorocentrum minimum have caused serious environmental damage and economic losses. The detection of P. minimum plays an important role in warning the outbreak of P. minimum-forming HABs. By utilizing the powerful absorption of graphene oxide (GO) on short-stranded DNA, a GO-assisted nucleic acid chromatography strip (GO-NACS) was proposed here to achieve a highly sensitive, specific, intuitive, and convenient detection of P. minimum. In particular, this study used our previously reported conventional-NACS (C-NACS) as a control to evaluate the improvement of detection performance with the use of GO. The performance of GO-NACS was evaluated from the perspectives of specificity, sensitivity, stability, and practicality. The specificity test demonstrated that it had a high degree of specificity and did not display cross-reacting with non-target algal species. The sensitivity test with the genomic DNA indicated that it had a detection limit of 1.30 × 10-3 ng µL-1, representing a 10-fold higher sensitivity than C-NACS and a 100-fold higher sensitivity than agarose gel electrophoresis (AGE). The interference test with non-target algal species demonstrated that it had a good detection stability, and the interfering algal species had no obvious effect on the detection of P. minimum. The practicality test with simulated natural water samples showed that the cellular detection limit of GO-NACS was 6.8 cells mL-1, which was 10-fold and 100-fold lower than that of C-NACS and AGE, respectively. In conclusion, the established GO-NACS may offer a novel alternative technique for the detection of P. minimum while guaranteeing specificity and enhancing sensitivity without requiring extensive apparatus.

Sensorimotor rhythm and muscle activity in patients with stroke using mobile serious games to assist upper extremity rehabilitation.

Introduction: Exercise rehabilitation is crucial for neurological recovery in hemiplegia-induced upper limb dysfunction. Technology-assisted cortical activation in sensorimotor areas has shown potential for restoring motor function. This study assessed the feasibility of mobile serious games for stroke patients' motor rehabilitation. Methods: A dedicated mobile application targeted shoulder, elbow, and wrist training. Twelve stroke survivors attempted a motor task under two conditions: serious mobile game-assisted and conventional rehabilitation. Electroencephalography and electromyography measured the therapy effects. Results: Patients undergoing game-assisted rehabilitation showed stronger event-related desynchronization (ERD) in the contralateral hemisphere's motor perception areas compared to conventional rehabilitation (p < 0.05). RMS was notably higher in game-assisted rehabilitation, particularly in shoulder training (p < 0.05). Discussion: Serious mobile game rehabilitation activated the motor cortex without directly improving muscle activity. This suggests its potential in neurological recovery for stroke patients.

Triazophos exposure on maternal Daphnia magna at environmental-related concentrations revealed toxic effects to its offspring.

Due to chemical and photochemical stability, triazophos has been frequently detected in rivers and oceans over the years with extensive use for pest control in agriculture, and it has become a worldwide ecological concern to the aquatic environment. Until now, fewer data are available regarding the potential long-term adverse effects of triazophos on aquatic invertebrates, which plays an essential role in aquatic food webs, as a key group for water ecosystems. In this experiment, the F1- and F2 progenies of Daphnia magna were recovered when daphnias (F0) exposure to triazophos at environmental-related concentrations (0.1 and 1.0 µg/L) for 21 d; and the indexes related to phenotypic traits, reproduction and gene expression were measured in tested animals. The results showed that heart rate and total number of neonates in exposed F0-daphnias were significantly lower than those of control group, and the detoxification genes (HR96 and P-gp) were up-regulated while genes related reproduction (Vtg) and molting (Nvd and Shd) were significantly down-regulated. The heart rate and individual size of F1-daphnias (<24 h) were significantly reduced in the treatment group. After 21-d recovery, the heart rate and expression of HR96, P-gp, Vtg, Nvd and Shd were declined in F1-daphnias. There was no obvious difference of morphological traits and heart rate between treatment and control in F2-daphnias (<24 h). In summary, daphnias (F0) exposure to triazophos with environmental dose could raise toxic effects on its offspring (F1), which is mainly manifested by reduced heart rate, the accumulated number and individual size of offspring and decreased expression of genes related to molting and reproduction.

Screen and Optimization of an Aptamer for Alexandrium tamarense-A Common Toxin-Producing Harmful Alga.

Among all the paralytic shellfish toxins (PSTs)-producing algae, Alexandrium tamarense is one of the most widespread harmful species posing a serious threat to marine resources and human health. Therefore, it is extremely important to establish a rapid and accurate monitoring method for A. tamarense that can provide early warnings of harmful algal blooms (HABs) caused by this alga and limit the contamination due to PSTs. In this study, an ssDNA library was first obtained by whole cell systematic evolution of ligands by exponential enrichment after 18 consecutive rounds of iterative screening. After sequencing in combination with subsequent multiple alignment of sequences and secondary structure simulation, the library could be classified into 2 families, namely, Family1 and Family2, according to sequence similarity. Flow cytometry was used to test the affinity and cross-reactivity of Ata19, Ata6, Ata25 and Ata29 belonging to Family2. Ata19 was selected to be modified by truncation, through which a new resultant aptamer named as Ata19-1-1 was obtained. Ata19-1-1 with a KD of 75.16 ± 11.10 nM displayed a much higher affinity than Ata19. The specificity test showed that Ata19-1-1 has the same discrimination ability as Ata19 and can at least distinguish the target microalga from other microalgae. The observation under a fluorescence microscopy showed that the A. tamarense cells labeled with Ata19-1-1 are exhibiting bright green fluorescence and could be easily identified, factually confirming the binding of the aptamer with target cells. In summary, the aptamer Ata19-1-1 produced in this study may serve as an ideal molecular recognition element for A. tamarense, which has the potential to be developed into a novel detection method for this harmful alga in the future.

Disposition and Metabolomic Effects of 2,2',5,5'-Tetrachlorobiphenyl in Female Rats Following Intraperitoneal Exposure.

The disposition and toxicity of lower chlorinated PCBs (LC-PCBs) with less than five chlorine substituents have received little attention. This study characterizes the distribution and metabolomic effects of PCB 52, an LC-PCB found in indoor and outdoor air, three weeks after intraperitoneal exposure of female Sprague Dawley rats to 0, 1, 10, or 100 mg/kg BW. PCB 52 exposure did not affect overall body weight. Gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis identified PCB 52 in all tissues investigated. Hydroxylated, sulfated, and methylated PCB metabolites, identified using GC-MS/MS and nontarget liquid chromatography-high resolution mass spectrometry (Nt-LCMS), were primarily found in the serum and liver of rats exposed to 100 mg/kg BW. Metabolomic analysis revealed minor effects on L-cysteine, glycine, cytosine, sphingosine, thymine, linoleic acid, orotic acid, L-histidine, and erythrose serum levels. Thus, the metabolism of PCB 52 and its effects on the metabolome must be considered in toxicity studies. Highlights: PCB 52 was present in adipose, brain, liver, and serum 3 weeks after PCB exposureLiver and serum contained hydroxylated, sulfated, and methylated PCB 52 metabolitesMetabolomics analysis revealed minor changes in endogenous serum metabolitesLevels of dopamine and its metabolites in the brain were not affected by PCB 52.

Cerebral glucagon-like peptide-1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice.

AIM: We aimed to assess the effects of cerebral glucagon-like peptide-1 receptor (GLP-1R) activation on the glymphatic system and whether this effect was therapeutic for traumatic brain injury (TBI). METHODS: Immunofluorescence was employed to evaluate glymphatic system function. The blood-brain barrier (BBB) permeability, microvascular basement membrane, and tight junction expression were assessed using Evans blue extravasation, immunofluorescence, and western blot. Immunohistochemistry was performed to assess axonal damage. Neuronal apoptosis was evaluated using Nissl staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and western blot. Cognitive function was assessed using behavioral tests. RESULTS: Cerebral GLP-1R activation restored glymphatic transport following TBI, alleviating BBB disruption and neuronal apoptosis, thereby improving cognitive function following TBI. Glymphatic function suppression by treatment using aquaporin 4 inhibitor TGN-020 abolished the protective effect of the GLP-1R agonist against cognitive impairment. CONCLUSION: Cerebral GLP-1R activation can effectively ameliorate neuropathological changes and cognitive impairment following TBI; the underlying mechanism could involve the repair of the glymphatic system damaged by TBI.

A review of advances in aptamer-based cell detection technology.

Since cells are the basic structural and functional units of organisms, the detection or quantitation of cells is one of the most common basic problems in life science research. The established cell detection techniques mainly include fluorescent dye labeling, colorimetric assay, and lateral flow assay, all of which employ antibodies as cell recognition elements. However, the widespread application of the established methods generally dependent on antibodies is limited, because the preparation of antibodies is complicated and time-consuming, and unrecoverable denaturation is prone to occur with antibodies. By contrast, aptamers that are generally selected through the systematic evolution of ligands by exponential enrichment can avoid the disadvantages of antibodies due to their controllable synthesis, thermostability, and long shelf life, etc. Accordingly, aptamers may serve as novel molecular recognition elements like antibodies in combination with various techniques for cell detection. This paper reviews the developed aptamer-based cell detection methods, mainly including aptamer-fluorescent labeling, aptamer-isothermal amplification assay, electrochemical aptamer sensor, aptamer-based lateral flow analysis, and aptamer-colorimetric assay. The principles, advantages, progress of application in cell detection and future development trend of these methods were specially discussed. Overall, different assays are suitable for different detection purposes, and the development of more accurate, economical, efficient, and rapid aptamer-based cell detection methods is always on the road in the future. This review is expected to provide a reference for achieving efficient and accurate detection of cells as well as improving the usefulness of aptamers in the field of analytical applications.

Establishment of a multiplex polymerase chain reaction detection assay for three common harmful microalgae in the East China Sea.

It is urgent to develop techniques that can simultaneously detect multiple microalgae, due to the diversity of harmful algal blooms (HABs)-forming algal species. The target algae species in this study are Heterosigma akashiwo, Prorocentrum donghaiense and Karenia mikimotoi. These algae are the dominant species that cause HABs in the East China Sea, and the multiple detection technique focusing on these three algae is not common. Therefore, this study established a multiplex polymerase chain reaction(mPCR) to diagnose the three algae, which is simple and low cost. First, the corresponding specific primers were designed based on the D1-D2 region of the large subunit (LSU) ribosomal DNA sequence. Then, mPCR was established and the reaction conditions were optimized. And the specificity, sensitivity, and stability of mPCR were evaluated. The result of specificity test showed that the established mPCR had good specificity for the target microalgae and did not cross-react with eighteen non-target microalgae. The sensitivity of experiment was 3.3 × 10-1 ng µL-1, and the established mPCR was not affected by the interfering microalgae. Moreover, the practicability evaluation of mPCR by using the simulated natural water samples showed that the detection limit of target microalgae was 100 cells mL-1, which could meet the demand for early warning of HABs. In summary, the established mPCR is characterized by strong specificity, good stability, and multiple analysis to detect H. akashiwo, P. donghaiense, and K. mikimotoi.

A detection method for Prorocentrum minimum by an aptamer-gold nanoparticles based colorimetric assay.

Here, to give early waring for harmful algal blooms caused by Prorocentrum minimum, we reported a simple and rapid colorimetric assay that is named aptamer-gold nanoparticles (GNPs) based colorimetric assay (AGBCA). The GNPs maintain a dispersed state and have a strong characteristic absorption peak at 520 nm. With the addition of NaCl, the stability of the solution will be destroyed and the dispersed GNPs will aggregate. Therefore, the characteristic absorption peak of the GNPs solution will change from 520 nm to 670 nm. Aptamers can be adsorbed on the surface of GNPs, effectively preventing the aggregation of GNPs. In the presence of P. minimum, aptamers will specifically bind to P. minimum, causing the dissociation of the aptamers from GNPs. Consequently, the GNPs will aggregate in the NaCl solution, corresponding to a new absorption peak at 670 nm. A linear relationship between the absorbance ratio variation (ΔA670/A520) and the P. minimum concentration was observed in the concentration range of 1 × 102 - 1 × 107 cells mL-1, with a low detection limit of 8 cells mL-1. The developed AGBCA is characterized by simplicity, strong specificity, and high sensitivity and is thus promising for the quantitative detection of P. minimum in natural samples.

The temporal dynamics of Large-Scale brain network changes in disorders of consciousness: A Microstate-Based study.

BACKGROUND AND OBJECTIVES: The resting-state brain is composed of several discrete networks, which remain stable for 10-100 ms. These functional microstates are considered the building blocks of spontaneous consciousness. Electroencephalography (EEG) microstate analysis may provide insight into the altered brain dynamics underlying consciousness recovery in patients with disorders of consciousness (DOC). We aimed to analyze microstates in the resting-state EEG source space in patients with DOC, the relationship between state-specific features and consciousness levels, and the corresponding patterns of microstates and functional networks. METHODS: We obtained resting-state EEG data from 84 patients with DOC (27 in a minimally conscious state [MCS] and 57 in a vegetative state [VS] or with unresponsive wakefulness syndrome). We conducted a microstate analysis of the resting-state (EEG) source space and developed a state-transition analysis protocol for patients with DOC. RESULTS: We identified seven microstates with distinct spatial distributions of cortical activation. Multivariate pattern analyses revealed that different functional connectivity patterns were associated with source-level microstates. There were significant differences in the microstate properties, including spatial activation patterns, temporal dynamics, state shifts, and connectivity construction, between the MCS and VS groups. DISCUSSION: Our findings suggest that consciousness depends on complex dynamics within the brain and may originate from the anterior cortex.

Inhibition of MLL1-menin interaction attenuates renal fibrosis in obstructive nephropathy.

Mixed lineage leukemia 1 (MLL1), a histone H3 lysine 4 (H3K4) methyltransferase, exerts its enzymatic activity by interacting with menin and other proteins. It is unclear whether inhibition of the MLL1-menin interaction influences epithelial-mesenchymal transition (EMT), renal fibroblast activation, and renal fibrosis. In this study, we investigated the effect of disrupting MLL1-menin interaction on those events and mechanisms involved in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), in cultured mouse proximal tubular cells and renal interstitial fibroblasts. Injury to the kidney increased the expression of MLL1 and menin and H3K4 monomethylation (H3K4me1); MLL1 and menin were expressed in renal epithelial cells and renal interstitial fibroblasts. Inhibition of the MLL1-menin interaction by MI-503 administration or siRNA-mediated silencing of MLL1 attenuated UUO-induced renal fibrosis, and reduced expression of α-smooth muscle actin (α-SMA) and fibronectin. These treatments also inhibited UUO-induced expression of transcription factors Snail and Twist and transforming growth factor ß1 (TGF-ß1) while expression of E-cadherin was preserved. Moreover, treatment with MI-503 and transfection with either MLL siRNA or menin siRNA inhibited TGF-ß1-induced upregulation of α-SMA, fibronectin and Snail, phosphorylation of Smad3 and AKT, and downregulation of E-cadherin in cultured renal epithelial cells. Finally, MI-503 was effective in abrogating serum or TGFß1-induced transformation of renal interstitial fibroblasts to myofibroblasts in vitro. Taken together, these results suggest that targeting disruption of the MLL1-menin interaction attenuates renal fibrosis through inhibition of partial EMT and renal fibroblast activation.

Optimization of an aptamer against Prorocentrum minimum - A common harmful algae by truncation and G-quadruplex-forming mutation.

Harmful algal blooms (HABs) caused by Prorocentrum minimum have seriously posed economic losses and ecological disasters. To reduce these losses, aptamers are used as a new molecular probe to establish rapid methods. Herein, to improve the affinity and application of aptamers in the detection of harmful algae, the optimization was performed on the previously reported aptamers against P. minimum. First, a total of seven candidate aptamers, including three truncated aptamers (TA1, TA2 and TA3) and four mutant aptamers (MA1, MA2, MA3 and MA4), were obtained by truncation and G-quadruplex (GQ)-forming mutation. Next, the specificity and affinity test by flow cytometry revealed that except for TA1 and TA2, all of the candidate aptamers are specific with the equilibrium dissociation constant of (40.4 ± 5.5) nM for TA3, (63.3 ± 24.0) nM for MA1, (71.7 ± 14.6) nM for MA2, (365.9 ± 74.4) nM for MA3, and (21.1 ± 0.5) nM for MA4, respectively. The circular dichroism analysis of the mutant aptamers demonstrated that the GQ structures formed by MA1/MA2, MA3 and MA4 were antiparallel, mixed parallel and parallel, respectively. The affinity of aptamers with various GQ is in the order of parallel structure > antiparallel structure > mixed parallel structure. In addition, to further improve binding ability, the binding conditions of MA4 were optimized as follows: binding time, 60 min; binding temperature, 37 °C; pH of the binding buffer, 7.5; and Na+/Mg2+ concentration in the binding buffer, 100 mM/0.5 mM. The binding examination by fluorescence microscopy showed that MA4 had a stronger binding ability to P. minimum than the original aptamer. Taken together, this study not only obtained an aptamer with higher affinity than the original aptamer, which laid a good foundation for subsequent application, but also may provide a feasible reference method for aptamer optimization.

Easy detection of Prorocentrum donghaiense by polymerase chain reaction-nucleic acid chromatography strip.

In recent years, Prorocentrum donghaiense, as a dominant species, has ranked first in terms of cumulative number and area of algal blooms in the East China Sea. In this study, the D1-D2 region of the large ribosomal subunit of P. donghaiense was used as the target gene, and specific primers DH-FP/DH-RP were designed according to the species-specific region of the target gene. An easy, sensitive and visual detection method refered to as polymerase chain reaction-nucleic acid chromatography strip (PCR-NACS) was established for P. donghaiense. The optimized parameters of the PCR amplification system are as follows: primer concentration, 0.15 µM; annealing temperature, 62 °C; and Mg2+ concentration, 1.5 mM. The specificity test showed that PCR-NACS was exlusively specific for the detection of the target algae. The sensitivity test show that the lowest detection limit (LDL) of PCR-NACS was 2.7 × 10-2 ng·µL-1 for genomic DNA and 3.58 × 102 copies·µL-1 for plasmid DNA, respectively. The tests using both genomic DNA and plasmid DNA as templates showed that the sensitivity of PCR-NACS was 10 times higher than that of ordinary PCR. The stability test showed that the interfering algal species did not affect the detection of the target algae by PCR-NACS. In addition, the test with simulated natural samples containing target algae showed that the LDL of PCR-NACS could reach 1.27 × 101 cells·mL-1. In summary, the PCR-NACS established in this study may provide a new method for easy identification of P. donghaiense in natural water samples.

The accuracy of different mismatch negativity amplitude representations in predicting the levels of consciousness in patients with disorders of consciousness.

Introduction: The mismatch negativity (MMN) index has been used to evaluate consciousness levels in patients with disorders of consciousness (DoC). Indeed, MMN has been validated for the diagnosis of vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state (MCS). In this study, we evaluated the accuracy of different MMN amplitude representations in predicting levels of consciousness. Methods: Task-state electroencephalography (EEG) data were obtained from 67 patients with DoC (35 VS and 32 MCS). We performed a microstate analysis of the task-state EEG and used four different representations (the peak amplitude of MMN at electrode Fz (Peak), the average amplitude within a time window -25- 25 ms entered on the latency of peak MMN component (Avg for peak ± 25 ms), the average amplitude of averaged difference wave for 100-250 ms (Avg for 100-250 ms), and the average amplitude difference between the standard stimulus ("S") and the deviant stimulus ("D") at the time corresponding to Microstate 1 (MS1) (Avg for MS1) of the MMN amplitude to predict the levels of consciousness. Results: The results showed that among the four microstates clustered, MS1 showed statistical significance in terms of time proportion during the 100-250 ms period. Our results confirmed the activation patterns of MMN through functional connectivity analysis. Among the four MMN amplitude representations, the microstate-based representation showed the highest accuracy in distinguishing different levels of consciousness in patients with DoC (AUC = 0.89). Conclusion: We discovered a prediction model based on microstate calculation of MMN amplitude can accurately distinguish between MCS and VS states. And the functional connection of the MS1 is consistent with the activation mode of MMN.

Regulation of Podocyte Injury by CircHIPK3/FUS Complex in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and is one of the leading causes of end-stage kidney disease. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that play important roles in various diseases, yet their roles in DKD are poorly understood. CircRNA HIPK3 (circHIPK3), a highly conserved circRNA, is closely related to various cellular functions, including cell proliferation and apoptosis. The association between circHIPK3 and diabetic complications has been well demonstrated in multiple previous studies. However, the role of circHIPK3 in podocyte injury in DKD remains unclear. Herein, we discovered that circHIPK3 expression is markedly elevated in cultured podocytes under high-glucose (HG) conditions and glomeruli of diabetic mice, which is closely associated with podocyte injury in DKD. Functionally, lentivirus-mediated knockdown of circHIPK3 dramatically suppresses HG-induced podocyte apoptosis in vitro. Therapeutically, silencing circHIPK3 by adeno-associated virus-mediated RNA interference ameliorates podocyte injury and albuminuria in STZ-induced diabetic mice. Mechanistically, circHIPK3 facilitates the enrichment of fused in sarcoma (FUS) on the ectodysplasin A2 receptor (EDA2R) promoter, resulting in the upregulation of EDA2R expression and activation of apoptotic signaling. Taken together, these results indicate circHIPK3/FUS/EDA2R axis as a therapeutic target for podocyte injury and DKD progression.

Brain re-expansion predict the recurrence of unilateral CSDH: A clinical grading system.

Objective: Assessing the risk of postoperative recurrence of chronic subdural hematoma (CSDH) is a clinical focus. To screen the main factors associated with the perioperative hematoma recurrence. The brain re-expansion is the core factor of recurrence. A clinical prognostic scoring system was also proposed. Methods: We included 295 patients with unilateral CSDH as the training group for modeling. Factors predicting postoperative recurrence requiring reoperation (RrR) were determined using univariate and multivariate regression analyses, and bivariate Pearson correlation coefficient analysis was used to exclude related factors. Receiver operating characteristic curve analysis evaluates the ability of main factors to predict RrR and determines the cut-off value of brain re-expansion rate. We developed a prognostic scoring system and conducted preliminary verification. A verification group including 119 patients with unilateral CSDH was used to verify the grading systems. Results: The key factors for predicting unilateral CSDH recurrence were cerebral re-expansion rate (≤ 40%) at postoperative days 7-9 (OR 25.91, p < 0.001) and the preoperative CT density classification (isodense or hyperdense, or separated or laminar types) (OR 8.19, p = 0.007). Cerebral atrophy played a key role in brain re-expansion (OR 2.36, p = 0.002). The CSDH prognostic grading system ranged from 0 to 3. An increased score was associated with a more accurate progressive increase in the RrR rate (AUC = 0.856). Conclusions: Our prognostic grading system could screen clinically high-risk RrR patients with unilateral CSDH. However, increased attention should be paid to brain re-expansion rate after surgery in patients with CSDH.

Histone methyltransferase MLL1 drives renal tubular cell apoptosis by p53-dependent repression of E-cadherin during cisplatin-induced acute kidney injury.

Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase that interacts with WD repeat domain 5 (WDR5) to regulate cell survival, proliferation, and senescence. The role of MLL1 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we demonstrate that MLL1, WDR5, and trimethylated H3K4 (H3K4me3) were upregulated in renal tubular cells of cisplatin-induced AKI in mice, along with increased phosphorylation of p53 and decreased expression of E-cadherin. Administration of MM102, a selective MLL1/WDR5 complex inhibitor, improved renal function and attenuated tubular injury and apoptosis, while repressing MLL1, WDR5, and H3K4me3, dephosphorylating p53 and preserving E-cadherin. In cultured mouse renal proximal tubular cells (RPTCs) exposed to cisplatin, treatment with MM102 or transfection with siRNAs for either MLL1 or WDR5 also inhibited apoptosis and p53 phosphorylation while preserving E-cadherin expression; p53 inhibition with Pifithrin-α lowered cisplatin-induced apoptosis without affecting expression of MLL1, WDR5, and H3K4me3. Interestingly, silencing of E-cadherin offset MM102's cytoprotective effects, but had no effect on p53 phosphorylation. These findings suggest that MLL1/WDR5 activates p53, which, in turn, represses E-cadherin, leading to apoptosis during cisplatin-induced AKI. Further studies showed that MM102 effectively inhibited cisplatin-triggered DNA damage response (DDR), as indicated by dephosphorylation of ataxia telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR) proteins, dephosphorylation of checkpoint kinase 1 and 2 (Chk1 and Chk2); depression of γ-H2AX; and restrained cell cycle arrest, as evidenced by decreased expression of p21 and phospho-histone H3 at serine 10 in vitro and in vivo. Overall, we identify MLL1 as a novel DDR regulator that drives cisplatin-induced RPTC apoptosis and AKI by modulating the MLL1/WDR5-/ATR/ATM-Chk-p53-E-cadherin axis. Targeting the MLL1/WDR5 complex may have a therapeutic potential for the treatment of AKI.