Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development.

Spatiotemporal regulation of the mechanistic target of rapamycin (mTOR) pathway is pivotal for establishment of brain architecture. Dysregulation of mTOR signaling is associated with a variety of neurodevelopmental disorders. Here, we demonstrate that the UBE4B-KLHL22 E3 ubiquitin ligase cascade regulates mTOR activity in neurodevelopment. In a mouse model with UBE4B conditionally deleted in the nervous system, animals display severe growth defects, spontaneous seizures and premature death. Loss of UBE4B in the brains of mutant mice results in depletion of neural precursor cells and impairment of neurogenesis. Mechanistically, UBE4B polyubiquitylates and degrades KLHL22, an E3 ligase previously shown to degrade the GATOR1 component DEPDC5. Deletion of UBE4B causes upregulation of KLHL22 and hyperactivation of mTOR, leading to defective proliferation and differentiation of neural precursor cells. Suppression of KLHL22 expression reverses the elevated activity of mTOR caused by acute local deletion of UBE4B. Prenatal treatment with the mTOR inhibitor rapamycin rescues neurogenesis defects in Ube4b mutant mice. Taken together, these findings demonstrate that UBE4B and KLHL22 are essential for maintenance and differentiation of the precursor pool through fine-tuning of mTOR activity.

Planar perovskite solar cells with long-term stability using ionic liquid additives.

Solar cells based on metal halide perovskites are one of the most promising photovoltaic technologies1-4. Over the past few years, the long-term operational stability of such devices has been greatly improved by tuning the composition of the perovskites5-9, optimizing the interfaces within the device structures10-13, and using new encapsulation techniques14,15. However, further improvements are required in order to deliver a longer-lasting technology. Ion migration in the perovskite active layer-especially under illumination and heat-is arguably the most difficult aspect to mitigate16-18. Here we incorporate ionic liquids into the perovskite film and thence into positive-intrinsic-negative photovoltaic devices, increasing the device efficiency and markedly improving the long-term device stability. Specifically, we observe a degradation in performance of only around five per cent for the most stable encapsulated device under continuous simulated full-spectrum sunlight for more than 1,800 hours at 70 to 75 degrees Celsius, and estimate that the time required for the device to drop to eighty per cent of its peak performance is about 5,200 hours. Our demonstration of long-term operational, stable solar cells under intense conditions is a key step towards a reliable perovskite photovoltaic technology.

Recent development and applications of differential electrochemical mass spectrometry in emerging energy conversion and storage solutions.

Electrochemical energy conversion and storage are playing an increasingly important role in shaping the sustainable future. Differential electrochemical mass spectrometry (DEMS) offers an operando and cost-effective tool to monitor the evolution of gaseous/volatile intermediates and products during these processes. It can deliver potential-, time-, mass- and space-resolved signals which facilitate the understanding of reaction kinetics. In this review, we show the latest developments and applications of DEMS in various energy-related electrochemical reactions from three distinct perspectives. (I) What is DEMS addresses the working principles and key components of DEMS, highlighting the new and distinct instrumental configurations for different applications. (II) How to use DEMS tackles practical matters including the electrochemical test protocols, quantification of both potential and mass signals, and error analysis. (III) Where to apply DEMS is the focus of this review, dealing with concrete examples and unique values of DEMS studies in both energy conversion applications (CO2 reduction, water electrolysis, carbon corrosion, N-related catalysis, electrosynthesis, fuel cells, photo-electrocatalysis and beyond) and energy storage applications (Li-ion batteries and beyond, metal-air batteries, supercapacitors and flow batteries). The recent development of DEMS-hyphenated techniques and the outlook of the DEMS technique are discussed at the end. As DEMS celebrates its 40th anniversary in 2024, we hope this review can offer electrochemistry researchers a comprehensive understanding of the latest developments of DEMS and will inspire them to tackle emerging scientific questions using DEMS.

Gd(III)-Catalyzed Regio-, Diastereo-, and Enantioselective [4 + 2] Photocycloaddition of Naphthalene Derivatives.

Catalytic asymmetric dearomatization (CADA) reactions have evolved into an efficient strategy for accessing chiral polycyclic and spirocyclic scaffolds from readily available planar aromatics. Despite the significant developments, the CADA reaction of naphthalenes remains underdeveloped. Herein, we report a Gd(III)-catalyzed asymmetric dearomatization reaction of naphthalene with a chiral PyBox ligand via visible-light-enabled [4 + 2] cycloaddition. This reaction features application of a chiral Gd/PyBox complex, which regulates the reactivity and selectivity simultaneously, in excited-state catalysis. A wide range of functional groups is compatible with this protocol, giving the highly enantioenriched bridged polycycles in excellent yields (up to 96%) and selectivity (up to >20:1 chemoselectivity, >20:1 dr, >99% ee). The synthetic utility is demonstrated by a 2 mmol scale reaction, removal of directing group, and diversifications of products. Preliminary mechanistic experiments are performed to elucidate the reaction mechanism.

The role of gut microbiota involved in prostate microenvironment and symptoms improvement in chronic prostatitis/chronic pelvic pain syndrome patients treated with low-intensity extracorporeal shock wave.

BACKGROUND: Low-intensity extracorporeal shockwave therapy (Li-ESWT) is emerging as a promising and safe treatment for Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). In this study, we aimed to investigate the role of the gut microbiota involved in the prostate microenvironment and symptom improvement during the Li-ESWT for CP/CPPS patients. METHODS: CP/CPPS patients not taking antibiotics or other treatments were included. NIH-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score (IPSS), and International Index of Erectile Function (IIEF-5) were used to evaluate the effectiveness of Li-ESWT at the end of treatment. Visual analogue scale/score was used to evaluate the pain during procedure. Stool and semen samples were collected before and after Li-ESWT. Shotgun metagenomics analyzed gut microbiota, while ELISA and other diagnostic kits detected biochemical changes in seminal plasma. RESULT: Of the 60 enrolled patients, 52 completed treatment. Li-ESWT response rate was 78.8% (41/52) at end of treatment. Among responders, the subitems of the NIH-CPSI; IPSS; and IIEF-5 scores improved significantly, and the seminal plasma analysis showed decreased TNF-a and MDA levels and increased SOD and Zn2+ levels posttreatment. Gut microbiome analysis indicated that posttreatment, both α and ß diversity increased, and the abundance of certain specific species significantly increased. Fifty-eight pathways significantly enriched posttreatment, notably in branched-chain amino acid synthesis and butyrate synthesis. The abundance of several specific species was found to be significantly higher in non-responders than responders. Among responders, at the species level, some bacteria associated with NIH-CPSI and its subscales, IPSS, IIEF-5, and prostate microenvironment markers (TNF-a, MDA, Zn2+, and SOD) were identified. CONCLUSIONS: Our study demonstrates for the first time that Li-ESWT improves the prostate microenvironment and gut microbiota in CP/CPPS patients. Treatment nonresponse may be associated with a high abundance of specific pathogens before treatment. The gut microbiota could have a significant impact on Li-ESWT response and the prostate microenvironment.

Controlling Nucleation and Crystallization of CsPbI3 Perovskites for Efficient Inverted Solar Cells.

The unfavorable morphology and high crystallization temperature (Tc) of inorganic perovskites pose a significant challenge to their widespread application in photovoltaics. In this study, an effective approach is proposed to enhance the morphology of cesium lead triiodide (CsPbI3) while lowering its Tc. By introducing dimethylammonium acetate into the perovskite precursor solution, a rapid nucleation stage is facilitated, and significantly enhances the crystal growth of the intermediate phase at low annealing temperatures, followed by a slow crystal growth stage at higher annealing temperatures. This results in a uniform and dense morphology in CsPbI3 perovskite films with enhanced crystallinity, simultaneously reducing the Tc from 200 to 150 °C. Applying this approach in positive-intrinsic-negative (p-i-n) inverted cells yields a high power conversion efficiency of 19.23%. Importantly, these cells exhibit significantly enhanced stability, even under stress at 85 °C.

Critical Residues Involved in the Coassembly of L1 and L2 Capsid Proteins of Human Papillomavirus 16.

Human papillomaviruses (HPV) are small DNA viruses associated with cervical cancer, warts, and other epithelial tumors. Structural studies have shown that the HPV capsid consists of 360 copies of the major capsid protein, L1, arranged as 72 pentamers in a T=7 icosahedral lattice, coassembling with substoichiometric amounts of the minor capsid protein, L2. However, the residues involved in the coassembly of L1 and L2 remain undefined due to the lack of structure information. Here, we investigated the solvent accessibility surfaces (SASs) of the central cavity residues of the HPV16 L1 pentamer in the crystal structure because those internal exposed residues might mediate the association with L2. Twenty residues in L1 protein were selected to be analyzed, with four residues in the lumen of the L1 pentamer identified as important: F256, R315, Q317, and T340. Mutations to these four residues reduced the PsV (pseudovirus) infection capacity in 293FT cells, and mutations to R315, Q317, and T340 substantially perturb L2 from coassembling into L1 capsid. Compared with wild-type (WT) PsVs, these mutant PsVs also have a reduced ability to become internalized into host cells. Finally, we identified a stretch of negatively charged residues on L2 (amino acids [aa] 337 to 340 [EEIE]), mutations to which completely abrogate L2 assembly into L1 capsid and subsequently impair the endocytosis and infectivity of HPV16 PsVs. These findings shed light on the elusive coassembly between HPV L1 and L2. IMPORTANCE Over 200 types of HPV have been isolated, with several high-risk types correlated with the occurrence of cervical cancer. The HPV major capsid protein, L1, assembles into a T=7 icosahedral viral shell, and associates with the minor capsid protein, L2, which plays a critical role in the HPV life cycle. Despite the important role of the L2 protein, its structure and coassembly with L1 remain elusive. In this study, we analyzed the amino acid residues at the proposed interface between L1 and L2. Certain mutations at these sites decreased the amount of L2 protein assembled into the capsid, which, in turn, led to a decrease in viral infectivity. Knowledge about these residues and the coassembly of L1 and L2 could help to expand our understanding of HPV biology and aid in the development of countermeasures against a wide range of HPV types by targeting the L2 protein.

Low-frequency electric field sensing via superposition orbital angular momentum light.

The polarization and orbital angular momentum (OAM) degrees of freedom carried by light have important applications in precision optical measurement and optical sensing. Here we show that the electro-optic Pockels effect of a magnesium-doped lithium niobate (MgO:LiNbO3) crystal can be used to measure a low-frequency electric field. By exploiting the rotation property of superposition OAM light, we experimentally observe that the minimum measured precision of electric field intensity is about 0.18 V/m. This study offers a method to perform low-frequency electric field sensing.

Linear-space-variant model for Fourier ptychographic microscopy.

Fourier ptychographic microscopy (FPM) needs to realize well-accepted reconstruction by image segmentation and discarding problematic data due to artifacts caused by vignetting. However, the imaging results have long suffered from uneven color blocks and the consequent digital stitching artifacts, failing to bring satisfying experiences to researchers and users over the past decade since the invention of FPM. In fact, the fundamental reason for vignetting artifacts lies in that the acquired data does not match the adopted linear-space-invariant (LSI) forward model, i.e., the actual object function is modulated by a quadratic phase factor during data acquisition, which has been neglected in the advancement of FPM. In this Letter, we rederive a linear-space-variant (LSV) model for FPM and design the corresponding loss function for FPM, termed LSV-FPM. Utilizing LSV-FPM for optimization enables the efficient removal of wrinkle artifacts caused by vignetting in the reconstruction results, without the need of segmenting or discarding images. The effectiveness of LSV-FPM is validated through data acquired in both 4f and finite conjugate single-lens systems.

Transarterial Chemoembolization Combined with Lenvatinib for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The treatment of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) and lenvatinib individually has shown favorable outcomes, but there is currently no meta-analysis based on randomized controlled trials (RCTs) to investigate the efficacy and safety of this combined treatment for HCC. The aim of this study was to identify the efficacy and safety of TACE plus lenvatinib for the treatment of HCC. METHODS: A systematic search of MEDLINE (via PubMed), the Cochrane Library, EMBASE, and the Web of Science was conducted on July 31, 2023. RCTs evaluating the efficacy and safety of TACE in combination with lenvatinib for the treatment of HCC were included. The risk of bias in the included studies was assessed using the Risk of Bias 2 tool. Outcome measures such as objective response rate (ORR), complete remission (CR), progression-free survival (PFS), overall survival (OS), and safety parameters were extracted from the included studies. Binary outcomes were analyzed using odds ratio (OR), risk ratio, or hazard ratio (HR), while continuous variables were analyzed using mean difference (MD) or standardized MD in RStudio. The quality of the evidence was graded using the GRADE approach. Heterogeneity was considered significant when the I-squared was 50% or less. RESULTS: Five RCTs involving 638 patients were included. The meta-analysis revealed that patients in the TACE plus lenvatinib group had a significantly higher mean ORR compared to the control group (OR: 3.65, 95% confidence interval [CI]: 2.50-5.32, fixed-effects model; OR: 3.58, 95% CI: 2.45-5.24, random-effects model, I2 = 0, moderate quality). Specifically, 40.9% of patients in the TACE plus lenvatinib group achieved a PR, which was significantly higher than the control group (OR: 3.51, 95% CI: 2.41-5.13, fixed-effects model; OR: 3.46, 95% CI: 2.36-5.07, random-effects model, I2 = 0, moderate quality). The HR for OS was 0.47 (95% CI: 0.35-0.62, fixed-effects model and random-effects model, I2 = 0, moderate quality). The meta-analysis revealed that the TACE plus lenvatinib group had a significantly higher total adverse effects rate than the control group (OR: 1.86, 95% CI: 1.01-3.43, fixed-effects model; OR: 1.85, 95% CI: 1.00-3.43, random-effects model, I2 = 0, moderate quality). CONCLUSION: Our study suggests that the combination of TACE and lenvatinib in the treatment of HCC has shown promising results, with extended OS and improved ORR.

Ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension mediated by neural precursor cell-expressed developmentally down-regulated gene 4-Like.

OBJECTIVES: In this study, we investigated whether neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L) is the E3 enzyme of angiotensin-converting enzyme 2 (ACE2) and whether NEDD4L degrades ACE2 via ubiquitination, leading to the progression of pulmonary arterial hypertension (PAH). METHODS: Bioinformatic analyses were used to explore the E3 ligase that ubiquitinates ACE2. Cultured pulmonary arterial smooth muscle cells (PASMCs) and specimens from patients with PAH were used to investigate the crosstalk between NEDD4L and ACE2 and its ubiquitination in the context of PAH. RESULTS: The inhibition of ubiquitination attenuated hypoxia-induced proliferation of PASMCs. The levels of NEDD4L were increased, and those of ACE2 were decreased in lung tissues from patients with PAH and in PASMCs. NEDD4L, the E3 ligase of ACE2, inhibited the expression of ACE2 in PASMCs, possibly through ubiquitination-mediated degradation. PAH was associated with upregulation of NEDD4L expression and downregulation of ACE2 expression. CONCLUSIONS: NEDD4L, the E3 ubiquitination enzyme of ACE2, promotes the proliferation of PASMCs, ultimately leading to PAH.

Perioperative outcomes and continence following robotic-assisted radical cystectomy with mainz pouch II urinary diversion in patients with bladder cancer.

PURPOSE: To present the widely unknown perioperative outcomes and continence status of bladder cancer patients following robotic-assisted radical cystectomy (RARC) with Mainz pouch II urinary diversion (UD). MATERIALS AND METHODS: From November 2020 to December 2023, 37 bladder cancer patients who underwent RARC with Mainz pouch II UD were retrospectively assessed (ChiCTR2300070279). The results, which included patient demographics, perioperative data, continence, and complications (early ≤ 30 days and late ≤ 30 days) were reported using the RC-pentafecta criteria. RC-pentafecta criteria included ≥ 16 lymph nodes removed, negative soft tissue surgical margins, absence of major (Grade III-IV) complication at 90 days, absence of clinical recurrence at ≤ 12 months, and absence of long-term UD-related sequelae. A numeric rating scale assessed patient satisfaction with urinary continence 30 days after surgery. The validated Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire was used to evaluate bowel function. The Kaplan-Meier curve was used to evaluate overall survival (OS). RESULTS: Of the 37 patients evaluated over a median (range) follow-up period of 23.0 (12.0-36.5) months. The median (range) age was 65 (40-81) years. The median (range) time to urinary continence after surgery was 2.3 (1.5-6) months. Of the 37 patients, 31 (83.8%) were continent both during the day and at night, 34 (91.9%) were continent during the day, 32 (86.5%) were continent at night, 35 (94.6%) were satisfied with their urinary continence status, and 21 (56.8%) were very satisfied. The mean (range) voiding frequency was 6 (4-10) during the day and 3 (2-5.5) at night. The mean (range) PAC-SYM total score was 9.50 (4.00-15.00). In 12 (32.4%) of the patients, RC-pentafecta was achieved, and achieving RC-pentafecta was linked to better satisfaction scores (7.3 vs. 5.5, p = 0.034). There was no significant difference between RC-pentafecta and No RC-pentafecta groups in terms of OS (25.6 vs. 21.5 months, p = 0.16). 7 (19.4%) patients experienced late complications. CONCLUSIONS: Mainz pouch II UD following RARC in bladder cancer patients results in a satisfactory continence rate. Achieving RC-pentafecta was correlated with better satisfaction scores. The intracorporeal approach to Mainz pouch II UD is beneficial for female patients due to its reduced invasiveness. TRIAL REGISTRATION: ChiCTR2300070279; Registration: 07/04/2023, Last updated version: 01/06/2023. Retrospectively registered.

Risk factors of high fluid absorption in patients treated with mini-PCNL: a single-center prospective study.

BACKGROUND: The factors influencing fluid absorption in mini-percutaneous nephrolithotripsy (mini-PCNL) are still unknown. We aim to investigate the factors that influence irrigation fluid absorption during mini-PCNL. METHODS: A total of 94 patients who underwent mini-PCNL were included in this prospective study. The endoscopic surgical monitoring system (ESMS) was used to measure the volume of irrigation fluid absorbed during the procedure. Irrigating time, the total volume of irrigation fluid, stone size, S.T.O.N.E. score, hemoglobin, electrolyte levels, and postoperative complications were recorded. RESULTS: A significant correlation was observed between fluid absorption and the presence of postoperative fever, and based on this phenomenon, patients were divided into low and high fluid absorption groups. The serum creatinine level in the high fluid absorption group was significantly high (7 vs. 16.5, p = 0.02). Significant differences were observed between the low and high fluid absorption groups in terms of mean stone size (21.70 mm vs. 26.78 mm), presence of stone burden ≥ 800 mm2 (4% vs. 23%), S.T.O.N.E. score > 8 (4% vs. 38%), the fluid used > 18,596 ml (19% vs. 78%), irrigation time (55.61 min vs. 91.28 min), and perfusion rate (24% vs. 45%) (all p < 0.05). The rates of postoperative fever and SIRS in the high fluid absorption group were significantly high (p < 0.05). CONCLUSIONS: Mean stone size, presence of stone burden ≥ 800 mm2, S.T.O.N.E. score > 8, the fluid used > 18596 mL, irrigation time, and perfusion rate are risk factors of intraoperative fluid absorption in mini-PCNL.

Hypoxia-induced factor-1α promotes radioresistance of esophageal cancer cells by transcriptionally activating LINC01116 and suppressing miR-3612 under hypoxia.

Esophageal cancer (EC) is a challenging tumor to treat with radiotherapy, often exhibiting resistance to this treatment modality. To explore the factors influencing radioresistance, we focused on the role of hypoxia-induced factor-1α (HIF-1α), and its interaction with the long noncoding RNA long intergenic nonprotein coding RNA 1116 (LINC01116). We analyzed the LINC01116 expression in EC and EC cell lines/human normal esophageal epithelial cell line (Het-1A). LINC01116 was silenced/overexpressed in EC109/KYSE30 cells under hypoxia, followed by radioresistance assessment. We measured HIF-1α levels in hypoxic EC cells and further validated the binding of HIF-1α with LINC01116, analyzing their interaction in EC cells. We then performed experiments in EC109 cells by transfection them with sh-HIF-1α/oe-LINC01116 to verify the effects. Additonally, we analyzed the localization of LINC01116 and its binding with miR-3612, followed by a combined experiment performed to validate the results. Our findings indicated that LINC01116 was highly expressed in EC and further elevated in hypoxic EC cells. LINC01116 was expressed at a high level in EC, which was further elevated in EC cells under hypoxic conditions. Knockdown of LINC01116 triggered EC cell apoptosis, thus suppressing radioresistance. Further investigation revealed that HIF-1α transcriptionally activated LINC01116 expression under hypoxia, and silencing HIF-1α lowered EC cell radioresistance by downregulating LINC01116. Under hypoxic conditions, LINC01116 could function as a sponge for miR-3612 and inhibit its expression. This interaction between LINC01116 and miR-3612 played a crucial role in mediating radioresistance in EC cells. Briefly, under hypoxic conditions, HIF-1α facilitates radioresistance of EC cells by transcriptionally activating LINC01116 expression and downregulating miR-3612.

FL118: A potential bladder cancer therapeutic compound targeting H2A.X identified through library screening.

The treatment of bladder cancer is limited by low drug efficacy and drug resistance. Hence, this study aimed to screen and identify potential drug precursors and investigate their mechanism of action. A set of camptothecin derivatives showing high anti-tumor potential was selected from early-stage research or literature and synthesized to construct a compound library. A total of 135 compounds were screened in T24 and J82 cells, revealing that FL118 significantly inhibited the proliferation of GC (gemcitabine + cisplatin)-sensitive/insensitive cells. FL118 exhibited excellent penetration and killing ability in organoids and three GC-insensitive patient-derived xenografts. Chemical proteomic and docking calculations were employed to identify binding proteins, indicating that FL118 can bind into H2A.X and its entwined DNA. The results of Cellular thermal shift assay and surface plasmon resonance (Kd = 3.77E-6) support the above findings. Fluorescence localization revealed widespread binding of FL118 within the cell nucleus. Furthermore, WB showed that FL118 increased cellular DNA damage, resulting in significant cell cycle inhibition. The binding of FL118 to H2A.X hindered the damage repair process, leading to apoptosis. Controllable adverse reactions were observed in mice treated with FL118. In conclusion, FL118 may be a superior anti-bladder cancer compound that acts as a molecular glue binding to both H2A.X and DNA. The resistance mediated by the DNA damage repair to DNA damage caused by GC regimen can be reversed by FL118. This distinct mechanism of FL118 has the potential to complement existing mainstream treatment approaches for bladder cancer.

A large population-based and validated study on the follow-up management and supportive strategy of locally advanced rectal cancer patients.

OBJECTIVE: Our objective was to evaluate the predictive factors and metastatic time for liver and lung metastasis in locally advanced rectal cancer (RC) patients. METHODS: Univariate and multivariate analysis were performed to identify risk factors and prognostic factors for liver metastasis and lung metastasis in RC. Survival probabilities were calculated using the Kaplan-Meier model and compared using the log-rank test between groups. The probability of time-to-event occurrence was calculated using the random survival forest model. Finally, the SEER database was used to verify our findings. RESULTS: Our results indicated that pathological T stage and pathological N stage were independent predictive factors for liver metastasis. Furthermore, CEA level, pathological T stage, and tumor deposit were independent predictive factors for lung metastasis. Based on the results of a multivariate Cox analysis, we categorized patients with liver and lung metastasis into three groups based on their scores. The results revealed that patients with higher scores had a higher probability of experiencing metastasis. For liver metastasis, Groups 1, 2, and 3 all exhibited higher occurrence rates within the first 24 months. However, for lung metastasis, Group 4 showed the highest occurrence rate at the 12th month, while Groups 5 and 6 exhibited the highest occurrence rates at the 15th month. CONCLUSIONS: In summary, we developed predictive models to determine the likelihood of liver and lung metastasis in RC patients. It is crucial to implement a more intensive surveillance program for patients with unfavorable risk profiles in order to facilitate early detection of metastasis.

The ZSWIM8 ubiquitin ligase regulates neurodevelopment by guarding the protein quality of intrinsically disordered Dab1.

Protein quality control (PQC) is essential for maintaining protein homeostasis and guarding the accuracy of neurodevelopment. Previously, we found that a conserved EBAX-type CRL regulates the protein quality of SAX-3/ROBO guidance receptors in Caenorhabditis elegans. Here, we report that ZSWIM8, the mammalian homolog of EBAX-1, is essential for developmental stability of mammalian brains. Conditional deletion of Zswim8 in the embryonic nervous system causes global cellular stress, partial perinatal lethality and defective migration of neural progenitor cells. CRISPR-mediated knockout of ZSWIM8 impairs spine formation and synaptogenesis in hippocampal neurons. Mechanistic studies reveal that ZSWIM8 controls protein quality of Disabled 1 (Dab1), a key signal molecule for brain development, thus protecting the signaling strength of Dab1. As a ubiquitin ligase enriched with intrinsically disordered regions (IDRs), ZSWIM8 specifically recognizes IDRs of Dab1 through a "disorder targets misorder" mechanism and eliminates misfolded Dab1 that cannot be properly phosphorylated. Adult survivors of ZSWIM8 CKO show permanent hippocampal abnormality and display severely impaired learning and memory behaviors. Altogether, our results demonstrate that ZSWIM8-mediated PQC is critical for the stability of mammalian brain development.

Family intimacy and adaptability and non-suicidal self-injury: a mediation analysis.

BACKGROUND: Current research has been focusing on non-suicidal self-injury (NSSI) behaviors among adolescents with depression. Although family intimacy and adaptability are considered protective factors for NSSI, evidence supporting this relationship is lacking. OBJECTIVE: This study aims to examine the mechanisms operating in the relationship between family intimacy and adaptability and NSSI behaviors among adolescents. METHODS: A self-administered general demographic information questionnaire, the Behavioral Functional Assessment Scale for Non-Suicidal Self-Injury, the Family Intimacy and Adaptability Scale, the Connor-Davidson Resilience Scale, and the Self-Assessment of Depression Scale were distributed among adolescents with depression in three tertiary hospitals in Jiangsu Province. RESULTS: The relationship between family intimacy and adaptability and NSSI was assessed among 596 adolescents with depression. The results revealed the following: (1) Family intimacy and adaptability were negatively correlated with NSSI behavior. (2) Psychological resilience and depression levels acted as chain mediators in the relationship between family intimacy and adaptability and NSSI behavior. CONCLUSIONS: Enhancing psychological resilience, controlling depressive symptoms, and reducing depression severity among adolescents by improving their family intimacy and adaptability are conducive to preventing and mitigating their NSSI behaviors.

Transperitoneal vs retroperitoneal laparoscopic radical nephrectomy: a double-arm, parallel-group randomized clinical trial.

OBJECTIVE: To compare the outcomes of patients undergoing Retroperitoneal laparoscopic Radical nephrectomy (RLRN) and Transperitoneal laparoscopic Radical nephrectomy (TLRN). METHODS: A total of 120 patients with localized renal cell carcinoma were randomized into either RLRN or TLRN group. Mainly by comparing the patient perioperative related data, surgical specimen integrity, pathological results and tumor results. RESULTS: Each group comprised 60 patients. The two group were equivalent in terms of perioperative and pathological outcomes. The mean integrity score was significantly lower in the RLRN group than TLRN group. With a median follow-up of 36.4 months after the operation, Kaplan-Meier survival analysis showed no significant difference between RLRN and TLRN in overall survival (89.8% vs. 88.5%; P = 0.898), recurrence-free survival (77.9% vs. 87.7%; P = 0.180), and cancer-specific survival (91.4% vs. 98.3%; P = 0.153). In clinical T2 subgroup, the recurrence rate and recurrence-free survival in the RLRN group was significantly worse than that in the TLRN group (43.2% vs. 76.7%, P = 0.046). Univariate and multivariate COX regression analysis showed that RLRN (HR: 3.35; 95%CI: 1.12-10.03; P = 0.030), male (HR: 4.01; 95%CI: 1.07-14.99; P = 0.039) and tumor size (HR: 1.23; 95%CI: 1.01-1.51; P = 0.042) were independent risk factor for recurrence-free survival. CONCLUSIONS: Our study showed that although RLRN versus TLRN had roughly similar efficacy, TLRN outperformed RLRN in terms of surgical specimen integrity. TLRN was also significantly better than RLRN in controlling tumor recurrence for clinical T2 and above cases. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( https://www.chictr.org.cn/showproj.html?proj=24400 ), identifier: ChiCTR1800014431, date: 13/01/2018.

Effects of oral carbohydrate loading in patients scheduled for painless bidirectional endoscopy: a prospective randomized controlled trial.

PURPOSE: Traditional fasting causes considerable discomfort without added assurance of security, whereas oral carbohydrate beverage offers an alternative to improve medical experience. This study aims to explore the impact of different types and dosages of oral fluids loading before painless bidirectional endoscopy on the gastric emptying and wellbeing. METHODS: 180 patients arranged for bidirectional endoscopy with intravenous anesthesia were randomized: patients in the control group (Group C) obeyed standard fasting; the 200 mL carbohydrate group (Group P1), 400 mL carbohydrate group (Group P2), 200 mL water group (Group W1) and 400 mL water group (Group W2) respectively consumed 200 mL or 400 mL corresponding clear liquids 2 h before the procedure. Gastric emptying metrics under ultrasound, subjective comfort indexes, periprocedural blood glucose and vital signs were contrasted among the groups. RESULTS: No significant differences were detected in the gastric emptying including CSA (cross-sectional area), GV (gastric volume), cGV (corrected gastric volume) and the three-point grading system among groups, and none had a cGV > 1.5 mL/kg before anesthesia. Participants in Group P2 experienced less preprocedural thirst and mouth dryness, so as the postprocedural thirst, mouth dryness and hunger. Periprocedural blood glucose and MAP had the similar trend in all groups. The occurrence of hypotension, bradycardia, hypoxia, and the required norepinephrine was comparable among the groups. CONCLUSIONS: Oral beverage loading with 200 mL or 400 mL can be safely applicated 2 h before painless bidirectional endoscopy without increasing the gastric volume. 400 mL carbohydrate solution effectively relieves the discomfort and could serve as a consideration. TRIAL REGISTRATION: Registered in the Chinese Clinical Trial Registry on December 5, 2023 (ChiCTR2300078319).