Functional connectivity compensation in Parkinson's disease with freezing of gait.

Freezing of gait (FOG) is a disabling motor symptom prevalent in patients with Parkinson's disease (PD); however, its pathophysiological mechanisms are poorly understood. This study aimed to investigate whole-brain functional connectivity (FC) pattern alterations in PD patients with FOG. A total of 18 PD patients, 10 with FOG (PD-FOG) and 8 without FOG (PD-nFOG), and 10 healthy controls were enrolled. High-resolution 3D T1-weighted and resting-state functional MRI (rs-fMRI) data were obtained from all participants. The groups' internetwork connectivity differences were explored with rs-fMRI FC using seed-based analysis and graph theory. Multiple linear regression analysis estimated the relationship between FC changes and clinical measurements. Rs-fMRI analysis demonstrated alterations in FC in various brain regions between the three groups. Freezing of Gait Questionnaire severity was correlated with decreased brain functional connection between Vermis12 and the left temporal occipital fusiform cortex (r = -0.82, P < .001). Graph theory topological metrics indicated a decreased clustering coefficient in the right superior temporal gyrus in the PD-nFOG group. PD-FOG patients exhibited a compensatory increase in connectivity between the left inferior frontal gyrus language network and the postcentral gyrus compared to PD-nFOG patients. Further, the decreased connection between Vermis 12 and the left temporal occipital fusiform cortex may serve as a potential neuroimaging biomarker for tracking PD-FOG and distinguishing between PD subtypes.

Taiwan Nationwide Study of First-Line ALK-TKI Therapy in ALK-Positive Lung Adenocarcinoma.

BACKGROUND: The clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data. OBJECTIVE: In this study, we aimed to investigate the treatment discontinuation (TTD) and overall survival (OS) of patients with ALK+ advanced lung adenocarcinoma treated with first-line ALK-TKIs in Taiwan. PATIENTS AND METHODS: This retrospective study evaluated all advanced lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2020 who had ALK rearrangement and received ALK-TKI treatment, using data from Taiwan's National Health Insurance Research Database (NHIRD). The TKI treatment sequences were classified into first generation (G1: crizotinib), second generation (G2: ceritinib, alectinib, brigatinib), and third generation (G3: lorlatinib). RESULTS: A total of 587 patients were analyzed, with a median age of 60.0 years, 91 (15.5%) aged ≥ 74 years, 293 (49.9%) female, 397 (67.6%) never smoked, and 534 (91.0%) with stage IV disease. Patients who received next-generation ALK-TKIs during the treatment course had longer median time to ALK-TKI TTD and OS. The TTD of the G1, G1+2, G1+2+3, G2, and G2+3 groups was 7.5 (5.4-11.1), 40.6 (29.4-not calculated (NC)), 50.3 (41.3-NC), 34.3 (29.2-43.0), and 36.3 (22.4-NC) months, respectively (p < 0.001). The median OS of the patients in the G1, G1+2, G1+2+3, G2, and G2+3 groups was 10.6 (7.5-14.6), not reached (NR) (NC-NC), NR (NC-NC), 43.0 (36.3-NC), and NR (30.3-NC) months, respectively (p < 0.001). Compared with treatment with crizotinib alone, the multivariate analysis revealed that treatment with next-generation TKIs was independently associated with longer TTD (G1+2 (hazard ratio (HR), 0.24; 95% CI 0.17-0.33; p < 0.001), G1+2+3 or G1+3 (HR, 0.17; 95% confidence interval (CI), 0.10-0.28; p < 0.001), G2 (HR, 0.26; 95% CI 0.19-0.36; p < 0.001), and G2+3 (HR, 0.25; 95% CI 0.14-0.44; p < 0.001)) and median OS (G12 (HR, 0.24; 95% CI 0.17-0.35; p < 0.001), G1+2+3 or G1+3 (HR, 0.09; 95% CI 0.04-0.21; p < 0.001), G2 (HR, 0.22; 95% CI 0.15-0.31; p < 0.001), and G2+3 (HR, 0.20; 95% CI 0.10-0.42; p < 0.001)). CONCLUSIONS: For patients with ALK+ NSCLC, treatments including next-generation ALK-TKIs were independently associated with longer survival outcomes.

Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.

Actin is a critical component of the eukaryotic cytoskeleton. In animals, actins undergo unique N-terminal processing by dedicated enzymes resulting in mature acidic and acetylated forms. The final step, N-terminal acetylation, is catalyzed by NAA80 in humans. N-terminal acetylation of actin is crucial for maintaining normal cytoskeletal dynamics and cell motility in human cell lines. However, the physiological impact of actin N-terminal acetylation remains to be fully understood. We developed a zebrafish naa80 knockout model and demonstrated that Naa80 acetylates both muscle and non-muscle actins in vivo. Assays with purified Naa80 revealed a preference for acetylating actin N-termini. Zebrafish lacking actin N-terminal acetylation exhibited normal development, morphology, and behavior. In contrast, humans with pathogenic actin variants can present with hypotonia and hearing impairment. Whereas zebrafish lacking naa80 showed no obvious muscle defects or abnormalities, we observed abnormal inner ear development, small otoliths, and impaired response to sound. In conclusion, we have established that zebrafish Naa80 N-terminally acetylates actins in vitro and in vivo, and that actin N-terminal acetylation is essential for normal hearing.

Integrated metabolomic and microbiome analysis identifies Cupriavidus metallidurans as a potential therapeutic target for ß-thalassemia.

ß-thalassemia(ß-TH) is an inherited hemoglobin disorder marked by ineffective erythropoiesis, anemia, splenomegaly, and systemic iron overload, predominantly affecting developing countries in tropical and subtropical regions. Despite extensive research on its pathogenesis, the interactions between gut microbiota and metabolites in ß-TH remain poorly understood. This study compares fecal metabolomics and metagenomics between wildtype (Wt) and heterozygous Th3/+ mice, a model for non-transfusion-dependent ß-thalassemia intermedia. Our results show increased intestinal bilirubin metabolism, with significant elevations in metabolites such as biliverdin, bilirubin, and stercobilin. Metagenomic analysis revealed notable differences in bacterial composition between Th3/+ and Wt mice. Specifically, Cupriavidus metallidurans was identified as a key bacterium that mitigates anemia by reducing liver and spleen iron deposition. This is the first study to ameliorate anemia in mice by altering gut microbiota, presenting new strategies for ß-TH management.

The efficacy of mobile applications for reducing depression in adolescents and young adults: A meta-analysis of randomized control trials.

BACKGROUND: Mobile applications for mental health have the potential to aid people with mental health disorders, especially depression, by providing them with tools and coping mechanisms. Adolescents and young adults, being at risk of depressive symptoms and leading mobile users, are among the main targets of using mobile applications to alleviate symptoms. OBJECTIVE: This study aimed to evaluate the impact of mobile application-based psychological interventions in reducing depression symptoms in adolescents and young adults compared to those not exposed to the intervention. METHODS: We conducted a meta-analysis focusing on mobile applications for reducing depressive symptoms. We searched two databases: MEDLINE and EMBASE and included randomized controlled trials conducted in English among participants aged 18-35 years old who were assessed for depressive symptoms using a validated screening measure and used mobile applications-based psychological interventions. Two of six independent reviewers conducted study selection, data extraction, and bias assessment. A pooled mean standardized difference (Cohen's d) and 95% CI were calculated using random-effects meta-analysis. Risk of bias was assessed using I2 statistics and forest plot. Egger's test was used for assessing publication bias. RESULTS: After screening 740 references, we identified 12 trials with 1869 participants, with a mean age of participants ranging from 14.70 to 25.1 years. The interventions ranged from cognitive behavioral therapy (CBT)-based mobile apps to interactive story-telling apps and apps delivering a mix of CBT, interpersonal psychotherapy for adolescents, and dialectical behavior therapy elements. Control groups included information-only, waitlist, no intervention, and treatment as usual. Seven studies used Patient Health Questionnaire-9 (PHQ-9) to assess the severity of depressive symptoms, while the other five used different scales. There was no evidence of publication bias (p = 0.325). The mobile applications reduced depression score by 0.08 units of standardized difference more than the control, with a 95% CI of -0.19 to 0.03 (p = 0.294, I2 = 15.4%) using standardized mean difference (SMD) as the effect estimate. In a sensitivity analysis including only studies that used PHQ-9, we found a similar trend, SMD -0.72 (95%CI -1.48 to 0.03). However, both findings were not significant. CONCLUSIONS: Current evidence is insufficient to support mobile applications to relieve depression symptoms in adolescents and young adults. Further trials with larger sample size are needed to confirm our findings of a positive trend. With emerging technologies and the high exposure of apps in this population, mobile applications for depression hold promise for the future of treatment and awareness of mental health disorders in this population.

Allosteric regulation of Keap1 by 8ß-hydroxy-α-cyclocostunolide for the treatment of acute lung injury.

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Physicochemical, Antioxidant, Starch Digestibility, and Sensory Properties of Wheat Bread Fortified with Taiwanese Cocoa Bean Shells.

The effects of replacing 5-25% of wheat flour (WF) with Taiwanese cocoa bean shells (CBSs) on the physicochemical, antioxidant, starch digestion, and sensory properties of the bread were studied. The lead (0.18) and cadmium (0.77) contents (mg/kg) of the CBSs were below the Codex Alimentarius specifications for cocoa powder. Ochratoxin A and aflatoxins (B1, B2, G1, and G2) were not detected in the CBSs. The CBSs were rich in dietary fiber (42.9%) and bioactive components and showed good antioxidant capacity. The ash, fat, protein, dietary fiber, crumb a* and c*, hardness, chewiness, total phenols, and antioxidant activities of the bread increased with an increasing CBSs level. The starch hydrolysis rate (45.1-36.49%) of the CBS breads at 180 min was lower than that of the control (49.6%). The predicted glycemic index of the bread (CBS20 and CBS25) with 20-25% of the WF replaced with CBSs was classified as a medium-GI food using white bread as a reference. In the nine-point hedonic test, the overall preference scores were highest for control (6.8) and CBS breads, where CBSs replaced 5-10% of WF, with scores of 7.2 and 6.7. CBS20 supplemented with an additional 20-30% water improved its volume, specific volume, and staling rate, but the overall liking score (6.5-7.2) was not significantly different from the control (p > 0.05). Overall, partially replacing wheat flour with CBSs in the production of baked bread can result in a new medium-GI value food containing more dietary fiber, bioactive compounds, and enhanced antioxidant capacity.

Mouth-controlled mouse for quadriplegic disabled people: System design and validation.

Disabled people with a high cervical cord injury or quadriplegia face difficulties when controlling a computer. This study presents a digital mouth-controlled mouse-control aid called the bite-press mouth-controlled mouse (BPMCM) to replace the traditional computer mouse. The BPMCM is equipped with a joystick and micro switch, and the disabled person uses neck and head movements to push the joystick and control the cursor position while the three mouse functions (i.e., left-click, right-click, and drag) are activated by bite-pressing for different time intervals. The proposed design eliminates the sip-and-puff technique and the need to recite orders for reduced adaptation time and increased convenience. Furthermore, this design supports plug-and-play and hot plugging in modern mainstream operating systems that can often be directly operated via mouse functions. Experimental results demonstrated that disabled people using a BPMCM were as capable as healthy participants in operating a computer, with both experiments completed within 5 min, and voluntary disabled people immediately adapted to the BPMCM. The proposed design is expected to allow disabled people to operate computers at the same level as healthy participants. The BPMCM also required only half the physical exertion of other mouth-controlled mouse-control aids that require orders to be recited.

Fe-S dually modulated adsorbate evolution and lattice oxygen compatible mechanism for water oxidation.

Simultaneously activating metal and lattice oxygen sites to construct a compatible multi-mechanism catalysis is expected for the oxygen evolution reaction (OER) by providing highly available active sites and mediate catalytic activity/stability, but significant challenges remain. Herein, Fe and S dually modulated NiFe oxyhydroxide (R-NiFeOOH@SO4) is conceived by complete reconstruction of NiMoO4·xH2O@Fe,S during OER, and achieves compatible adsorbate evolution mechanism and lattice oxygen oxidation mechanism with simultaneously optimized metal/oxygen sites, as substantiated by in situ spectroscopy/mass spectrometry and chemical probe. Further theoretical analyses reveal that Fe promotes the OER kinetics under adsorbate evolution mechanism, while S excites the lattice oxygen activity under lattice oxygen oxidation mechanism, featuring upshifted O 2p band centers, enlarged d-d Coulomb interaction, weakened metal-oxygen bond and optimized intermediate adsorption free energy. Benefiting from the compatible multi-mechanism, R-NiFeOOH@SO4 only requires overpotentials of 251 ± 5/291 ± 1 mV to drive current densities of 100/500 mA cm-2 in alkaline media, with robust stability for over 300 h. This work provides insights in understanding the OER mechanism to better design high-performance OER catalysts.

Prognostic Implications of Unexpected Positive Intraoperative Cultures in Two-Stage Knee Arthroplasty Reimplantations: A Minimum Five-Year Retrospective Analysis.

BACKGROUND: The clinical challenge of unexpected positive intraoperative cultures (UPICs) persists in 2-stage resection arthroplasty for managing periprosthetic joint infections (PJIs) following total knee arthroplasty.(TKA). This study aimed to investigate the incidence of UPICs during the definitive reimplantation phase of 2-stage resection arthroplasty of the knee and to assess both the infection-free and revision-free survivorship of the implanted prosthesis. METHODS: This retrospective study included 450 2-stage resection arthroplasties of primary knee prostheses performed between January 2012 and April 2017. Patients were excluded if they: (1) underwent three or more staged resections, (2) had ambiguous clinical documentation or deviated from the 2-stage protocol, or (3) underwent revision arthroplasty prior to the PJI. Additionally, patients presumed aseptic before the second-stage reimplantation were excluded if they lacked joint aspiration or met the 2011 Musculoskeletal Infection Society criteria for PJI before implantation. RESULTS: After exclusions, 300 patients were analyzed. Among them, 14% had UPIC during the second-stage reimplantation. The follow-up time was 2,316 (range, 1,888 to 3,737) days and 2,531 (range, 1,947 to 3,349) days for UPIC and negative intraoperative culture (NIC) groups, respectively. Rerevision due to subsequent PJI occurred in 26.2% of UPIC patients and 15.1% of NIC patients. The 2-year infection-free survival rates for the NIC, one UPIC, and ≥ two UPIC cohorts were 99.5, 98.2, and 94.3%, respectively, while the 5-year survival rates were 92.1, 91.1, and 54.3%, respectively. The unfavorable survivorship was significantly different in multiple UPIC cases (P < 0.001). Multiple UPICs with pathogens consistent with the first-stage findings were strongly associated with the risk of reinfection (P < 0.001). CONCLUSIONS: An UPIC was identified in 14% of second-stage reimplantations. Patients who had multiple UPICs demonstrated truncated survivorship and suboptimal outcomes relative to the NIC and single UPIC cohorts, especially with pathogen consistency to the first-stage surgery. LEVEL OF EVIDENCE: III.

High-performance electrochemical immunosensor based on bimetallic gold/silver functionalized carbon spheres for CYFRA 21-1 detection and information protection.

Bimetallic nanomaterial-based systems have been widely utilized across various fields due to their remarkable expandability and flexibility, including nanomedicine, diagnostics, and molecular information technology. Here, we constructed an electrochemical immunosensor using bimetallic gold/silver functionalized carbon spheres (AuAg@CSs) and mesoporous silica nanoparticles (MSNs) for the sensitive determination of cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1) and ensuring information protection for textual data. The AuAg@CSs demonstrated exceptional catalytic activity towards hydrogen peroxide, generating a significant current signal. The introduction of CYFRA 21-1 facilitated the binding of MSNs, thereby forming a sandwich-type electrochemical immunosensor that resulted in a notable decrease in current. Notably, the detection limit for CYFRA 21-1 was determined to be 31 fg mL-1, accompanied by high selectivity. Furthermore, extensive textual information can be encrypted and concealed within the current responses of the electrochemical nanosensing system. By establishing a threshold, these current signals can be represented as a series of binary strings, which can subsequently be segmented into shorter strings. Through information coding methods, these shorter binary strings can be assembled and decrypted, ultimately merging into meaningful textual content. This study promotes the synthesis and multifunctional application of bimetallic nanomaterials, providing innovative solutions to enhance the sensing sensitivity of electrochemical immunosensors and paving the way for advancements in molecular digitization.

Association between Exposure of Rare Earth Elements and Outcomes of In Vitro Fertilization-Embryo Transfer in Beijing.

Objective: The study aimed to investigate the impact of rare earth elements (REEs) exposure on pregnancy outcomes of in vitro fertilization-embryo transfer (IVF-ET) by analyzing samples from spouses. Methods: A total of 141 couples were included. Blood and follicular fluid from the wives and semen plasma from the husbands, were analyzed for REEs using inductively coupled plasma mass spectrometry (ICP-MS). Spearman's correlation coefficients and the Mann-Whitney U test were used to assess correlations and compare REE concentrations among three types of samples, respectively. Logistic models were utilized to estimate the individual REE effect on IVF-ET outcomes, while BKMR and WQS models explored the mixture of REE interaction effects on IVF-ET outcomes. Results: Higher La concentration in semen (median 0.089 ng/mL, P = 0.03) was associated with a lower fertilization rate. However, this effect was not observed after artificial selection intervention through intracytoplasmic sperm injection (ICSI) ( P = 0.27). In semen, the REEs mixture did not exhibit any significant association with clinical pregnancy. Conclusion: Our study revealed a potential association between high La exposure in semen and a decline in fertilization rate, but not clinical pregnancy rate. This is the first to report REEs concentrations in follicular fluid with La, Ce, Pr, and Nd found at significantly lower concentrations than in serum, suggesting that these four REEs may not accumulate in the female reproductive system. However, at the current exposure levels, mixed REEs exposure did not exhibit reproductive toxicity.

Alternation of psychological resilience may moderate mentalization toward mental health conditions from macro- and microstructure aspects.

OBJECTIVE: We aim to investigate the interplay between mentalization, brain microstructure, and psychological resilience as potential protective factors against mental illness. METHOD: Four hundred and twenty-six participants (mean age 40.12±16.95; 202 males, 224 females), without psychiatric or neurological history, completed assessments: Dissociative Process Scale (DPS), Peace of Mind (PoM), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Resilience Scale for Adults (RSA), and Magnetic Resonance Imaging (MRI) structures with selected regions of interest, and Diffusion Tensor Imaging (DTI) maps from various tracts in the right hemisphere and connection to the frontal areas, including anterior thalamic radiation (ATR), Cingulum (hippocampus) (CH), Corticospinal tract (CST), Superior longitudinal fasciculus (SLF), Inferior fronto-occipital fasciculus (IFOF), and Uncinate fasciculus (UF) were analyzed. RESULTS: Two clusters, representing hypomentalization (HypoM) and hypermentalization (HyperM), were identified based on DPS, CPSS, and RFQ responses. One-way ANOVA showed no significant age or gender differences between clusters. The HypoM group exhibited lower PoM scores, higher BDI and BAI scores, and lower RSA scores (ps< 0.05). Structural brain metric comparison showed significant differences in GMV in the right caudal middle frontal gyrus (rcMFG), right superior frontal gyrus (rsFG), and right frontal pole (rFP) between groups. In addition, the HyperM individuals with a higher risk of depression and a higher ratio of intrapersonal to interpersonal factors of resilience were found with reduced GMV on the rcMFG. Additionally, analyses of DTI metrics revealed significant differences between two groups in rATR and rSLF in terms of fractional anisotropy (FA) values; rATR, rCST, rUF, rSLF, rCH and rIFOF in terms of mean diffusivity (MD) values, and radial diffusivity (RD) (corrected p = 0.05). Moreover, the positive correlation between different domains of resilience and white matter (WM) integrity implied further enhancement of intrapersonal or interpersonal resilience factors that are different for people with different mentalization. CONCLUSIONS: The findings underscore the importance of considering both intrapersonal and interpersonal factors in understanding the interactions between psychological resilience and mental health conditions relevant to brain mechanisms.

Mitigation of PBDE net discharge in hazardous waste thermal treatment system through reintroducion of sludge and fly ash into GASMILD operations.

The presence of polybrominated diphenyl ethers (PBDEs) in consumer products, waste treatment processes, and treated ashes poses a significant environmental threat. Due to the lack of research on the removal of PBDEs during waste incineration, this study investigated the effectiveness of a Hazardous Waste Thermal Treatment System (HAWTTS) utilizing reburning of sludge and fly ash (SFA) with gasification-moderate or intense low-oxygen dilution (GASMILD) combustion for PBDE removal. The closed-loop treatment of sludge and ash within the HAWTTS provides a potential pathway for near-zero PBDE emissions. The GASMILD combustion addresses potential combustion issues associated with fly ash recirculation. The system achieved an impressive overall removal efficiency of 98.4% for PBDEs, with minimal stack emissions (2.45 ng/Nm³) and a negative net discharge rate (-1.02 µg/h). GASMILD combustion played a crucial role (92.7%-97.6% destruction) in addressing challenges associated with high-moisture feedstocks and SFA residues. Debromination of highly brominated PBDEs occurred within the incinerator, resulting in an increased proportion of lower brominated PBDEs in the bottom slag compared to the feedstock. Air Pollution Control Devices (APCDs) achieved a total PBDE removal efficiency of 74.4%. However, the hydrophobic nature of PBDEs limited removal efficiency in scrubbers (36.0%) and cyclonic demisters (37.86%). This study demonstrates that reintroducing SFA into the GASMILD combustion process offers an effective and environmentally sustainable strategy for reducing net PBDE levels in hazardous waste. This approach also provides additional benefits such as energy conservation, reduced carbon emissions, and lower operating costs associated with secondary treatment of thermally treated byproducts.

Mechanism of the impacts of older adults social participation on their health.

Purpose: Against the background of population aging challenges in China, focusing on health, security, and social participation as core elements of positive aging, this study aims to formulate strategies for promoting the health of the older adults and reveal the pathways and trends of social participation in promoting health. Method: The study analyzed 1,015 randomly selected older adults individuals living at home in Beijing using household survey questionnaires. Drawing on group dynamics theory and structural equation modeling, the study proposed hypotheses regarding the relationships between social participation, group cohesion, and health status. Results: First, the triangular path model of social participation, group cohesion, and health status among the older adults was established. The direct path coefficient of social participation on health status was 0.15, that of social participation on group cohesion was 0.56, and that of group cohesion on health status was 0.32. The indirect path coefficient of social participation on health status through group cohesion was calculated at 0.56 × 0.32 = 0.18. Second, of the older adults age groups-younger, middle, and older-social participation's direct path effects on health status were present only in the older age group. Social participation's indirect path effects on health status through group cohesion were relatively high in all three groups, with a slight increase in the older age group. Conclusion: First, just the older adults participation in social activities serves as a benign stimulus to physical and mental health. Additionally, group cohesion formed through interaction with others during social activities encourages self-improvement behaviors, indirectly promoting health. In fact, indirect pathways of health promotion through group cohesion are stronger than direct pathways, highlighting the importance of group cohesion during social participation. Second, participation in activities alone can provide only sufficient benign stimuli for the older adults aged 80 and above, with the direct path effect of social participation on health beginning to appear only with increasing age. With age, selectivity of interaction with others decreases, and dependence increases; social participation's indirect path effect on health through group cohesion continues to grow slightly.

Benzaldehyde stimulates autophagy via the sonic hedgehog signaling pathway in mouse brain astrocytes after treatment with Angiostrongylus cantonensis excretory-secretory products.

Autophagy is a vital cellular process responsible for digesting various cytoplasmic organelles. This process plays a crucial role in maintaining cell survival and homeostasis, especially under conditions that cause nutrient deficiency, cellular damage, and oxidative stress. Neuroangiostrongyliasis is an infection caused by the parasitic nematode Angiostrongylus cantonensis and is considered as an emerging disease in many parts of the world. However, effective therapeutic strategies for neuroangiostrongyliasis still need to be further developed. In this study, we investigated the effects of benzaldehyde treatment on autophagy and sonic hedgehog (Shh) signaling in A. cantonensis-infected mice and its mechanisms. First, we found autophagosome generation in the central nervous system after A. cantonensis infection. Next, benzaldehyde combined with albendazole treatment reduced eosinophilic meningitis and upregulated the expression of Shh signaling- and autophagy-related molecules in A. cantonensis-infected mouse brains. In vitro experiments demonstrated that benzaldehyde could induce autophagy via the Shh signaling pathway in A. cantonensis excretory-secretory products (ESPs)-treated mouse astrocytes. Finally, benzaldehyde treatment also decreased lipid droplet accumulation and increased cholesterol production by activating the Shh pathway after ESPs treatment. In conclusion, these findings suggested that benzaldehyde treatment could alleviate brain damage by stimulating autophagy generation through the Shh signaling pathway.

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.