Enhanced Cd2+ removal from aqueous solution using olivine and magnesite combination: New insights into the mechanochemical synergistic effect.

In this study, an efficient stabilizer material for cadmium (Cd2+) treatment was successfully prepared by simply co-milling olivine with magnesite. Several analytical methods including XRD, TEM, SEM and FTIR, combined with theoretical calculations (DFT), were used to investigate mechanochemical interfacial reaction between two minerals, and the reaction mechanism of Cd removal, with ion exchange between Cd2+ and Mg2+ as the main pathway. A fixation capacity of Cd2+ as high as 270.61 mg/g, much higher than that of the pristine minerals and even the individual/physical mixture of milled olivine and magnesite, has been obtained at optimized conditions, with a neutral pH value of the solution after treatment to allow its direct discharge. The as-proposed Mg-based stabilizer with various advantages such as cost benefits, green feature etc., will boosts the utilization efficiency of natural minerals over the elaborately prepared adsorbents.

Tailoring the Li+ Intercalation Energy of Carbon Nanocage Anodes Via Atomic Al-Doping for High-Performance Lithium-Ion Batteries.

Graphitic carbon materials are widely used in lithium-ion batteries (LIBs) due to their stability and high conductivity. However, graphite anodes have low specific capacity and degrade over time, limiting their application. To meet advanced energy storage needs, high-performance graphitic carbon materials are required. Enhancing the electrochemical performance of carbon materials can be achieved through boron and nitrogen doping and incorporating 3D structures such as carbon nanocages (CNCs). In this study, aluminum (Al) is introduced into CNC lattices via chemical vapor deposition (CVD). The hollow structure of CNCs enables fast electrolyte penetration. Density functional theory (DFT) calculations show that Al doping lowers the intercalation energy of Li+. The Al-boron (B)-nitrogen (N-doped CNC (AlBN-CNC) anode demonstrates an ultrahigh rate capacity (≈300 mAh g-1 at 10 A g-1) and a prolonged fast-charging lifespan (862.82 mAh g-1 at 5 A g-1 after 1000 cycles), surpassing the N-doped or BN-doped CNCs. Al doping improves charging kinetics and structural stability. Surprisingly, AlBN-CNCs exhibit increased capacity upon cycling due to enlarged graphitic interlayer spacing. Characterization of graphitic nanostructures confirms that Al doping effectively tailors and enhances their electrochemical properties, providing a new strategy for high-capacity, fast-charging graphitic carbon anode materials for next-generation LIBs.

Genome-Wide Identification of GH17s Family Genes and Biological Function Analysis of SlA6 in Tomato.

Glycoside hydrolases (GHs), enzymes that break down glycosidic bonds in carbohydrates and between carbohydrates and non-carbohydrates, are prevalent in plants, animals, microorganisms, and other organisms. The tomato is a significant crop that contains the GH17 gene family. However, its role in tomatoes has yet to be fully investigated. In this study, we identified 43 GH17 genes from the tomato genome, distributed unevenly across 12 chromosomes. We further analyzed their gene structure, phylogenetic relationships, promoter elements, and expression patterns. The promoter element analysis indicated their potential roles in response to biotic and abiotic stresses as well as phytohormone effects on growth and development. The expression studies across different tomato tissues revealed that 10 genes were specifically expressed in floral organs, with SlA6 prominently expressed early during bud formation. By using CRISPR/Cas9 gene-editing technology, SlA6 knockout plants were generated. Phenotypic characterization showed that pollen viability, pollen tube germination, fruit weight, and seed number were significantly reduced in the Sla6 mutant, but the soluble solids content (TSS) was significantly higher in the Sla6 mutant, suggesting that SlA6 affects pollen development and fruit quality.

Clear aligner treatment of an adult open bite with bilateral missing mandibular first molars through molar protraction with Albert cantilever arms.

Premature loss of first permanent molars is a common occurrence in clinical practice, leading to abnormal occlusion and inefficient mastication for patients. This case report presented the orthodontic retreatment of a 32-year-old female patient who suffered from premature loss of mandibular bilateral first molars. The mesial tipping of the mandibular second molars led to an occlusal interference, resulting in a clockwise rotation of the lower jaw and an anterior open bite (AOB). We achieved long-distance molar mesialization using clear aligners with Albert cantilever arms. After 42 months of treatment, the patient's occlusion and facial profile significantly improved. The cantilever combined with the cleat aligner treatment has been clinically effective for the protraction of mandibular posterior teeth, extending the field of application of clear aligners.

SlHB8 Is a Novel Factor in Enhancing Cold Resistance in Tomato Anthers by Modulating Tapetal Cell Death.

Tomato plants favor warmth, making them particularly susceptible to cold conditions, especially their reproductive development. Therefore, understanding how pollen reacts to cold stress is vital for selecting and improving cold-resistant tomato varieties. The programmed cell death (PCD) in the tapetum is particularly susceptible to cold temperatures which could hinder the degradation of the tapetal layer in the anthers, thus affecting pollen development. However, it is not clear yet how genes integral to tapetal degradation respond to cold stress. Here, we report that SlHB8, working upstream of the conserved genetic module DYT1-TDF1-AMS-MYB80, is crucial for regulating cold tolerance in tomato anthers. SlHB8 expression increases in the tapetum when exposed to low temperatures. CRISPR/Cas9-generated SlHB8-knockout mutants exhibit improved pollen cold tolerance due to the reduced temperature sensitivity of the tapetum. SlHB8 directly upregulates SlDYT1 and SlMYB80 by binding to their promoters. In normal anthers, cold treatment boosts SlHB8 levels, which then elevates the expression of genes like SlDYT1, SlTDF1, SlAMS, and SlMYB80; however, slhb8 mutants do not show this gene activation during cold stress, leading to a complete blockage of delayed tapetal programmed cell death (PCD). Furthermore, we found that SlHB8 can interact with both SlTDF1 and SlMYB80, suggesting the possibility that SlHB8 might regulate tapetal PCD at the protein level. This study sheds light on molecular mechanisms of anther adaptation to temperature fluctuations.

Robust fatigue markers obtained from muscle synergy analysis.

This study aimed to utilize the nonnegative matrix factorization (NNMF) algorithm for muscle synergy analysis, extracting synergy structures and muscle weightings and mining biomarkers reflecting changes in muscle fatigue from these synergy structures. A leg press exercise to induce fatigue was performed by 11 participants. Surface electromyography (sEMG) data from seven muscles, electrocardiography (ECG) data, Borg CR-10 scale scores, and the z-axis acceleration of the weight block were simultaneously collected. Three indices were derived from the synergy structures: activation phase difference, coactivation area, and coactivation time. The indicators were further validated for single-leg landing. Differences in heart rate (HR) and heart rate variability (HRV) were observed across different fatigue levels, with varying degrees of disparity. The median frequency (MDF) exhibited a consistent decline in the primary working muscle groups. Significant differences were noted in activation phase difference, coactivation area, and coactivation time before and after fatigue onset. Moreover, a significant correlation was found between the activation phase difference and the coactivation area with fatigue intensity. The further application of single-leg landing demonstrated the effectiveness of the coactivation area. These indices can serve as biomarkers reflecting simultaneous alterations in the central nervous system and muscle activity post-exertion.

Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma.

Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter's tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.

Genetics of causal relationships between circulating inflammatory proteins and postherpetic neuralgia: a bidirectional Mendelian randomization study.

Objective: According to data from several observational studies, there is a strong association between circulating inflammatory cytokines and postherpetic neuralgia (PHN), but it is not clear whether this association is causal or confounding; therefore, the main aim of the present study was to analyze whether circulating inflammatory proteins have a bidirectional relationship with PHN at the genetic inheritance level using a Mendelian randomization (MR) study. Methods: The Genome-Wide Association Study (GWAS) database was used for our analysis. We gathered data on inflammation-related genetic variation from three GWASs of human cytokines. These proteins included 91 circulating inflammatory proteins, tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein 1b (MIP-1b), and CXC chemokine 13 (CXCL13). The PHN dataset was obtained from the FinnGen biobank analysis round 5, and consisted of 1,413 cases and 275,212 controls. We conducted a two-sample bidirectional MR study using the TwoSampleMR and MRPRESSO R packages (version R.4.3.1). Our main analytical method was inverse variance weighting (IVW), and we performed sensitivity analyses to assess heterogeneity and pleiotropy, as well as the potential influence of individual SNPs, to validate our findings. Results: According to our forward analysis, five circulating inflammatory proteins were causally associated with the development of PHN: interleukin (IL)-18 was positively associated with PHN, and IL-13, fibroblast growth factor 19 (FGF-19), MIP-1b, and stem cell growth factor (SCF) showed reverse causality with PHN. Conversely, we found that PHN was closely associated with 12 inflammatory cytokines, but no significant correlation was found among the other inflammatory factors. Among them, only IL-18 had a bidirectional causal relationship with PHN. Conclusion: Our research advances the current understanding of the role of certain inflammatory biomarker pathways in the development of PHN. Additional verification is required to evaluate the viability of these proteins as targeted inflammatory factors for PHN-based treatments.

Metagenomics reveals unique gut mycobiome biomarkers in psoriasis.

PURPOSE: In present, the diagnosis of psoriasis is mainly based on the patient's typical clinical manifestations, dermoscopy and skin biopsy, and unlike other immune diseases, psoriasis lacks specific indicators in the blood. Therefore, we are required to search novel biomarkers for the diagnosis of psoriasis. METHODS: In this study, we analyzed the composition and the differences of intestinal fungal communities composition between psoriasis patients and healthy individuals in order to find the intestinal fungal communities associated with the diagnosis of psoriasis. We built a machine learning model and identified potential microbial markers for the diagnosis of psoriasis. RESULTS: The results of AUROC (area under ROC) showed that Aspergillus puulaauensis (AUROC = 0.779), Kazachstania africana (AUROC = 0.750) and Torulaspora delbrueckii (AUROC = 0.745) had high predictive ability (AUROC > 0.7) for predicting psoriasis, While Fusarium keratoplasticum (AUROC = 0.670) was relatively lower (AUROC < 0.7). CONCLUSION: The strategy based on the prediction of intestinal fungal communities provides a new idea for the diagnosis of psoriasis and is expected to become an auxiliary diagnostic method for psoriasis.

Neuraminidase 1 regulates the cellular state of microglia by modulating the sialylation of Trem2.

Neuraminidase 1 (Neu1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, Neu1 regulates immune cells, primarily those of the monocytic lineage. Here we examined how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 was deficient/downregulated, Trem2-FL remained sialylated, accumulated intracellularly, and was excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) did not hinder Trem2-FL-DAP12-Syk complex assembly but impaired signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampened NFκB signaling, while sTrem2 propagated Akt-dependent cell survival and NFAT1-mediated production of TNFα and CCL3. Because Neu1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease (AD) and sialidosis, modulating Neu1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.

Evidences of neurological injury caused by COVID-19 from glioma tissues and glioma organoids.

INTRODUCTION: Despite the extensive neurological symptoms induced by COVID-19 and the identification of SARS-CoV-2 in post-mortem brain samples from COVID-19 patients months after death, the precise mechanisms of SARS-CoV-2 invasion into the central nervous system remain unclear due to the lack of research models. METHODS: We collected glioma tissue samples from glioma patients who had a recent history of COVID-19 and examined the presence of the SARS-CoV-2 spike protein. Subsequently, spatial transcriptomic analyses were conducted on normal brain tissues, glioma tissues, and glioma tissues from glioma patients with recent COVID-19 history. Additionally, single-cell sequencing data from both glioma tissues and glioma organoids were collected and analyzed. Glioma organoids were utilized to evaluate the efficacy of potential COVID-19 blocking agents. RESULTS: Glioma tissues from glioma patients with recent COVID-19 history exhibited the presence of the SARS-CoV-2 spike protein. Differences between glioma tissues from glioma patients who had a recent history of COVID-19 and healthy brain tissues primarily manifested in neuronal cells. Notably, neuronal cells within glioma tissues of COVID-19 history demonstrated heightened susceptibility to Alzheimer's disease, depression, and synaptic dysfunction, indicative of neuronal aberrations. Expressions of SARS-CoV-2 entry factors were confirmed in both glioma tissues and glioma organoids. Moreover, glioma organoids were susceptible to pseudo-SARS-CoV-2 infection and the infections could be partly blocked by the potential COVID-19 drugs. CONCLUSIONS: Gliomas had inherent traits that render them susceptible to SARS-CoV-2 infection, leading to their representability of COVID-19 neurological symptoms. This established a biological foundation for the rationality and feasibility of utilization of glioma organoids as research and blocking drug testing model in SARS-CoV-2 infection within the central nervous system.

The impact of positive-pressure breathing apparatus on muscle fatigue of volunteer firefighter.

Muscle fatigue is one of the leading causes that contributes tremendously to injuries among volunteer firefighters in the workplace. The purpose of this study was to investigate the impact of positive-pressure breathing apparatus on muscle fatigue in the shoulder, back, and legs of volunteer firefighters. A total of 60 volunteer firefighters were recruited to perform a running task on a motorized treadmill in a controlled laboratory environment. Surface electromyography and rating of perceived exertion scores were collected from all participants every 60 seconds during the running task. Results show that the median frequency values for all measured muscle groups were significantly lower, and the rating of perceived exertion score was significantly higher after running with the positive-pressure breathing apparatus. Meanwhile, there were no significant differences in the median frequency values for the upper trapezius, erector spinae, and biceps femoris between the initial and final periods of running task without load. However, the median frequency values with load for gastrocnemius, rectus femoris, and tibialis anterior exhibited a greater downward trend compared to those without load. Additionally, using a breathing apparatus can cause asymmetric muscle fatigue in bilateral upper trapezius, erector spinae, gastrocnemius, and tibialis anterior muscles. The decreased performance due to muscle fatigue increases the risk of accidents, thereby posing a threat to the safety of volunteer firefighters. This study offers valuable insights into the effects of positive-pressure breathing apparatus on muscle fatigue among volunteer firefighters. These results may serve as a reference for developing improved fatigue management strategies and optimizing the design features of breathing apparatus.

Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma.

Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.

Clinical association between plan complexity and the local-recurrence-free-survival of non-small-cell lung cancer patients receiving stereotactic body radiation therapy.

PURPOSE: To investigate the clinical impact of plan complexity on the local recurrence-free survival (LRFS) of non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). METHODS: Data from 123 treatment plans for 113 NSCLC patients were analyzed. Plan-averaged beam modulation (PM), plan beam irregularity (PI), monitor unit/Gy (MU/Gy) and spherical disproportion (SD) were calculated. The γ passing rates (GPR) were measured using ArcCHECK 3D phantom with 2 %/2mm criteria. High complexity (HC) and low complexity (LC) groups were statistically stratified based on the aforementioned metrics, using cutoffs determined by their significance in correlation with survival time, as calculated using the R-3.6.1 packages. Kaplan-Meier analysis, Cox regression, and Random Survival Forest (RSF) models were employed for the analysis of local recurrence-free survival (LRFS). Propensity-score-matched pairs were generated to minimize bias in the analysis. RESULTS: The median follow-up time for all patients was 25.5 months (interquartile range 13.4-41.2). The prognostic capacity of PM was suggested using RSF, based on Variable Importance and Minimal Depth methods. The 1-, 2-, and 3-year LRFS rates in the HC group were significantly lower than those in the LC group (p = 0.023), when plan complexity was defined by PM. However, no significant difference was observed between the HC and LC groups when defined by other metrics (p > 0.05). All γ passing rates exceeded 90.5 %. CONCLUSIONS: This study revealed a significant association between higher PM and worse LRFS in NSCLC patients treated with SBRT. This finding offers additional clinical evidence supporting the potential optimization of pre-treatment quality assurance protocols.

Divergent Synthesis of 2-Chromonyl-3-hydrazono-chromones and 2-Alkoxy-3-hydrazono-chromones through Switchable Annulation Reactions of o-Hydroxyphenylenaminones with Aryldiazonium Salts.

An unprecedented selective chromone annulation reaction controlled by solvent for the divergent synthesis of two types of 2,3-disubstituted chromone skeletons has been developed. A variety of 2-chromonyl-3-hydrazono-chromones and 2-alkoxy-3-hydrazono-chromones were constructed efficiently from readily available o-hydroxyphenylenaminones (o-HPEs) and aryldiazonium salts at room temperature. This strategy is highly chemoselective and features mild reaction conditions, broad substrate scope, broad functional group tolerance, easy gram-scale preparation, and simple filtration to obtain the pure products without tedious column chromatography.

AAV-mediated gene therapy for sialidosis.

Sialidosis (mucolipidosis I) is a glycoprotein storage disease, clinically characterized by a spectrum of systemic and neurological phenotypes. The primary cause of the disease is deficiency of the lysosomal sialidase NEU1, resulting in accumulation of sialylated glycoproteins/oligosaccharides in tissues and body fluids. Neu1-/- mice recapitulate the severe, early-onset forms of the disease, affecting visceral organs, muscles, and the nervous system, with widespread lysosomal vacuolization evident in most cell types. Sialidosis is considered an orphan disorder with no therapy currently available. Here, we assessed the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis. Neu1-/- mice were co-injected with two scAAV2/8 vectors, expressing human NEU1 and its chaperone PPCA. Treated mice were phenotypically indistinguishable from their WT controls. NEU1 activity was restored to different extent in most tissues, including the brain, heart, muscle, and visceral organs. This resulted in diminished/absent lysosomal vacuolization in multiple cell types and reversal of sialyl-oligosacchariduria. Lastly, normalization of lysosomal exocytosis in the cerebrospinal fluids and serum of treated mice, coupled to diminished neuroinflammation, were measures of therapeutic efficacy. These findings point to AAV-mediated gene therapy as a suitable treatment for sialidosis and possibly other diseases, associated with low NEU1 expression.

Efficient incorporation of highly migratory thallium into struvite structure: Unraveling the stabilization mechanisms from a mineralogical perspective.

The remediation of high-concentration thallium (Tl+) contaminated wastewater is a critical environmental concern. Current research emphasizes the effectiveness of adsorption and oxidation methods for Tl+ treatment, yet challenges persist in enhancing their performance. This study explores the feasibility of emergency Tl+ wastewater treatment and elucidates the mechanisms of Tl+ incorporation into mineral structures, with a focus on the struvite mineral as a framework for Tl+ integration via NH4+ ion exchange. To assess the efficacy and mechanisms of Tl+ immobilization, we utilized comprehensive analytical techniques, including X-ray Diffraction (XRD), X-ray Photoelectron Spectroscopy (XPS), Fourier-Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy with Energy-Dispersive X-ray Spectroscopy (SEM-EDS), Thermogravimetric Analysis (TG), and Density Functional Theory (DFT) calculations. The findings reveal that struvite adsorbs Tl+ onto its surface, followed by an ion exchange process between monovalent cations (NH4+/K+) within the structure and Tl+. Ultimately, Tl+ is incorporated in the form of a (NH4,Tl)MgPO4 solid solution within the structure, achieving a remarkable maximum incorporation capacity of 320.56 mg/g, which significantly surpasses the capacity of typical adsorbents. The findings demonstrate significant Tl+ incorporation, validating the approach for emergency wastewater treatment and suggesting the potential of mineralogy in environmental remediation. This research contributes to advancing heavy metal wastewater treatment strategies, offering a foundation for further investigation.

Circadian changes of autonomic function in patients with zoster-associated pain: A heart rate variability analysis.

OBJECTIVE: To investigate the circadian changes of the autonomic function in patients with zoster-associated pain (ZAP). METHODS: A total of 37 patients with ZAP from April 2022 to October 2022 were enrolled as the observation group, and 37 normal volunteers at the same time were selected as the control group. All participants were required to wear a 24-h Holter, which was used to compare the heart rate variability (HRV) between the two groups. HRV analysis involved time- and frequency-domain parameters. RESULTS: There was no statistically significant difference in general information between two groups. Patients with ZAP had an increased mean heart rate and decreased the standard deviation of normal-to-normal (SDNN) R-R interval, the root mean square of the differences (RMSSD) in successive RR interval, low frequency (LF), and high frequency (HF) compared with control groups in all periods (p < .05). The ratio of LF/HF between two groups had no significant difference (p = .245). SDNN had no significant difference between day and night in the control group (p > .05), whereas SDNN of ZAP patients in night period was reduced than that in day period (p < .001). The level of RMSSD during the day was lower than those at night in the control group (p < .05), whereas no significant difference of RMSSD between two periods was observed in patients with ZAP (p > .05). CONCLUSION: The results of this study indicated that ZAP contributes to the decline of autonomic nervous system (ANS) function, especially parasympathetic components. The patients with ZAP lost parasympathetic advantage and had a worse ANS during the night.

Altered GM1 catabolism affects NMDAR-mediated Ca2+ signaling at ER-PM junctions and increases synaptic spine formation in a GM1-gangliosidosis model.

Endoplasmic reticulum-plasma membrane (ER-PM) junctions mediate Ca2+ flux across neuronal membranes. The properties of these membrane contact sites are defined by their lipid content, but little attention has been given to glycosphingolipids (GSLs). Here, we show that GM1-ganglioside, an abundant GSL in neuronal membranes, is integral to ER-PM junctions; it interacts with synaptic proteins/receptors and regulates Ca2+ signaling. In a model of the neurodegenerative lysosomal storage disease, GM1-gangliosidosis, pathogenic accumulation of GM1 at ER-PM junctions due to ß-galactosidase deficiency drastically alters neuronal Ca2+ homeostasis. Mechanistically, we show that GM1 interacts with the phosphorylated N-methyl D-aspartate receptor (NMDAR) Ca2+ channel, thereby increasing Ca2+ flux, activating extracellular signal-regulated kinase (ERK) signaling, and increasing the number of synaptic spines without increasing synaptic connectivity. Thus, GM1 clustering at ER-PM junctions alters synaptic plasticity and worsens the generalized neuronal cell death characteristic of GM1-gangliosidosis.