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Jing Li,1,* Yicong Chen,2,* Yunxiang Chao,1 Yupeng Zhang,1 Fan Gan,1 Zhipeng You1 1Department of Vitreoretinal Diseases, The Affiliated Eye Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China; 2Department of Otolaryngology, Nanchang First Hospital, Nanchang, 330008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhipeng You, Department of Vitreoretinal Diseases, The Affiliated Eye Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China, Email yzp74@sina.comBackground: Diabetic retinopathy (DR) is a major complication of diabetes leading to severe visual impairment. PANoptosis, a pro-inflammatory programmed cell death (PCD), has emerged as a potential pathological mechanism. This study aimed to elucidate the role of membrane protein-mediated PANoptosis in key cell populations during DR progression and to screen for coregulated genes with therapeutic potential.Methods: We integrated rat single-cell (scRNA-seq) and human bulk transcriptomes to identify differentially expressed PANoptosis-related genes (DE-PRGs). Single-sample gene set enrichment analysis (ssGSEA) was used to score PANoptosis activity, and CellChat was employed to examine ligand-receptor communications. Key cell subpopulations were characterized, and a protein-protein interaction (PPI) network was constructed to identify hub genes. Drug targets were predicted via the DGIDB database. Key findings were validated in a DR rat model and high-glucose-treated retinal Müller cells (RMC-1) using qRT-PCR, Western blotting, cell death assays, and siRNA-mediated PSAP knockdown.Results: We identified 27 DE-PRGs enriched in TNF, PCD, and p53 signaling pathways. Müller cells exhibited significantly elevated PANoptosis scores in the DR group. Intercellular communication analysis indicated that Müller cells transmit pro-apoptotic signals via the PSAP-GPR37 ligand-receptor axis. Sub-clustering identified “Müller2” as the key pathogenic subpopulation, characterized by high PSAP-GPR37 expression. Ten hub genes were screened, yielding 26 potential drug targets. Validation confirmed the downregulation of DLG4 and the upregulation of FN1, EMP3, PDGFRβ, and PSAP in DR models. In vitro, high glucose induced cell death and upregulated PANoptosis markers (NLRP3, cleaved caspase-8, and the p-MLKL/MLKL ratio). Notably, siRNA-mediated PSAP knockdown effectively attenuated the high glucose-induced elevation of these PANoptosis proteins.Conclusion: Integrating single-cell and bulk transcriptomics, this study suggests Müller cells—specifically the Müller2 subpopulation—as central drivers of PANoptosis in DR via PSAP-GPR37 signaling. Furthermore, the identified hub genes and PSAP provide a theoretical basis for precise, cell-subpopulation-specific intervention strategies.Keywords: diabetic retinopathy, PANoptosis, Müller cell, PSAP, bioinformatics analysis, transcriptomics

Diabetic retinopathy (DR) is a major complication of diabetes leading to severe visual impairment. PANoptosis, a pro-inflammatory programmed cell death (PCD), has emerged as a potential pathological mechanism. This study aimed to elucidate the role of membrane protein-mediated PANoptosis in key cell populations during DR progression and to screen for coregulated genes with therapeutic potential. We integrated rat single-cell (scRNA-seq) and human bulk transcriptomes to identify differentially expressed PANoptosis-related genes (DE-PRGs). Single-sample gene set enrichment analysis (ssGSEA) was used to score PANoptosis activity, and CellChat was employed to examine ligand-receptor communications. Key cell subpopulations were characterized, and a protein-protein interaction (PPI) network was constructed to identify hub genes. Drug targets were predicted via the DGIDB database. Key findings were validated in a DR rat model and high-glucose-treated retinal Müller cells (RMC-1) using qRT-PCR, Western blotting, cell death assays, and siRNA-mediated PSAP knockdown. We identified 27 DE-PRGs enriched in TNF, PCD, and p53 signaling pathways. Müller cells exhibited significantly elevated PANoptosis scores in the DR group. Intercellular communication analysis indicated that Müller cells transmit pro-apoptotic signals via the PSAP-GPR37 ligand-receptor axis. Sub-clustering identified \"Müller2\" as the key pathogenic subpopulation, characterized by high PSAP-GPR37 expression. Ten hub genes were screened, yielding 26 potential drug targets. Validation confirmed the downregulation of DLG4 and the upregulation of FN1, EMP3, PDGFRβ, and PSAP in DR models. In vitro, high glucose induced cell death and upregulated PANoptosis markers (NLRP3, cleaved caspase-8, and the p-MLKL/MLKL ratio). Notably, siRNA-mediated PSAP knockdown effectively attenuated the high glucose-induced elevation of these PANoptosis proteins. Integrating single-cell and bulk transcriptomics, this study suggests Müller cells-specifically the Müller2 subpopulation-as central drivers of PANoptosis in DR via PSAP-GPR37 signaling. Furthermore, the identified hub genes and PSAP provide a theoretical basis for precise, cell-subpopulation-specific intervention strategies.

The ability to successfully suppress impulses and angry affect is fundamental to control aggressive reactions following provocations. The aim of this study was to examine neural responses to provocations and aggression using a laboratory model of reactive aggression. We used a novel functional magnetic resonance imaging point-subtraction aggression paradigm in 44 men, of whom 18 were incarcerated violent offenders and 26 were control non-offenders. We measured brain activation following provocations (monetary subtractions), while the subjects had the possibility to behave aggressively or pursue monetary rewards. The violent offenders behaved more aggressively than controls (aggression frequency 150 vs 84, P = 0.03) and showed significantly higher brain reactivity to provocations within the amygdala and striatum, as well as reduced amygdala-prefrontal and striato-prefrontal connectivity. Amygdala reactivity to provocations was positively correlated with task-related behavior in the violent offenders. Across groups, striatal and prefrontal reactivity to provocations was positively associated with trait anger and trait aggression. These results suggest that violent individuals display abnormally high neural sensitivity to social provocations, a sensitivity related to aggressive behavior. These findings provide novel insight into the neural pathways that are sensitive to provocations, which is critical to more effectively shaped interventions that aim to reduce pathological aggressive behavior.

Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme β-glucocerebrosidase (β-GCase), considered the main genetic risk factor for sporadic PD. The loss of β-GCase activity results in the formation of α-synuclein deposits. The present study was aimed to determine the activity of the main lysosomal enzymes and the cofactors Prosaposin (PSAP) and Saposin C in PD and healthy controls, and their contribution to α-synuclein (α-Syn) aggregation. 42 PD patients and 37 age-matched healthy controls were included in the study. We first analyzed the β-GCase, β-galactosidase (β-gal), β-hexosaminidase (Hex B) and Cathepsin D (CatD) activities in white blood cells. We also measured the GBA, β-GAL, β-HEX, CTSD, PSAP, Saposin C and α-Syn protein levels by Western-blot. We found a 20% reduced β-GCase and β-gal activities in PD patients compared to controls. PSAP and Saposin C protein levels were significantly lower in PD patients and correlated with increased levels of α-synuclein. CatD, in contrast, showed significantly increased activity and protein levels in PD patients compared to controls. Increased CTSD protein levels in PD patients correlated, intriguingly, with a higher concentration of α-Syn. Our findings suggest that lysosomal dysfunction in sporadic PD is due, at least in part, to an alteration in Saposin C derived from reduced PSAP levels. That would lead to a significant decrease in the β-GCase activity, resulting in the accumulation of α-syn. The accumulation of monohexosylceramides might act in favor of CTSD activation and, therefore, increase its enzymatic activity. The evaluation of lysosomal activity in the peripheral blood of patients is expected to be a promising approach to investigate pathological mechanisms and novel therapies aimed to restore the lysosomal function in sporadic PD.

Perineural invasion (PNI) is an established adverse prognostic factor in gastric cancer (GC), yet the molecular events initiating this process remain poorly defined. In this study, we identify Schwann cells (SCs) as active facilitators of PNI and elucidate a reciprocal signaling axis between GC cells and SCs that promotes PNI. Using a GC–SCs co-culture model, we show that SCs enhance PNI potential in GC cells, accompanied by increased expression of prosaposin (PSAP), a lysosomal secretory protein, in both co-cultured cells and PNI-positive tumor specimens. Mechanistic studies reveal that PSAP forms a complex with cathepsin D (CTSD) and galactocerebrosidase (GALC) to inhibit autophagy and to promote PNI progression. GC-derived PSAP activates the G protein–coupled receptor 37(GPR37) on SCs, initiating RAC1-dependent cytoskeletal remodeling. This activation also induces secretion of transforming growth factor-β-1(TGFβ1) by SCs, which, in turn, binds transforming growth factor-β receptor-II (TGFβRII) on GC cells and activates a TGFβ1/Smad4/Sortilin signaling cascade. This pathway amplifies PSAP production and reinforces tumor–nerve interactions, establishing a feedforward paracrine loop that drives PNI. Functionally, enforced PSAP expression in GC cells significantly enhances PNI both in vitro and in vivo. Clinically, co-expression of PSAP, TGFβ1, and SCs marker S100β correlates with PNI incidence and improve PNI discrimination. Collectively, these findings define a novel PSAP–TGFβ1–Sortilin axis that mediates SCs–tumor crosstalk and sustains PNI in GC. Disrupting this paracrine loop may provide a therapeutic avenue to limit PNI and improve outcomes. Graphical Abstract This schematic model illustrates a self-amplifying tumor–nerve signaling circuit between GC cells and SCs that promotes PNI by coupling intracellular PSAP sorting to paracrine communication. PSAP is overexpressed in GC cells. The 65 kDa PSAP synthesized in the endoplasmic reticulum (ER) is transported to the Golgi and sorted into two trafficking routes. A fraction binds Sortilin in the trans-Golgi network (TGN) and is delivered to lysosomes, during which PSAP forms a complex with CTSD/GALC to inhibit autophagy and potentiate malignant traits. In parallel, another fraction is processed and secreted as a 75 kDa form, which engages GPR37 on SCs, activates RAC1-dependent cytoskeletal remodeling, and induces TGF-β1 secretion. SC-derived TGF-β1 signals back to GC cells via the TGF-β1/Smad4 pathway to repress Sortilin expression, reducing PSAP–Sortilin interaction and limiting lysosomal targeting, which in turn increases PSAP abundance and secretion. Collectively, these events establish a feed-forward paracrine amplification loop that sustains tumor–nerve crosstalk and accelerates PNI.

Background In-vivo observations of neural processes during human aggressive behavior are difficult to obtain, limiting the number of studies in this area. To address this gap, the present study implemented a social reactive aggression paradigm in 29 healthy men, employing non-violent provocation in a two-player game to elicit aggressive behavior in fMRI settings. Results Participants responded more aggressively after high provocation reflected in taking more money from their opponents. Comparing aggression trials after high provocation to those after low provocation revealed activations in neural circuits involved in aggression: the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), the dorsolateral prefrontal cortex (dlPFC), the anterior cingulate cortex (ACC), and the insula. In general, our findings indicate that aggressive behavior activates a complex, widespread brain network, reflecting a cortico-limbic interaction and overlapping with circuits underlying negative emotions and conflicting decision-making. Brain activation during provocation in the OFC was associated with the degree of aggressive behavior in this task. Conclusion Therefore, data suggest there is greater susceptibility for provocation, rather than less inhibition of aggressive tendencies, in individuals with higher aggressive responses. This further supports the hypothesis that reactive aggression can be seen as a consequence of provocation of aggressive emotional responses and parallel evaluative regulatory processes mediated mainly by the insula and prefrontal areas (OFC, mPFC, dlPFC, and ACC) respectively.

The systematic identification of host factors that modulate SARS-CoV-2 infection is critical for elucidating the mechanisms of virus-host interaction and for advancing the development of novel host-directed therapeutic interventions. In this study, we identify the human protein prosaposin (PSAP) as a novel and potent innate restriction factor that effectively blocks SARS-CoV-2 infection. By binding with high affinity to the spike protein’s receptor-binding domain (RBD) at a unique site, PSAP neutralizes the virus, thereby preventing cellular entry. Consequently, this discovery establishes a foundation for a novel host-directed therapeutic strategy. The development of pharmacologic agents that recapitulate PSAP’s action could yield a new class of antivirals that neutralize SARS-CoV-2 by mechanistically disrupting spike protein integrity, offering a complementary approach to conventional antibody therapies.

Metachromatic leukodystrophy (MLD) is a genetic lysosomal disease. Here, we investigated the role of prosaposin (PSAP) gene mutations in MLD. This current case report describes a female patient who presented with motor development regression at two years and five months of age. The symptoms included difficulty walking, loss of ambulation, increased muscle tension, limb pain, and intentional tremors. Brain magnetic resonance imaging revealed potential white matter lesions, while electromyography indicated neurogenic damage in both lower limbs. Gesell assessment showed severe motor retardation, along with mild retardation in adaptability, speech, and social communication. Whole exome sequencing analysis identified a homozygous mutation in the PSAP gene, specifically c.643A>G, resulting in the amino acid change p.N215D. Immunofluorescence assays of cultured cells indicated no impact on the PSAP protein lysosomal localization, but the mutation was associated with a decreased lysosomal pH and reduced cathepsin D activity. Transmission electron microscopy revealed changes in lysosome morphology and abnormal protein aggregation. These findings suggest that the PSAP c.643A>G (p.N215D) mutation may be a causal factor for MLD in this patient. This discovery may provide new insights into the genetic basis and pathophysiological mechanisms of MLD.

The characteristic neuropathology of Parkinson’s disease (PD) involves the abnormal accumulation of phosphorylated α-synuclein (αSyn), as well as a significant decrease in neuromelanin (NM) levels within dopamine neurons (DaNs). Unlike αSyn aggregates, the relationship between NM levels and PD pathogenesis is not well understood. In this study, we engineered an E. coli MG1655 strain to produce exosomes containing melanin (E.melanin), and investigated its potential neuroprotective effects on DaNs in the context of PD. By employing a combination of cell cultures, biochemical studies, single nuclear RNA sequencing (snRNA seq), and various in vivo validations, we found that administration of E.melanin effectively alleviated DaNs loss and improved motor behavior impairments observed in both pharmacological and transgenic PD mouse models. Mechanistically, snRNA seq data suggested that E.melanin activated the PSAP-GPR37L1 signaling pathway specifically within astrocytes, leading to a reduction in astrocytic engulfment of synapses. Notably, activation of the GPR37L1 receptor using Tx14(A) peptide successfully rescued motor defects as well as protected against DaNs degeneration in mice with PD. Overall, our findings provide novel insights into understanding the molecular mechanisms underlying melanin’s protective effects on DaNs in PD while offering potential strategies for manipulating and treating its pathophysiological progression.

In this study we evaluate the recently upgraded aethalometer (AE33) and the newly released tricolor absorption photometer (TAP) with respect to their response to wildfire aerosol plumes during their deployment at the Mount Bachelor Observatory (MBO; 2763 m a.s.l.) in central Oregon, USA, during the summer of 2016. While both instruments use similar methodology (i.e., light extinction through an aerosol-laden filter), each has a unique set of correction schemes to address artifacts originating from filter loading, scattering from captured aerosol particles, and multiple scattering effects of the filter fibers. We also utilize a Single Particle Soot Photometer (SP2) to determine refractory black carbon (rBC) in these air masses. In addition to comparing the AE33 filter-loading correction methodology to previously published aethalometer correction schemes, we also compare the AE33 to the correction schemes used for the TAP and evaluate the degree to which the different correction factors influence the derived absorption Ångström exponents (AAE) and mass absorption cross sections (MACs). We find that while the different correction factors for either the AE33 or TAP do exert an influence on the derived MACs, AAEs exhibit the most sensitivity to the correction schemes. Our study finds that using the AE33 manufacturer’s recommended settings results in aerosol light absorption coefficients that are 3.4 to 4 times greater than the aerosol light absorption coefficients reported by the TAP. We calculated a correction factor (C f ) of 4.35 for the AE33 by normalizing the AE33 to match the TAP. The uncorrected AE33 also gives equivalent black carbon (eBC) values that are approximately 2 times the rBC measured by the SP2 instrument. We also find that biomass burning aerosols result in significant MAC enhancements, particularly at lower wavelengths, which is attributable to brown carbon (BrC).