Synaptojanin 1 is a brain enriched phosphoinositide phosphatase implicated in endocytosis at the synapse. A mutation (R258Q) that selectively impairs its Sac1 phosphatase domain causes early onset familial Parkinsonism. Neurons of mice with this mutation display synaptic vesicle traffic defects across the brain, but selective dystrophic changes in a subset of dopaminergic axons in the dorsolateral striatum. Using correlative light microscopy-FIB-SEM of mutant mouse striata to visualize in 3D these abnormal structures we show that they represent clusters of focal axonal dilations harboring massive, onion-like DAT enriched plasma membrane infoldings, generally localized next to cell bodies of neighboring cells, often engulfing evaginations of such cells. This dysmorphia was associated with a deficit in dopamine release in the same striatal region. Given the involvement of Synj1 in endocytic mechanisms, these structures may reflect an imbalance between exocytosis and endocytosis. Their occurrence only in a subset of axons suggests a vulnerability threshold of these axons beyond which the expansion of the plasma membrane is not counteracted by compensatory mechanisms.

Parkinson's disease (PD) is increasingly recognized as a multi-system disorder with immune dysregulation extending beyond the central nervous system. Although numerous studies have examined peripheral immune alterations in people with PD, findings remain heterogeneous and difficult to reconcile. To clarify the current landscape, we conducted a comprehensive scoping review of human studies profiling peripheral blood immune cells in PD. Following PRISMA-ScR guidelines, we systematically screened the literature and curated studies reporting in vivo and ex vivo immune characterizations from PD patients. Eligible studies based on pre-defined criteria were assessed for patient demographics and clinical variables, experimental and analytical approaches, and reported immune outcomes. Our synthesis reveals a steady expansion and diversification of peripheral immune cell research in PD especially over the last decade. Deep immunophenotyping identifies convergent signatures across in vivo studies of both innate and adaptive compartments, including expanded pro-inflammatory T-cell subsets, altered monocyte subset distributions, increased cytotoxic natural killer cells and neutrophil-to-lymphocyte ratio, and dysregulated pathways related to immune activation, chemotaxis, mitochondrial function, and autophagy-lysosomal processes. Stimulation-based ex vivo assays further demonstrate recurrent T-cell hyper-responsiveness in PD, whereas myeloid cell responses are more variable and context dependent. Critically, this review highlights substantial variability and under-reporting in study design, which impeded our ability to make strong conclusions relating to many aspects of PD peripheral immunity.

Three new species of Eucorydia from China are described using an integrative taxonomic approach combining morphology and COI sequences, with ASAP and GMYC methods: Eucorydia parva Cai & Che, sp. nov., Eucorydia qinlingensis Cai & Che, sp. nov., and Eucorydia absens Cai & Che, sp. nov. The female genitalia are illustrated and comparatively analyzed, demonstrating their taxonomic significance. Although genetic divergence between the zonata population of E. dasytoides and E. qinlingensis is low, phylogenetic analysis supports the distinctiveness of the three new species. A key to the Chinese species of Eucorydia is also provided.

Automated Essay Scoring (AES) has emerged as an important application of natural language processing providing scalable and consistent evaluation of written responses. These assessments can be conducted using holistic or analytic evaluation approaches. Recent studies have heavily focused on utilizing deep learning models and particularly transformer-based models in holistic essay scoring, while accurately modeling the multi-dimensional analytical scoring remains a challenging problem. Despite their strong performance in holistic essay scoring, most existing approaches work as black-box predictors and do not explicitly model the reasoning process underlying analytic rubric-based evaluation. In this paper, we propose ARGUE-TIRA, a multi-task framework for joint holistic and analytic essay scoring. The proposed framework first predicts multiple analytic writing traits and subsequently applies a Trait Interaction Reasoning Attention (TIRA) to explicitly model dependencies among rubric dimensions before generating the final holistic score. Unlike conventional multi-task AES approaches that independently predict analytic traits, the proposed reasoning mechanism captures inter-trait relationships through structured self-attention reasoning, improving both scoring consistency and interpretability. Experiments conducted on the ASAP and ASAP++ datasets demonstrate that ARGUE-TIRA achieves competitive holistic performance and strong analytic trait-scoring performance. The framework obtains an average holistic QWK of 0.762 on ASAP and the highest average analytic QWK of 0.7424 on ASAP++. Furthermore, it achieves the best performance in seven of the eight evaluated analytic traits, including content, organization, word choice, sentence fluency, conventions, prompt adherence, and language quality.

Autophagy degrades cellular material by sequestering it within autophagosomes, which form de novo from precursors called phagophores. Phagophore assembly and expansion require ATG9A-positive seed compartments, the lipid transfer protein ATG2A, and the class III phosphatidylinositol 3-phosphate kinase complex I (PI3KC3-C1). PI3KC3-C1 synthesizes phosphatidylinositol 3-phosphate (PI3P), a key lipid that drives downstream processes for phagophore expansion, including ATG8 lipidation. We find that ATG9A compartments contain only traces of phosphatidylinositol (PI), likely insufficient for efficient PI3P production or recruitment of PI3P-binding effectors. Nevertheless, ATG2A is recruited to these compartments and mediates lipid transfer, including PI, into them. Remarkably, even without detectable PI3P, ATG9A compartments are direct substrates for ATG8 lipidation, and ATG8 proteins themselves enhance ATG2A-mediated lipid transfer. In cells, ATG2A is essential for the appearance of PI3P on ATG9A compartments. Our findings support a model in which a lipid transfer-driven feedback loop activates ATG9A compartments for phagophore expansion.

The balance of plasma membrane protein degradation and recycling during endocytosis is regulated, in part, by the large J-domain-containing protein DNAJC13/RME-8 and WASH complexes, which function together with Retromer to support cargo trafficking into recycling endosomes. Despite extensive cellular and biochemical studies, the structural basis and proteomic landscape of DNAJC13 function remain elusive. Here, we find that DNAJC13 forms an unexpected antiparallel homodimeric architecture involving distinctive symmetrical interactions between composite IWN1 and α-solenoid ARM2 domains in each protomer. Additionally, two PH-like domains of unknown function (PHL2 and PHL3), adjacent to the PI(3)P-binding PHL1 domain, form an unanticipated composite, positively charged pocket occupied by InsP6, as visualized structurally and verified by mass spectrometry. Proteomic profiling of DNAJC13-associated endosomes revealed enrichment of recycling endosomal components and WASH complexes. Mutations disrupting the dimer interface disable recruitment of WASH complexes to endosomes and result in elongated endosomal tubulation. Disruption of InsP6 binding impairs DNAJC13 binding to PI(3)P-containing vesicles in vitro and Transferrin-positive endosomes in cells. We further demonstrate that DNAJC13 dimerization and InsP6 binding promote melanin production during melanosome maturation, a process known to require recycling endosomes. This work provides a structural and mechanistic framework for understanding DNAJC13 function in recycling endosome control.

Background.Energy absorption in the skin caused by photobiomodulation therapy is highly dependent on the presence of epidermal melanin pigmentation. Accurate determination of the spatial energy distribution is vital for dosimetric purposes based on pigmentation.Methods.A voxel-based numerical model that utilizes the ASAP software package was created to model light scattering and absorption in the skin, comprised of a three-layer system (stratum corneum, epidermis, dermis). The absorbed power density (W mm[3]) was determined from the voxel-based absorbed energy for an input laser power of 2-20 MW at a wavelength of 635 nm. Low and high pigmentation models were considered using epidermal absorption coefficients selected to represent conditions associated with Fitzpatrick skin types I-II and V-VI, respectively.Results.Power density was shown to have pronounced depth dependence, with maximum power absorption observed at a depth of about 0.02-0.04 mm in the basal epidermis. High pigmentation was accompanied by higher absorption within the superficial epidermal region, with the increased absorption remaining concentrated near the epidermis. The energy-balance check showed agreement between total absorbed and incident power within 5%-8% under the modeled conditions.Conclusion.Skin pigmentation considerably affects spatial power deposition in 635 nm irradiation. The proposed approach represents a physically consistent framework to study effects related to skin pigmentation in optical dosimetry, while its physiological implications need experimental verification.

Although metabolism was originally studied across an array of mammals, contemporary metabolic studies moved towards human and mouse cells. A newfound interest in how metabolism regulates cell state during homeostasis, tissue repair and disease has uncovered key roles for energy flux inside and outside of mitochondria. Fibroblasts are key mediators of wound healing outcomes and prior work uncovered that cells from highly regenerative mammals (spiny mice and rabbits) exhibit enhanced resistance to oxidative stress compared to those from non-regenerating laboratory mice and rats. Using a battery of cellular tests in primary ear pinna fibroblasts from spiny mice, rabbits, laboratory mice and rats, we show that cells from spiny mice and rabbits exhibit a baseline preference for glycolysis supporting lower ROS-production. Mitochondria from spiny mouse fibroblasts were generally low respiring and depolarized while exhibiting a large, spherical morphology. We observed this large, spherical phenotype consistently across lifespan in ear pinna fibroblasts from fetal, young and old spiny mice and cells from all ages were highly resistant to oxidative stress. While rabbit, mouse and rat fibroblasts had polarized tubular mitochondrial networks typical of adult mammalian fibroblasts, isolated rabbit and spiny mice fibroblasts shared lower oxygen consumption efficiency even in the absence of a potential gradient. Taken together, our results support that a shared metabolic signature exists in stromal cells from highly regenerative mammals, although possibly driven by different mechanisms, to converge on a ROS-resistant phenotype that increases cellular resilience.

Latent fingermarks are vital evidence for identifying criminals using the unique ridge pattern and mass spectrometry can identify relevant chemical information from contact or exposure. Ambient ionisation mass spectrometry has many advantages that make it suitable for forensic workflows such as being user-friendly, low cost and having a small footprint. This work is concerned with detection of fentanyl, a highly potent synthetic opioid that has recently caused a significant number of overdoses, in latent fingermarks. A protocol was developed to produce fentanyl spiked fingermarks that were subsequently sampled using a liquid extraction method and analysed on a Waters RADIAN ASAP-MS. Initial results showed most fentanyl was recovered from a spiked fingermark and the detection limit was determined to be less than a nanogram. Latent fingermarks are typically visualised using an appropriate development technique before additional chemical information is recovered. Therefore, further studies assessed the ability to detect fentanyl in spiked fingermarks following three development techniques: cyanoacrylate (CyanoBloom), cyanoacrylate with UV dye (PolyCyano UV), and cyanoacrylate followed by staining with Basic Yellow 40 (BY40). Fentanyl was still detected after all three development methods tested, with detection limits reaching 10 ng or less present on the surface. This highlights that trace chemicals can be retained in fingermarks and recovered after development, the success of a simple liquid extraction method to recover analytes of interest and demonstrates how ambient ionisation methods are capable of reliably detecting analytes such as synthetic opioids from a complex matrix. This further exemplifies ambient ionisation as a solution to forensic testing backlogs by providing valuable information to criminal investigations quickly and effectively.

Exercise is a promising non-pharmacological intervention for motor and non-motor symptoms in Parkinson's disease (PD). However, direct comparisons between basic physical training (BPT) and dual-task training remain limited. The objective of the current clinical trial is to evaluate clinical and functional effects of BPT and a BPT combined with dual-task functional exercises (BPT + FE) in individuals with PD. In this randomized controlled trial, 24 participants with idiopathic PD were allocated to BPT, BPT + FE, or a no-intervention control group (Con). Interventions lasted 12 weeks (three 60-minute sessions/week). Outcomes included quality of life (PDQ-39), depressive symptoms (BDI), lower-limb strength (1-minute Sit-to-Stand Test, STS), and functional mobility (Timed Up and Go, TUG). Group effects were analyzed using permutation-based ANOVA with Bonferroni correction. Both interventions significantly improved physical performance vs. controls. STS gains were observed for BPT vs. Con (Mean Difference, MD = 31.00; p = .0026) and BPT + FE vs. Con (MD = 19.00; p = .0026). TUG times improved for BPT vs. Con (MD = -2.07s; p = .0039) and BPT + FE vs. Con (MD = -2.43s; p = .0028). Although BDI and PDQ-39 did not show statistically significant changes between group differences (r_rb = -0.429 and -0.339, respectively), several subscales demonstrated medium effect sizes suggesting potentially meaningful trends: emotional well-being (BPT: r_rb = -0.428; BPT + FE: r_rb = -0.446), bodily discomfort (BPT: r_rb = -0.524), and activities of daily living (BPT + FE: r_rb = -0.429). In conclusion, both programs improved physical performance in PD. Patient-reported outcomes did not reach statistical significance, but effect-size patterns suggest possible psychosocial benefits that warrant confirmation in larger trials. Trial registration ClinicalTrials.gov, NCT05963425.

Single-cell RNA sequencing and single-cell ATAC sequencing provide complementary views of transcriptional output and chromatin regulatory potential, but integrating unpaired profiles remains challenging because the modalities differ in feature space, sparsity and noise. Existing approaches often frame integration as distribution matching, which can over-align biologically distinct, condition-specific or modality-specific cell states. We present scHPGT, a single-cell Heterogeneous Prior-Guided Transformer for regulatory-prior-guided integration of unpaired RNA and chromatin accessibility profiles. scHPGT uses modality-specific encoders to model RNA and ATAC signals, a prior-guided cross-modal Transformer to constrain gene-peak attention using regulatory links, and a domain-adversarial objective to reduce modality-specific discrepancies in a shared latent space.