JID Innovations

Oculocutaneous albinism type 1 (OCA1) is a pigmentation disorder caused by biallelic tyrosinase (TYR) mutations, an essential enzyme for melanin synthesis. TYR inactivity results in loss of hair, skin, and eye pigment, which is detrimental for ocular function. Hypopigmentation of iris, retinal pigment epithelium (RPE), and choroid results in severe photosensitivity and low visual acuity. There are currently no FDA-approved pigment restoring therapies for OCA1, making therapeutic development an unmet clinical need. To address this gap, we have advanced an adeno-associated viral (AAV)-mediated Tyr replacement approach for OCA1 ocular pigment restoration. We evaluated the optimal viral delivery strategy and vector cell-type specificity for iris, RPE, and choroid pigmentation in an OCA1 mouse model, testing intraocular and systemic viral delivery methods in conjunction with viral constructs of varying RPE-specificity. Early, systemic delivery of an RPE-directed AAV-Tyr construct, AAV9.2yf-VMD2-Tyr, achieved widespread ocular pigment rescue with minimal off-target expression in non-ocular tissues. Animals treated with AAV9.2yf-VMD2-Tyr demonstrated reduced photophobic behavior compared to untreated controls, indicating that ocular pigmentation restores a debilitating functional consequence of OCA1. Our findings establish a foundation for clinical translation of an AAV-TYR therapy aimed at improving light sensitivity, glare, and low vision through pigment restoration in patients with OCA1.

Fibroproliferative diseases such as systemic sclerosis are complex conditions characterized by chronic skin inflammation and progressive fibrosis, with fibroblast activation as a central feature. While Transforming Growth Factor Beta (TGF-{beta}) signaling is a well-established driver of fibrosis in SSc, inflammatory pathways such as Nuclear Factor Kappa B (NF-{kappa}B) also contribute substantially to disease morbidity. We previously identified CD109 as a TGF-{beta} co-receptor and negative regulator of fibrotic signaling; however, its role in inflammatory signaling remains unknown. Here, we investigate the function of CD109 in regulating inflammatory signaling in skin fibroblasts. We show that, CD109 co-localizes and associates with Toll-like receptors (TLR2, TLR4) and tumor necrosis factor receptors (TNFRI, TNFRII), and that loss of CD109 enhances TNF--induced NF-{kappa}B activation and reprograms cytokine production in human dermal fibroblasts. Furthermore, both global and fibroblast-specific CD109 knockout mice exhibit increased immune cell infiltration and skin inflammation. In parallel, single-cell transcriptomic analyses across a pan-disease fibroblast atlas show that CD109 expression is preferentially maintained in structural and homeostatic fibroblast subtypes, whereas immune-interacting fibroblast subsets consistently display decreased CD109 levels. Pathway-level analyses of fibroblast pseudobulk samples reveal altered activity of canonical inflammatory pathways in SSc compared to healthy skin. Together, these findings identify CD109 as a fibroblast-intrinsic negative regulator of inflammatory signaling and suggest a broader role for CD109 in modulating inflammatory responses in systemic sclerosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/736423v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@be9e08org.highwire.dtl.DTLVardef@794173org.highwire.dtl.DTLVardef@b81eb5org.highwire.dtl.DTLVardef@1e811f5_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract: CD109 Restrains Fibroblast-Driven Inflammation by Modulating NF-{kappa}B Signaling. Generated using FigureLabs.ai and edited using Adobe Photoshop. C_FIG

Background: HIV infection has long been associated with increased incidence of severe cutaneous adverse reactions (SCAR). It remains unknown whether this increased incidence is a direct biological result of HIV infection, differences in drug exposure, or other demographic factors. Objective: To evaluate the association between HIV and SCAR and determine whether this relationship persists after adjusting for demographic factors and structured drug exposure. Methods: We analyzed reports from the FDA Adverse Event Reporting System (FAERS) from 2013-2023. SCAR outcomes included Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE). HIV status was determined using antiretroviral exposure, indication text, and machine-learning imputation. Logistic regression models were constructed sequentially: unadjusted, demographic-adjusted, and fully adjusted with drug principal components to account for polypharmacy. Drug-level disproportionality and HIV-drug interaction analyses were also performed. Results: In unadjusted models, HIV was strongly associated with SCAR (OR ~2.0-2.7). Adjustment for demographics attenuated this association, and further adjustment for drug exposure reduced the effect to near null for overall SCAR and DRESS. A modest residual association persisted for SJS/TEN (OR ~1.3). Disproportionality analyses demonstrated enrichment of specific high-risk drugs in PLWH. Interaction modeling revealed drug-specific amplification of SCAR risk in HIV, notably for carbamazepine and clarithromycin, whereas other drugs showed minimal interaction. Conclusion: The association between HIV and SCAR is largely explained by differences in drug exposure and demographic factors. Residual risk is drug-specific rather than uniform, supporting a model in which HIV modifies susceptibility to select drug triggers rather than acting as a global risk factor. Further prospective and retrospective studies are required to quantify associations.

Background Erythema nodosum leprosum (ENL) is a severe immune-mediated complication of multibacillary leprosy requiring prolonged immunosuppression. Steroid-sparing agents are essential to reduce relapse and treatment-related morbidity. Methods This longitudinal analytical observational study compared outcomes in patients with ENL treated with prednisolone plus thalidomide (Group A; n=30) and prednisolone plus tofacitinib (Group B; n=31). Patients were followed for 6 months. Primary outcomes included relapse rate and ENLIST ENL Severity Score (EESS). Secondary outcomes were neutrophil-lymphocyte ratio (NLR), Dermatology Life Quality Index (DLQI), steroid dependency, and adverse events. Inter-group comparisons and longitudinal analyses were performed using non-parametric tests. Correlations between NLR, EESS, and DLQI were assessed using Spearmans rank correlation. Results Relapse occurred in 36.7% of patients in Group A and 71.0% in Group B (p=0.007). The mean number of relapses was significantly lower in Group A (0.70{+/-}1.06 vs 1.84{+/-}1.51, p=0.002). At 3 and 6 months, Group A demonstrated significantly lower NLR values (p=0.017 and p<0.001, respectively). DLQI and EESS scores improved in both groups; however, sustained improvement was more consistent in Group A. Steroid-free status at 6 months was achieved in 93.3% of Group A compared with 58.1% of Group B (p<0.001). NLR showed a positive correlation with EESS ({rho}=0.269, p=0.018) and DLQI ({rho}=0.604, p<0.001) at 6 months. On multivariable logistic regression analysis adjusting for baseline confounders, patients receiving tofacitinib had significantly higher odds of relapse compared with those receiving thalidomide (adjusted OR 9.87, 95% CI 1.73-27.12; p = 0.006).Adverse events were predominantly mild to moderate, with differing safety profiles between groups. Conclusion Thalidomide demonstrated superior relapse prevention and steroid-sparing efficacy compared with tofacitinib in ENL. NLR correlated with disease severity and quality of life, supporting its role as a useful biomarker for monitoring disease activity during follow-up.

Background: Three-dimensional tumor spheroids are an established radiobiology model, but scalable, reproducible readouts of dose-dependent radiation response are lacking. We evaluated whether optical coherence tomography (OCT) radiomics can quantify dose-associated response in spheroids, and how it compares with conventional brightfield morphology. Methods: This in vitro, cross-sectional study used SAS oral squamous cell carcinoma spheroids seeded at two densities (5000 and 10000 cells), irradiated at 0 to 12 Gy, and imaged on days 1 to 11 post-irradiation. Each OCT acquisition yielded co-registered structural-intensity and speckle-variance volumes. Radiomic features (shape, first-order, texture) were extracted with Radiomics.jl, filtered for repeatability, correlation-pruned, and ensemble-ranked. Dose correlation was assessed by repeated 5-fold cross-validation across five regressors, comparing brightfield-only (BF), OCT-only, and combined OCT+BF feature sets with paired Wilcoxon tests. Results: OCT-only models consistently outperformed the BF baseline (median R2 0.77 to 0.85 versus 0.61 to 0.69; p<0.001 for all regressors). Adding brightfield to OCT gave no consistent benefit, reaching significance only for Random Forest (p=0.026, power 0.62). A compact shared feature subset combined brightfield area dynamics with OCT texture, shape, and speckle-variance descriptors, all showing low repeat-scan variability relative to cohort variability. Conclusions: OCT radiomics provides a sensitive, reproducible, label-free high-throughput readout of spheroid radiation dose response that outperforms the current brightfield-based approach, without requiring concurrent brightfield acquisition.

An autocrine pro-adhesive/pro-contractile signaling loop, through the mechanosensitive transcriptional cofactor YAP, promotes fibrosis. The CCN family of matricellular proteins modify adhesive signaling. Of these, CCN3 is antifibrotic. We show that BLR-200, a CCN3-derived peptide, has anti-fibrotic properties in the bleomycin-induced model of scleroderma skin fibrosis. In vitro, BLR-200 delayed, but did not abolish, fibroblast adhesion to collagen and nuclear YAP localization. In vivo, BLR-200 prevented/treated bleomycin-induced skin fibrosis, and reduced bleomycin-induced expression of profibrotic genes including alpha-smooth muscle actin, CCN1 and CCN2. Lineage tracing and scRNA-seq analyses revealed that the myofibroblasts in this model were quantitatively derived from collagen-lineage Pi16+/Col15+ve fibroblasts. BLR-200 prevented myofibroblast differentiation in this model and trajectory of fibroblasts toward a Sfrp2-positive subset, a cell type associated with poor clinical outcome. BLR-200 impairs YAP activation in vitro and appearance of translationally-relevant fibroblast subtypes in vivo and is a novel anti-fibrotic agent for SSc skin fibrosis.

Plasma proteins are promising biomarkers and potential drug targets in psoriasis. We conducted a two-sample Mendelian randomisation analysis integrating protein quantitative trait loci from UK Biobank and deCODE genetics with a psoriasis GWAS meta-analysis of 36,466 cases. To strengthen causal inference, we performed colocalisation analyses to evaluate shared genetic signals and applied summary data-based MR (SMR) with HEIDI testing using expression quantitative trait loci to exclude linkage-driven associations. After correction for multiple testing, 78 circulating proteins showed genetically predicted associations with psoriasis, with 27 demonstrating strong colocalisation (PPH4>80%). Triangulation prioritised 12 Tier 1 proteins, STX4, FLT3, NFKB1, IL18, PRSS53, SPAG1, SGSH, PLAT, RALB, TNFSF11, SPHK2, and STAT3, supported by consistent effects and no heterogeneity. Network profiling and Genome for REPositioning analyses assessed biological connectivity and druggability, revealing enrichment in anatomical therapeutic chemical groups L and B. Single-cell RNA sequencing confirmed cell-type-specific expression and modulation following IL-23 blockade.

Objective: Preclinical small-animal irradiators such as the FLASH-SARRP can support the advancement of photon-FLASH toward the clinic. This study aimed at characterizing the FLASH-SARRP and established a robust quality assurance (QA) workflow to enable accurate and reproducible preclinical experiments. Approach: Custom 3D-printed spacers were designed to ensure reproducible X-ray tube alignment, sample positioning and mounting of the dosimetric tools. Beam characteristics were evaluated using a combined dosimetric approach. High spatially resolved dose distributions were obtained from Gafchromic films, whereas a plastic scintillating fiber was employed to monitor in real-time the temporal pulse structure and synchronization between the two X-ray tubes. Day-to-day variability of the delivery was evaluated over several sessions. Main results: The FLASH-SARRP achieved dose-rates of around 80 Gy/s when both tubes were used simultaneously and provided a homogeneous irradiation field suitable for small-animal studies. A desynchronization between the two tubes was observed with an average delay of 10 ms, resulting in temporal dose-rate heterogeneity. Additionally, a substantial inter-session variability (~11%) was found, whereas the intra-session variability was relatively low (~4%). Inter-session variability was reduced to 5%, approaching the intra-session variability, by adding Gafchromic films/scintillator-based quality assurance (QA) workflow into the irradiation routine. Significance: This work highlights the importance of temporal dosimetry for preclinical FLASH studies. Additionally, a practical QA framework is proposed integrating real-time monitoring with reference dosimetry. The proposed work enables adaptive dose delivery, thereby enhancing the reproducibility of the irradiations, which is crucial for reliable preclinical studies on the FLASH effect.

Psoriasis is a chronic autoimmune skin disorder marked by IL-17-producing {gamma}{delta} T cell ({gamma}{delta}T17) and pruritus, but immunoregulatory roles of itch-inducing neurons in this context remain unclear. This study addressed whether non-peptidergic (NP) afferents bearing the Mas-related G protein-coupled receptor D (MrgprD/NP1) and MrgprA3/NP2 subsets had differential effects on psoriasiform immunopathology. Data show human NP1 and NP2 neurons basally expressed an array of pattern recognition and cytokine receptor genes, and psoriatic human skin had a profound dysregulation of neuropeptides and their receptors. In mice, imiquimod (IMQ) application reduced the density of MrgprD+ skin afferents, whereas NP1 neuron ablation exacerbated IMQ-induced disease. Strikingly, NP1 activation using either optogenetics or {beta}-alanine before IMQ exposure significantly reduced epidermal thickness, psoriatic clinical score, and {gamma}{delta}T17 cell accumulation. In stark contrast, NP2 activation increased the numbers of {gamma}{delta}T17 cells that co-expressed amphiregulin (Areg) and exacerbated IMQ-driven skin pathology. Instead, pre-emptive NP1 stimulation shifted {gamma}{delta} T cell profiles away from being IL-17 and Areg dominant to IL-13+ {gamma}{delta} T cells expressing the transcription factor GATA3 accompanied by IL-10 secretion. Importantly, IL-10 signaling blockade reversed NP1-mediated suppression of IMQ-induced dermatitis. These data show that sensory neuron subsets can distinctly modulate inflammatory skin disease.

Melanoma, one of the most metastatic and multidrug resistant cancer, is the first leading cause of death from skin cancer. This complex disease requires identification of additional cooperating events that contribute to progression, invasion and metastasis to reinforce therapeutics. RhoGTPases play key roles in cancer development and metastasis. Rhophilin-2 (RHPN2), a Rho effector, is amplified in various human cancers and its role in melanoma remains unexplored. Here, we combined knock-down experiments in human melanoma cells, with knock-out and overexpression experiments in zebrafish to uncover the roles of RHPN2 in melanoma development. We show that in human melanoma cells RHPN2 contributes to growth, and to clonogenic, migratory and invasive properties of the cells. Using NRASQ61L and BRAFV600E zebrafish models, we provide the first in vivo evidence that Rhpn2 promotes melanoma onset and development. Histological analysis of the Rhpn2 deficient tumors showed decreased cellular density and absence of primary cilia structures at the invasive tumor/stroma borders. Transcriptomic profiling of the Rhpn2-KO melanoma revealed increased expression of the IFN1-responsive genes and modulation of genes involved in lipid metabolism and cilia function. Together these findings position RHPN2 as a modulator of melanoma, offering new perspectives in considering it as a target to impair the development of the tumor.

Corneal epithelial integrity depends on continuous epithelial renewal by limbal epithelial stem cells (LESCs), a process tightly linked to sensory innervation. Loss or impairment of innervation causes neurotrophic keratopathy (NK), a sight-threatening degenerative disease for which rhNGF, the only FDA-approved pharmacologic therapy, often has limited efficacy in advanced or refractory disease. The mechanistic basis for this limited response remains unclear. Using surgical, genetic, and pharmacologic approaches in a rodent model of NK with corneal Schwann cell ablation or structural and functional denervation, together with primary human LESCs, we examined how denervation alters NGF receptor signaling during epithelial repair. In innervated corneas, NGF promoted epithelial regeneration through TrkA. Denervation, however, increased expression of a second NGF receptor, anti-regenerative p75NTR, and activation of its effector JNK, and reduced the activity of the TrkA effector AKT in LESCs. In this altered receptor context, denervation-induced elevation of endogenous NGF amplified p75NTR signaling, thereby explaining the failure of topical rhNGF to rescue severely denervated NK phenotype corneas. Conversely, selective TrkA activation, either with the clinical-stage agonist tavilermide, or pharmacologic or genetic inhibition/ablation of p75NTR, restored AKT signaling and rescued epithelial healing in denervated corneas independent of reinnervation. These findings identify a nerve-dependent NGF receptor switch as a key regulator of corneal epithelial renewal and establish receptor-selective modulation as a mechanistically rational therapeutic strategy for treating NK. One Sentence SummaryCorneal denervation shifts limbal epithelial stem cell signaling from pro-regenerative TrkA-AKT toward anti-regenerative p75NTR-JNK, explaining the limited efficacy of recombinant human nerve growth factor (rhNGF; cenegermin), the only approved pharmacologic therapy for neurotrophic keratopathy, in severely denervated corneas and identifying receptor-selective modulation as a mechanistically distinct therapeutic strategy.

Serial low-dose computed tomography (LDCT) scans in patients who are diagnosed with lung cancer during screening offer a history of the densities of tumors and the tissues that surround them during carcinogenesis and cancer progression. We built a CT-scan-resolution computational model to explore how variations in lung tissue density impact tumor growth and evolution in non-small cell lung cancer (NSCLC). Our findings indicate that tumors spread more rapidly through denser tissues when they upregulate glycolysis whilst tumors spread more rapidly through sparser tissues when they upregulate angiogenesis. We used data and images from the National Lung Screening Trial to calibrate our model for untreated lung cancer growth in patients and observed consistency with model predictions in low-density environments. SignificanceOur lung lesion model supports prior studies that find tumors tend to evolve toward angiogenic or glycolytic phenotypes. We demonstrate that these evolutionary strategies may be driven by the surrounding normal tissue density and may be observable on imaging.

Background: Epidemiological evidence links type 2 diabetes (T2D) to an increased risk of dementia, including Alzheimers disease (AD). However, previous syntheses often combined heterogeneous diabetes and dementia definitions and have not comprehensively quantified AD incidence among individuals with T2D. We aimed to estimate both the incidence of AD among individuals with T2D and the association between T2D and AD using studies with well-defined T2D and AD outcomes. Methods: We systematically searched MEDLINE, CINAHL (via EBSCO), Embase (via Ovid), and Scopus from inception to April 2026 for studies investigating the incidence of AD among individuals with T2D or the association between T2D and AD. Data were pooled using random-effects models and presented as incidence rates and adjusted relative risks (RRs) with 95% confidence intervals (CIs). Results Of the 9,430 articles identified, 40 studies involving 27,102,559 participants were included. Twenty-three studies contributed incidence data, and 26 reported adjusted relative risks (aRR). The pooled incidence of AD among individuals with T2D was 4.71 per 1,000 person-years (95% CI 3.31, 6.71). T2D was associated with an increased risk of AD (aRR 1.53, 95% CI 1.38, 1.70). Subgroup findings were generally consistent, results were robust in sensitivity analyses, and no publication bias was detected. Conclusions: This study provides a comprehensive quantification of the AD burden associated with T2D by focusing on well-defined AD and T2D outcomes and advancing the field beyond prior broad dementia syntheses. Integrating incidence and relative risk estimates clarifies both the absolute and relative burden of AD in T2D and extends previous syntheses that primarily emphasised relative risk. Individuals with T2D experienced approximately five AD cases per 1,000 person-years and a 53% higher risk of AD, supporting the rationale for integrating cognitive risk prevention into diabetes care.

Background: Cutaneous squamous cell carcinoma (cSCC) accounts for a significant proportion of skin malignancies in India, yet data on patterns of failure, particularly for extremity and truncal primaries remain scarce. We audited a decade of surgically treated cSCC at a tertiary cancer center to characterize failure patterns and associated risk factors. Methods: This retrospective study included 161 patients with histopathologically confirmed cSCC treated surgically between January 2013 and December 2023, comprising 127 upfront/residual and 34 recurrent presentations. Primary sites were extremities (64%), head and neck (26%) and torso (10%). 21 patients had Marjolin's ulcer. Outcomes included local, regional and distant failure, recurrence-free survival and overall survival. Brigham and Women's Hospital (BWH) staging was applied to assess prognostic utility. Statistical analysis was done using Kaplan-Meier and competing-risk methods. Results: Median follow-up was 2.4 years. Regional recurrence was the predominant failure pattern seen in 26 patients, local recurrence was seen in 14 patients and distant metastasis in 13. The 3-year cumulative incidences of local, regional and distant failure were 11%, 19% and 8.4% respectively. Rates of regional recurrence were substantially higher than Western series. Extremity primaries accounted for 19/26 regional recurrences. BWH T2b disease showed the highest regional failure rate (27.6%), exceeding T3 (17.8%) and T2a (6%) with perineural invasion significantly associated with regional failure in T2b/T3 tumors (p<0.001). Median time to regional metastasis was 8.4 months. At 3 years, overall survival was 77% and progression-free survival was 64%. Conclusion: Regional recurrence is the dominant mode of failure in this cohort, at rates higher than most published series, with extremity primaries and BWH T2b staging identifying particularly high-risk subgroups. These findings highlight the need for a comprehensive staging system encompassing non head and neck cSCC and support prospective evaluation of elective nodal staging and adjuvant radiotherapy in high-risk patients, alongside intensified surveillance.

Canine hemangiosarcoma (HSA) is an aggressive endothelial malignancy with limited therapeutic options, and its progression is closely associated with vascular architecture, stromal remodeling, and inflammatory cell recruitment. Sulfoquinovosylacylpropanediol (SQAP) is a sulfoquinovosyl lipid radiosensitizer reported to affect angiogenic and tumor-microenvironmental pathways, but its effects in canine HSA are unknown. Here, we evaluated SQAP in canine HSA cell lines and patient-derived xenograft (PDX) models. SQAP showed minimal direct cytotoxicity against HSA cell lines in vitro, whereas it significantly suppressed tumor growth in three canine HSA PDX models. Transcriptome analysis of SQAP-treated HSA PDX tumors detected more SQAP-responsive genes in mouse host-derived cells than in canine tumor cells. Gene-set enrichment analysis of the mouse host-derived fraction showed positive enrichment of angiogenesis, hypoxia, and stromal remodeling-related gene sets after SQAP treatment. Subsequent tissue analysis showed that SQAP reduced host-derived CD31-positive vascular area and increased -smooth muscle actin coverage of remaining vessels in two of the three PDX models, while altering macrophage-associated marker profiles in a model-dependent manner. These findings indicate that SQAP suppresses canine HSA PDX growth primarily through vascular and macrophage-associated remodeling of the tumor microenvironment rather than direct tumor-cell cytotoxicity.

Radiation exposure induces systemic and cellular damage, contributing to acute radiation syndrome and long-term effects such as premature aging and carcinogenesis. At the cellular level, radiation triggers apoptosis, mutation, and transformation through oxidative damage and activation of pathways including ER stress-mediated autophagy. Autophagy plays a context-dependent dual role in stressed cells, but its contribution to intestinal recovery after acute radiation remains unclear. Here, we evaluated combinatorial radiomodification using gamma radiation (8 Gy) and autophagy modulators in whole-body irradiated C57BL/6 mice (8-10 weeks old, n = 10). Mice were treated with autophagy inducers or inhibitors and euthanized at 3-, 8-, and 30-day post-irradiation. The jejunal-ileal region was analyzed via antioxidant assays, immunoblotting, H&E staining, and immunohistochemistry. Radiation significantly altered oxidative stress and autophagy markers, including increased LC3-II and decreased SQSTM1/p62. Autophagy induction enhanced intestinal proliferation (as measured by Ki-67), whereas inhibition impaired regeneration. Rapamycin pretreatment improved survival and reduced markers of intestinal injury following 8 Gy total body irradiation (TBI), whereas chloroquine exacerbated several injury-associated parameters. Overall, our findings suggest that targeted modulation of autophagy is a promising strategy for alleviating radiation-induced gastrointestinal injury and provide mechanistic insights relevant to therapeutic development.

Mutations in MYO7A result in the most severe subtype of Usher syndrome, the leading genetic cause of deafblindness. The large size of MYO7A requires dual adeno-associated virus (AAV) vectors for gene transfer or alternative methods to treat retinal defects. Here, we evaluated two treatment approaches: i) Supplementation of the human MYO7A gene via dual mRNA trans-splicing AAVs, and ii) CRISPR/Cas-mediated activation of the related murine Myo7b gene. Upon MYO7A supplementation, the transgenic MYO7A transcript and protein were expressed and correctly localized in retinal pigment epithelial (RPE) and photoreceptors of mice, pigs, and human retinal organoids. In RPE-and photoreceptor-specific Myo7a knockout mice, we could restore MYO7A expression and localization of melanosomes in RPE cells to wild-type levels. Myo7b activation led to partial restoration of melanosome localization, and the localization of MYO7B protein was largely comparable to MYO7A. These findings indicate that both approaches are in principle suitable for the therapy of Usher syndrome.

Spatial transcriptomics can reveal localized tumor-immune relationships, but thousands of spots from one tissue section do not provide thousands of biological replicates. We evaluated the distinction between within-section association and patient-level reproducibility using public breast cancer datasets. In a 10x Genomics Visium discovery section containing 3,798 spots, hypoxia-related transcription was inversely associated with cytotoxic gene activity in neighboring spots (Spearman{rho} = -0.202). High-hypoxia spots also had lower neighborhood cytotoxic scores than low-hypoxia spots (rank-biserial effect = -0.286). We then tested the directional association in an independent HER2-positive cohort comprising 36 sections, 13,619 spots, and eight patients. Only 19 of 36 sections and five of eight patients showed negative associations. The median patient-level correlation was -0.043 and did not differ from zero in a one-sided exact Wilcoxon test (P = 0.473). Sensitivity analyses using alternative cytotoxic and hypoxia signatures, neighborhood sizes, and Kendall correlation did not support a consistent inverse patient-level effect. Thus, a strong single-section association did not consistently reproduce across patients. These results caution against interpreting spot-level spatial associations from one section as patient-level biological effects.

When autopsy findings are presented on two-dimensional paper-based models, there is an inherent reduction of spatial information, which the viewer must infer from simplified anatomical and geometrical representations. Multiple diagrams representing trajectory angles must be integrated into a complete mental model, introducing potential for errors in viewer understanding. 3D models can address these issues but have shown limited adoption in forensic autopsy reporting given the technical competences and software required to produce them. Here, we present AutopsyPrint, a workflow and open web-based tool for generating 3D printable body models annotated with wound trajectories. The tool supports marking different wound types, including ballistic and stab wounds, on male and female bodies, which can be posed to accommodate a diversity of trajectories. Based on our testing, we present a set of suggested workflow steps and parameters based to facilitate standardization of the 3D models produced, balancing between precision and print time and materials. To ensure accessibility, the tool runs fully in the user's browser, and all annotated data is stored locally. By making AutopsyPrint open access, we intend to build practical experience with model creation, to ultimately advance the use of 3D models in the field.

The widespread use of synthetic food dyes, such as Acid Yellow 23 (AY 23), in the food, cosmetics, and pharmaceutical industries raises questions about their potential effects on biological systems and public health. The concentration-dependent interaction between AY 23 and bovine serum albumin (BSA), a crucial model protein for understanding pharmacokinetics and protein-ligand behaviour, was examined in this study. We demonstrate that, under physiological conditions, increasing dye concentrations from 50 M to 200 M results in notable conformational changes, increased surface hydrophobicity, and protein aggregation using a multimodal biophysical approach that includes fluorescence spectroscopy. Direct visualisation verified these structural changes and aggregate formation, whereas hemolytic assay confirmed the high hemolytic nature of AY 23-induced fibrils. Additionally, this study provides a mechanistic basis for the toxicological effects of AY 23, underscoring the implications of food dyes for public health.