The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.

Heptaellipside A, a rare new 2,28-bidesmosidic lupane-type saponin from the leaves of Heptapleurum ellipticum.

For the first time, phytochemical constituents of the leaves of Heptapleurum ellipticum were investigated. One rare new 2,28-bidesmosidic lupane-type saponin, named heptaellipside A (1), along with four other lupane-type analogs (2-5) were purified by combining differently chromatographic methods. All of the separated compounds (1-5) were communicated for the first time from H. ellipticum. The structures of them were definitely illustrated following extensive and comprehensive UV/VIS, FTIR, HRMS/ESI, and NMR techniques. Further, all isolated compounds were evaluated for their α-glucosidase and α-amylase inhibition. As the results, compound 3 respectively exhibited stronger in both inhibitory activities against α-glucosidase and α-amylase (IC50 values of 15.53 and 26.93 µM), than the acarbose standard (IC50 values of 214.50 and 143.48 µM).

A User-friendly Approach for the Diagnosis of Diabetic Retinopathy Using ChatGPT and Automated Machine Learning.

Purpose: To assess the capabilities of Chat Generative Pre-trained Transformer (ChatGPT) and Vertex AI in executing code-free preprocessing, training machine learning (ML) models, and analyzing the data. Design: Evaluation of diagnostic test or technology. Participants: ChatGPT and Vetrex AI as publicly available large language model and ML platform, respectively. Methods: ChatGPT was employed to improve the resolution of fundus photography images from the Methods to Evaluate Segmentation and Indexing Techniques in the field of Retinal Ophthalmology (Messidor-2) open-source dataset using the Contrast Limited Adaptive Histogram Equalization (CLAHE) technique by Fiji software. Subsequently, Vertex AI, an automated ML (AutoML) platform, was utilized to develop 2 classification models. The first model served as a binary classifier for detecting the presence of diabetic retinopathy (DR), while the second determined its severity. Finally, ChatGPT was used to provide scripts for R and Python programming languages for data analysis and was also directly employed in analyzing the data in a code-free method. Main Outcome Measures: Evaluating the utility of ChatGPT in generating scripts for preprocessing images using Fiji and analyzing data across Python and R and assessing its potential in analyzing data through a code-free method. Investigating the capabilities of Vertex AI to train image classification models for detection of DR and its severity. Results: Two ML models were trained using 1740 images from the Messidor-2 database. The first model, designed to detect the severity of DR, achieved an area under the precision-recall curve (AUPRC) of 0.81, with a precision rate of 81.81% and recall of 72.83%. The second model, tailored for the detection of the presence of DR, recorded a precision and recall of 84.48% with an AUPRC of 0.90. Conclusions: ChatGPT and Vertex AI have the potential to enable physicians without coding expertise to preprocess images, analyze data, and train ML models. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Risk factors for development of anti-adalimumab antibodies in non-infectious uveitis.

Purpose: To evaluate risk factors associated with development of anti-adalimumab antibodies (AAA) in patients with non-infectious uveitis treated with adalimumab. Methods: A retrospective, cross-sectional, case-control study was done evaluating patients with non-infectious uveitis treated with adalimumab for at least 12 months and have undergone testing for AAA levels. Demographics, clinical characteristics, grading of ocular inflammation, and previous and concomitant immunomodulatory therapy were assessed. Univariate and multivariate analysis were done to estimate odds ratio (OR) with 95% confidence intervals for the various risk factors. Results: A total of 31 patients were included in the analysis, in which 12 patients who tested positive (Group 1) were matched with 19 patients who tested negative for AAA (Group 2). The groups differed significantly in terms of sex (female) (91.7% vs 52.6%, p = 0.046), presence of systemic disease (91.7% vs 42.1%, p = 0.008), and presence of anterior chamber inflammation at baseline (100% vs 63.2%, p = 0.026). A history of interruption in anti-TNF therapy prior to starting or restarting adalimumab was found to have an increased odds for development of AAA (OR 16.89 [2.92, 107.11], p = 0.008), as well as flare-ups (reactivation of disease) during adalimumab therapy (OR 6.77 [1.80, 61.80], p = 0.027). Weekly dosing of adalimumab was shown to decrease odds of AAA development (OR 0.34 [0.02, 0.70], p = 0.040), while concomitant anti-metabolite therapy was not shown to be a statistically significant protective factor (OR 2.22 [0.50, 9.96], p = 0.148). Conclusions: History of interruption in anti-TNF therapy and flare during adalimumab were associated with development of AAA, while weekly dosing of adalimumab was protective against AAA. Identification of those with higher risk of developing AAA may guide in clinical decision making to optimize management for these patients.

Exercise rejuvenates microglia and reverses T cell accumulation in the aged female mouse brain.

Slowing and/or reversing brain ageing may alleviate cognitive impairments. Previous studies have found that exercise may mitigate cognitive decline, but the mechanisms underlying this remain largely unclear. Here we provide unbiased analyses of single-cell RNA sequencing data, showing the impacts of exercise and ageing on specific cell types in the mouse hippocampus. We demonstrate that exercise has a profound and selective effect on aged microglia, reverting their gene expression signature to that of young microglia. Pharmacologic depletion of microglia further demonstrated that these cells are required for the stimulatory effects of exercise on hippocampal neurogenesis but not cognition. Strikingly, allowing 18-month-old mice access to a running wheel did by and large also prevent and/or revert T cell presence in the ageing hippocampus. Taken together, our data highlight the profound impact of exercise in rejuvenating aged microglia, associated pro-neurogenic effects and on peripheral immune cell presence in the ageing female mouse brain.

Incidental Breast Hemangioma on Breast MRI: A Case Report.

Vascular tumors of the breast are rare, but benign hemangiomas are the most common type. Capillary hemangiomas are a subset of benign vascular tumors that involve smaller vessel sizes. They are difficult to diagnose with mammography and ultrasound, as they lack pathognomonic features and are frequently not seen. MRI is the most sensitive imaging tool. The lesions appear similar to angiosarcoma or ductal carcinoma in situ on imaging, which further complicates the diagnosis. A biopsy of the lesions is required for a definitive diagnosis. In this report, a 49-year-old female with newly diagnosed breast cancer is incidentally found to have a capillary hemangioma on staging breast MRI that was confirmed with a biopsy and excised along with the primary breast cancer with a partial mastectomy. The imaging findings of breast hemangioma on mammography, ultrasound, and MRI are also reviewed and described in this report.

Binary dataset for machine learning applications to tropical cyclone formation prediction.

Applications of machine learning (ML) in atmospheric science have been rapidly growing. To facilitate the development of ML models for tropical cyclone (TC) research, this binary dataset contains a specific customization of the National Center for Environmental Prediction (NCEP)/final analysis (FNL) data, in which key environmental conditions relevant to TC formation are extracted for a range of lead times (0-72 hours) during 1999-2023. The dataset is designed as multi-channel images centered on TC formation locations, with a positive and negative directory structure that can be readily read from any ML applications or common data interface. With its standard structure, this dataset provides users with a unique opportunity to conduct ML application research on TC formation as well as related predictability at different forecast lead times.

Importance of Baseline Fluorescein Angiography for Patients Presenting to Tertiary Uveitis Clinic.

PURPOSE: To ascertain whether the use of ultra-wide-field fluorescein angiography (UWFFA) at baseline visit alters the assessment of disease activity and localization, as well as the management of patients presenting to a tertiary uveitis clinic. DESIGN: Retrospective comparison of diagnostic approaches. METHODS: Baseline visits of 158 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were evaluated by 3 uveitis-trained ophthalmologists (I.K., A.B., and H.G.). Each eye had undergone clinical examination along with ultra-wide-field fundus photography (UWFFP) (Optos Plc), spectral-domain optical coherence tomography (SD-OCT, Spectralis Heidelberg, Heidelberg Engineering) and UWFFA (Optos Plc) at the baseline visit. Investigators were asked to successively determine disease activity, localization of disease (anterior, posterior or both), and management decisions based on clinical examination and UWFFP and SD-OCT (Set 1) and Set 1 plus UWFFA (Set 2). The primary outcome was the percentage of eyes whose management changed based on the availability of UWFFA compared with Set 1. RESULTS: The mean age of the patients was 46.9 ± 22.4 years (range, 7-96), and 91 (57.6%) were female. With Set 1 alone, 138 eyes (55.2%) were found to have active disease; localization was anterior in 58 eyes (42.0%), posterior in 53 eyes (38.4%), and anterior + posterior in 27 eyes (19.6%). With Set 2, 169 eyes of 107 patients had active anterior, posterior, or panuveitis. In comparison with Set 1, assessment with Set 2 identified additional 31 eyes (18.3%) with active disease (P = .006) and an additional 31 eyes (18.3%) having disease in both anterior + posterior segments (P < .001). Regarding the primary outcome, management was changed in 68 eyes (27.4%) in Set 2 compared with Set 1. CONCLUSIONS: Baseline UWFFA may alter assessment of disease activity, localization, and management decisions compared with clinical examination with only UWFFP and SD-OCT for eyes with uveitis. Thus, UWFFA may be considered as an essential tool in the evaluation of patients with uveitis at the baseline visit.

ROBIN: a randomised, double-masked, placebo-controlled Phase IIa study of the AOC3 inhibitor BI 1467335 in diabetic retinopathy.

OBJECTIVE: To evaluate the safety and efficacy of BI 1467335 in patients with non-proliferative diabetic retinopathy (NPDR). METHODS: ROBIN is a Phase IIa, double-masked, randomised, placebo-controlled study (NCT03238963). Patients with NPDR and without centre-involved diabetic macular oedema were included; all had a best corrected visual acuity letter score of ≥70 Early Treatment Diabetic Retinopathy Study letters in the study eye at screening. Patients received oral BI 1467335 10 mg or placebo once daily for 12 weeks. Post-treatment follow-up was 12 weeks. The primary endpoint was the proportion of patients over the 24 weeks with ocular adverse events (AEs). Secondary endpoints were the proportion of patients with ≥2-step improvement from baseline in DRSS severity level at Week 12 and the proportion of patients with non-ocular AEs at 24 weeks. RESULTS: Seventy-nine patients entered the study (BI 1467335, n = 40; placebo, n = 39). The proportion of patients with ocular AEs over 24 weeks was greater in the BI 1467335 versus the placebo group (35.0% vs 23.1%, respectively). Treatment-related AEs were reported for similar numbers of patients in the placebo and BI 1467335 group (7.7% vs 7.5%, respectively). At Week 12, 5.7% (n = 2) of patients in the BI 1467335 group had a 2-step improvement in DRSS severity level from baseline, compared with 0% in the placebo group. CONCLUSIONS: BI 1467335 was well tolerated by patients with NPDR. There was a high variability in DRSS levels for individual patients over time, with no clear efficacy signal.

The effect of polycystic ovarian syndrome on fibrocystic breast changes in postmenopausal women.

Background: Fibrocystic breast changes (FCCs) are benign lesions thought to be caused by an increased estrogen-to-progesterone ratio. One of the most common endocrinopathies that increases this ratio is polycystic ovarian syndrome (PCOS). Although nonproliferative FCCs do not increase the risk of breast cancer, they can make mammographic detection of malignancy in postmenopausal women more difficult. The aim of this study was to investigate the effects of PCOS on the development of postmenopausal FCCs. Methods: This retrospective cohort study used the TriNetX research network to identify two cohorts of postmenopausal women (Z78.0) older than 45, without a prior diagnosis of FCCs (N60.1) or hormone replacement therapy (Z79.890). One cohort included a diagnosis of PCOS (E28.2). The cohorts were balanced for age, race, ethnicity, and hormonally relevant comorbidities. The cohorts were then evaluated for the development of FCCs after menopause. Results: Postmenopausal patients with PCOS were 52% more likely to develop FCCs than those without PCOS (2.2% vs. 1.4%, relative risk 1.52, 95% confidence interval 1.05, 2.22, P = 0.03). Conclusion: Postmenopausal women with PCOS have a higher risk of developing FCCs. Further studies are needed to improve the differentiation of benign FCCs from malignant lesions on imaging for postmenopausal women with PCOS who develop FCCs.

Aqueous humour interleukin-6 and vision outcomes with anti-vascular endothelial growth factor therapy.

BACKGROUND: This analysis evaluated aqueous humour (AH) interleukin (IL)-6 concentrations and the association between AH IL-6 and visual outcomes in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular oedema (DMO) receiving anti-vascular endothelial growth factor (VEGF) monotherapy. METHODS: Post hoc analysis of the multicentre, double-masked, randomised HARBOR (NCT00891735) and READ-3 (NCT01077401) trials. HARBOR enrolled treatment-naïve nAMD patients. READ-3 enrolled treatment-naïve/previously treated DMO patients. HARBOR patients received ranibizumab 0.5 or 2.0 mg monthly or as needed; AH samples were collected at month 2, after two previous intravitreal injections. READ-3 patients received ranibizumab 0.5 or 2.0 mg as needed; AH samples were collected at baseline and months 3, 6, 9, and 12. MAIN OUTCOME MEASURE: association between AH IL-6 concentrations and month 24 best-corrected visual acuity (BCVA). RESULTS: In both trials (HARBOR, N = 36; READ-3, N = 137), patients with higher AH IL-6 concentrations had worse visual outcomes. HARBOR patients with low AH IL-6 concentrations at month 2 had a mean (95% CI) BCVA change at month 24 of +2.9 (-2.6, 8.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of -9.0 (-22.7, 4.7) letters. READ-3 patients with low AH concentrations at baseline had a mean (95% CI) BCVA change at month 12 of +9.3 (7.4, 11.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of +5.6 (2.2, 9.1) letters. CONCLUSIONS: Higher IL-6 AH concentrations may predict suboptimal visual responses to anti-VEGF monotherapy in patients with nAMD/DMO.

Intravenous cyclophosphamide therapy for patients with severe ocular inflammatory diseases who failed other immunomodulatory therapies.

BACKGROUND: Ocular inflammatory diseases, including scleritis and uveitis, have been widely treated with immunomodulatory therapies (IMTs) as a steroid-sparing approach. Such strategy includes conventional therapies (antimetabolites, alkylating agents, and calcineurin inhibitors) as well as biologic agents like adalimumab, infliximab, rituximab, and tocilizumab. Cyclophosphamide (CP) is an alkylating agent and mainly inhibits the functioning of both T and B cells. Though known to have potential adverse events, including bone marrow suppression, hemorrhagic cystitis, and sterility, CP has been shown to be efficacious, especially in recalcitrant cases and when used intravenous (IV) for a limited period. MAIN FINDINGS: We conducted a retrospective case-series to assess the safety and efficacy of CP therapy for patients with severe ocular inflammatory diseases who failed other IMTs. Medical records of 1295 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were reviewed. Seven patients (10 eyes) who received CP therapy for ocular inflammatory diseases with at least one year of follow-up were included. The mean age of the patients (4 males, 3 females) was 61.6 ± 14.9 (43.0-89.0) years. Clinical diagnoses included necrotizing scleritis (5 eyes), peripheral ulcerative keratitis (2 eyes), orbital pseudotumor (1 eye), HLA-B27 associated panuveitis and retinal vasculitis (2 eyes). Ocular disease was idiopathic in 3 patients, and was associated with rheumatoid arthritis, IgG-4 sclerosing disease, dermatomyositis, and ankylosing spondylitis in 1 patient each. All the patients had history of previous IMT use including methotrexate (5), mycophenolate mofetil (3), azathioprine (1), tacrolimus (1), adalimumab (2), infliximab (4), and rituximab (1). The mean follow-up time was 34.4 ± 11.0 (13-45) months, and mean duration of CP therapy was 11.9 ± 8.8 (5-28) months. Remission was achieved in 5 patients (71.4%). Four patients (57.1%) experienced transient leukopenia (white blood cell count < 4000/mL). SHORT CONCLUSION: CP therapy can be considered a potentially effective and relatively safe therapeutic option for patients with severe ocular inflammatory diseases who failed other IMTs including biologics (TNFa and CD20 inhibitors).

Single-cell RNA sequencing reveals peripheral blood leukocyte responses to spinal cord injury in mice with humanised immune systems.

Next-generation humanised mouse models and single-cell RNA sequencing (scRNAseq) approaches enable in-depth studies into human immune cell biology. Here we used NSG-SGM3 mice engrafted with human umbilical cord haematopoietic stem cells to investigate how human immune cells respond to and/or are changed by traumatic spinal cord injury (SCI). We hypothesised that the use of such mice could help advance our understanding of spinal cord injury-induced immune depression syndrome (SCI-IDS), and also how human leukocytes change as they migrate from the circulation into the lesion site. Our scRNAseq experiments, supplemented by flow cytometry, demonstrate the existence of up to 11 human immune cell (sub-) types and/or states across the blood and injured spinal cord (7 days post-SCI) of humanised NSG-SGM3 mice. Further comparisons of human immune cell transcriptomes between naïve, sham-operated and SCI mice identified a total of 579 differentially expressed genes, 190 of which were 'SCI-specific' (that is, genes regulated only in response to SCI but not sham surgery). Gene ontology analysis showed a prominent downregulation of immune cell function under SCI conditions, including for T cell receptor signalling and antigen presentation, confirming the presence of SCI-IDS and the transcriptional signature of human leukocytes in association with this phenomenon. We also highlight the activating influence of the local spinal cord lesion microenvironment by comparing the transcriptomes of circulating versus infiltrated human immune cells; those isolated from the lesion site were enriched for genes relating to both immune cell activity and function (e.g., oxidative phosphorylation, T cell proliferation and antigen presentation). We lastly applied an integrated bioinformatics approach to determine where immune responses in humanised NSG-SGM3 mice appear congruent to the native responses of human SCI patients, and where they diverge. Collectively, our study provides a valuable resource and methodological framework for the use of these mice in translational research.

Biosimilars of anti-vascular endothelial growth factor for ophthalmic diseases: A review.

The development of intravitreally injected biologic medicines (biologics) acting against vascular endothelial growth factor (VEGF) substantially improved the clinical outcomes of patients with common VEGF-driven retinal diseases. The relatively high cost of branded agents, however, represents a financial burden for most healthcare systems and patients, likely resulting in impaired access to treatment and poorer clinical outcomes for some patients. Biosimilar medicines (biosimilars) are clinically equivalent, potentially economic alternatives to reference products. Biosimilars approved by leading health authorities have been demonstrated to be similar to the reference product in a comprehensive comparability exercise, generating the totality of evidence necessary to support analytical, pre-clinical, and clinical biosimilarity. Anti-VEGF biosimilars have been entering the field of ophthalmology in the US since 2022. We review regulatory and scientific concepts of biosimilars, the biosimilar development landscape in ophthalmology, with a specific focus on anti-VEGF biosimilars, and discuss opportunities and challenges facing the uptake of biosimilars.

The Role of Corticosteroids and Immunomodulatory Therapy in the Management of Infectious Uveitis.

PURPOSE: The index review aims to provide an update on the role of corticosteroids and steroid-sparing immunomodulatory therapy (IMT) in managing patients with infectious uveitis. METHOD: Narrative literature review. RESULTS: Corticosteroids and immunomodulatory therapy (IMT) focus on the host defense system instead of the pathogen, adjusting exaggerated inflammatory reactions to reduce potential harm to ocular tissues. Systemic or local corticosteroids are primarily selected as adjunctive medication for infectious uveitis. Concomitant corticosteroids have also been used in cases of paradoxical worsening in ocular tuberculosis and immune recovery uveitis in cytomegalovirus (CMV) retinitis. While there is no well-established evidence to support the use of IMT in infectious uveitis, it is occasionally used in clinical settings to treat persistent inflammation following resolution of infection such as cases of ocular tuberculosis and ocular syphilis where an insufficient response is observed with corticosteroids. CONCLUSION: There is no consensus on the position of immunomodulatory therapy in the management of infectious uveitis with different etiologies. The index review provides an overview of available adjunctive corticosteroids and IMT options to assist clinicians in managing such disease entities more efficiently.

Cytomegalovirus Corneal Endotheliitis: A Comprehensive Review.

Cytomegalovirus (CMV) anterior uveitis and corneal endotheliitis are the most common ocular diseases caused by CMV infections in immunocompetent patients. The incidence of CMV corneal endotheliitis is relatively high in middle-aged men. CMV corneal endotheliitis presents with mild anterior chamber inflammation, corneal edema, keratic precipitates, and elevated intraocular pressure. It resembles Posner-Schlossman syndrome and Fuchs uveitis because of the elevated intraocular pressure. Without proper diagnosis and treatment, it may progress to bullous keratopathy or glaucoma, necessitating keratoplasty or glaucoma surgery. Therefore, early diagnosis and treatment are important for a good prognosis. Aqueous humor analysis can facilitate the diagnosis of CMV corneal endotheliitis, and early antiviral treatment can decrease the risk of corneal compensation or glaucomatous optic atrophy. In this article, we review the epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of CMV corneal endotheliitis along with the evidence for early clinical diagnosis and active antiviral treatment.

Challenges and perspectives in computational deconvolution of genomics data.

Deciphering cell-type heterogeneity is crucial for systematically understanding tissue homeostasis and its dysregulation in diseases. Computational deconvolution is an efficient approach for estimating cell-type abundances from a variety of omics data. Despite substantial methodological progress in computational deconvolution in recent years, challenges are still outstanding. Here we enlist four important challenges related to computational deconvolution: the quality of the reference data, generation of ground truth data, limitations of computational methodologies, and benchmarking design and implementation. Finally, we make recommendations on reference data generation, new directions of computational methodologies, and strategies to promote rigorous benchmarking.

Ocular syphilis masquerading as refractory retinal diseases.

PURPOSE: To report two cases of syphilis masquerading as chronic refractory macular diseases. CASE DESCRIPTIONS: Two patients had been diagnosed with neovascular age-related macular degeneration (neovascular AMD) and diabetic macular edema (DME), respectively. The disease worsened despite repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) and also surgical treatment (in suspected case of DME). Systemic evaluations were positive for syphilis. Intravenous penicillin was started, and the macular diseases improved. The lesions were well controlled afterward. CONCLUSIONS: The current two cases demonstrated that ocular syphilis can masquerade as refractory chronic retinal diseases such as DME and neovascular AMD. Laboratory evaluations for syphilis may be needed, not only for uveitis but also for refractory retinal diseases. Indocyanine green angiography may be helpful to reveal occult syphilis.