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Foundation Model of Neural Activity Predicts Response to New Stimulus Types
No full textThe complexity of neural circuits makes it challenging to decipher the brain’s algorithms of intelligence. Recent breakthroughs in deep learning have produced models that accurately simulate brain activity, enhancing our understanding of the brain’s computational objectives and neural coding. However, it is difficult for such models to generalize beyond their training distribution, limiting their utility. The emergence of foundation models1 trained on vast datasets has introduced a new artificial intelligence paradigm with remarkable generalization capabilities. Here we collected large amounts of neural activity from visual cortices of multiple mice and trained a foundation model to accurately predict neuronal responses to arbitrary natural videos. This model generalized to new mice with minimal training and successfully predicted responses across various new stimulus domains, such as coherent motion and noise patterns. Beyond neural response prediction, the model also accurately predicted anatomical cell types, dendritic features and neuronal connectivity within the MICrONS functional connectomics dataset2. Our work is a crucial step towards building foundation models of the brain. As neuroscience accumulates larger, multimodal datasets, foundation models will reveal statistical regularities, enable rapid adaptation to new tasks and accelerate research
Is Modulation of Immune Checkpoints on Glioblastoma-Infiltrating Myeloid Cells a Viable Therapeutic Strategy?
No full textThe field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate immunity, myeloid-specific checkpoints could also serve as potential therapeutics. To better understand the impact of immune checkpoint blockade on myeloid cells, we systematically summarize the current literature focusing on the direct immunological effects of PD-L1/PD-1, CD24/Siglec-10, collagen/LAIR-1, CX3CL1/CX3CR1, and CXCL10/CXCR3. By synthesizing the molecular mechanisms and the translational implications, we aim to prioritize agents in this category of therapeutics for glioblastoma
Predictors and Outcomes of First Pass Efficacy in Posterior Circulation Strokes: Insights From Star Collaboration
No full textBackground: First-pass efficacy (FPE) has been established as an important predictor of favorable functional outcomes after endovascular thrombectomy (ET) in anterior circulation strokes. In this retrospective cohort study, we investigate predictors and clinical outcomes of FPE in posterior circulation strokes (pcAIS).
Methods: The Stroke Thrombectomy and Aneurysm Registry database was used to identify pcAIS patients who achieved FPE. Their baseline characteristics and outcomes were compared with the non-FPE group. The primary outcome was a 90-day modified Rankin Scale (mRS) of 0-3. Univariate (UVA) and multivariate (MVA) analyses were done to evaluate predictors of FPE. Safety outcomes included distal emboli, vessel rupture, symptomatic intracranial hemorrhage, and mortality.
Results: Of 359 patients, 179 (50%) achieved FPE. Clot burden, occlusion site, and ET technique-related variables were similar between the two groups except for shorter procedure time with FPE. The primary outcome was significantly better with FPE (56.4% vs. 32.8%, p \u3c 0.001). Complications were similar except for a higher rate of distal emboli in non-FPE group (11.1% vs. 3.2%, p = 0.032). Atrial fibrillation (Afib) had increased odds (aOR: 2.06, 95% CI; 1.24, 3.4, p = 0.005) and prior ischemic stroke had decreased odds (aOR: 0.524, 95% CI; 0.28, 0.97, p = 0.04) of FPE. Afib was the only independent predictor of FPE on MVA (1.94, 95% CI; 1.1, 3.43, p = 0.022).
Conclusions: Higher rate of FPE in Afib-related pcAIS could possibly be explained by the differences in clot composition and degree of in-situ atherosclerotic disease burden. Future studies are warranted to explore the relationship of clot composition with ET outcomes
Weight Loss and a Shunt on “Off”: An Odd Case of Overshunting in an Idiopathic Intracranial Hypertension Patient. Illustrative Case
No full textBackground: CSF diversion with ventriculoperitoneal (VP) shunts is a common treatment for idiopathic intracranial hypertension (IIH). Rarely, overshunting can occur. Diagnosing and managing overshunting in an IIH patient with a shunt can be challenging. The authors present a unique etiology of overshunting successfully treated with shunt ligation.
Observations: A 48-year-old female with IIH who had undergone VP shunt placement with a programmable Certas valve presented with symptoms concerning for low-pressure headaches following a 25-kg weight loss. Intracranial pressure (ICP) monitoring along with an inpatient headache diary facilitated the diagnosis of intracranial hypotension secondary to CSF overdrainage through the shunt. Following shunt ligation, the patient experienced significant and durable symptom improvement.
Lessons: In the setting of low-pressure headaches in an IIH patient with a functioning shunt, reductions in intra-abdominal pressure from weight loss can increase anterograde flow through the shunt. Additionally, the Certas programmable valve at its highest setting remains patent, but with a high opening pressure, potentially allowing for overdrainage due to the siphoning effect. Finally, ICP monitoring and headache diaries can significantly aid in the characterization of low-pressure headaches, and shunt ligation can be a curative solution. https://thejns.org/doi/10.3171/CASE2510
Profiling Tumour-Infiltrating Immune Cells in a Large Paediatric Medulloblastoma Cohort: A Retrospective Analysis
No full textBackground: Tumour-infiltrating immune cells exert both pro-tumour and anti-tumour effects on intracranial tumours. In this study, we investigated the prognostic value of various infiltrating immune cells in medulloblastoma (MB) within a large cohort.
Methods: We employed multiplex immunofluorescent (mIF) staining of tissue microarrays to assess the densities of T cells, B cells, NK cells, macrophages, and immune checkpoints in tumour samples from 249 primary paediatric patients with primary MB. Overall survival (OS) analysis, progression-free survival (PFS), and Cox regression analyses were utilised to explore potential relationships between immune cell densities and survival outcomes. Subsequently, multivariate Cox regression was validated using an external database.
Findings: Significant differences in the immune microenvironment among molecular groups of MB and their prognostic implications were observed. CD4+ T cell infiltration was positively correlated with improved OS prognosis (Hazard Ratiolow vs high 2.19 [95% CI 1.197-4.016]), while M2 macrophages (HRlow vs high 0.50 [95% CI 0.250-1.003]), NK cells (HRlow vs high 0.40 [95% CI 0.207-0.792]), and B cells (HRlow vs high 0.51 [95% CI 0.291-0.902]) were associated with poorer PFS prognosis. We detected the presence of early tertiary lymphoid structures in MB. The infiltration of B cells (HRlow vs high 0.50 [95% CI 0.271-0.941]) correlated with poorer OS. The prognostic significance of B cells was further corroborated in cases from external data. Additionally, multivariate Cox regression confirmed that B cells were identified as independent negative prognosticators for OS (HRhigh vs low 2.21 [95% CI 1.341-3.651]) and PFS (HRhigh vs low 2.15 [95% CI 1.28-3.61]).
Interpretation: Our study provides a comprehensive characterisation of the spatial distribution of certain immune cells and tumour cells within the tumour core of patients with various subtypes of MB, underscoring the prognostic significance of B cells in these individuals.
Funding: Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (PWD & RPP-MRI: JYY2018-7); National Natural Science Foundation of China (32300773); China Postdoctoral Science Foundation (2022M721864)
Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma to Radiotherapy
No full textGroup 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma to reduce the risk of recurrence. In clinically relevant mouse models of G3 medulloblastoma, CT-guided fractionated radiotherapy extended overall survival and induced the clonal selection of radioresistant subpopulations of tumor cells that drove medulloblastoma recurrence. Comparison of recurrent tumors with treatment-naïve newly diagnosed tumors revealed a gene expression signature that was found to be a biomarker of radioresistance and poor prognosis. This prognostic gene signature was shown to be subgroup specific in a large patient cohort. Recurrent tumors had elevated expression of carbonic anhydrase 4, and genetic and pharmacologic modulation of carbonic anhydrase 4 could promote or reduce resistance to radiotherapy. These data suggest that the FDA-approved carbonic anhydrase inhibitor acetazolamide may be a useful radiosensitizer to improve the efficacy of the treatment of newly diagnosed G3 medulloblastoma that could reduce the risk of tumor recurrence and improve survival in pediatric patients.
Significance: G3 medulloblastoma features a prognostic subgroup-specific gene expression signature and can be targeted with a carbonic anhydrase inhibitor to enhance radiosensitivity, reducing the risk of recurrence and improving survival
Discover Consensus: AI for Academic Research
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The Microenvironment of Ocular Surface in Keratoconus: A Systematic Review
No full textPurpose: Keratoconus is a progressive corneal ectatic disorder characterized by thinning and irregularity of the cornea, significantly impairing visual acuity. Recent studies have explored how non-ectatic conditions, such as dry eye and tear film instability and alteration of the ocular surface microenvironment, contribute to the development and progression of keratoconus. This comprehensive review aims to investigate the complex relationship between keratoconus and ocular surface diseases by examining the microenvironmental changes that occur on the ocular surface throughout the course of keratoconus, as well as the related clinical implications.
Methods: In this PROSPERO-registered study (ID: CRD42025643808), PubMed, Scopus, Cochrane, Embase, Web of Science, and Google Scholar were thoroughly searched to retrieve all pertinent papers published up to January 2025. The retrieved publications were then reviewed, and the eligible ones were included.
Results: Keratoconus, with a similar inflammatory profile to that of ocular surface disease, has elevated Interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and matrix metalloproteinase (MMP)-9, contributing to extracellular matrix degradation and stromal thinning. Tear film instability, altered lipid secretion, and oxidative stress exacerbate disease progression. These findings suggest that keratoconus is not only a biomechanical disorder but also an inflammation-driven one.
Conclusion: This study comprehensively reviews the intricate relationship between the ocular surface microenvironment and keratoconus. Managing this microenvironment in keratoconus patients, as well as inflammation, oxidative stress, and tear film dysfunction, can potentially improve patient outcomes
A Natural Small Molecule Isoginkgetin Alleviates Hypercholesterolemia and Atherosclerosis by Targeting ACLY
No full textRationale: Atherosclerotic cardiovascular disease (ASCVD) represents the predominant cause of mortality and morbidity globally. Given the established role of hypercholesterolemia as a significant risk factor for ASCVD, the discovery of new lipid-lowering medications is of paramount importance. ATP citrate lyase (ACLY) is a crucial enzyme in cellular metabolism, providing acetyl-CoA as the building block for the biosynthesis of fatty acids and cholesterol. Consequently, it has emerged as a promising drug target for innovative treatments of lipid metabolic disorders.
Methods: Virtual screening of a natural product library was performed to identify small-molecule ACLY inhibitors, leading to the discovery of isoginkgetin (ISOGK). The lipid-lowering and anti-atherosclerotic effects of ISOGK were validated in hypercholesterolemic diet-induced animal models (mice and hamsters). The inhibitory effects of ISOGK on ACLY enzymatic activity were measured using commercial assay kits. The direct interaction between ISOGK and ACLY was confirmed by surface plasmon resonance (SPR) and cellular thermal shift assays (CETSA). Liver-specific ACLY knockdown mice were generated using GalNAc-conjugated siRNA (GalNAc-siAcly).
Results: ISOGK directly bind to ACLY and inhibit its enzymatic activity in vitro and in vivo. By inhibiting ACLY, ISOGK treatment thus alleviates hypercholesterolemia and atherosclerosis in mice and hamsters. However, ISOGK fails to attenuate lipid accumulation and the expression of lipid-metabolism related genes in Acly knockout or depleted hepatocytes. In vivo, the lipid-lowering and anti-atherosclerotic effects of ISOGK were reversed by hepatic knockdown of Acly via treatment with GalNAc-siAcly in mice.
Conclusions: Taken together, the present study identifies ISOGK as an effective and naturally-occurring small-molecule inhibitor of ACLY that limits hypercholesterolemia and atherosclerosis. ISOGK thus serves as a promising drug lead in cardiovascular therapeutics