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Anti-aging effect of Hedgehog signaling

Aging weakens the body’s ability to maintain balance and repair damage, increasing vulnerability to disease. This study reveals that the Hedgehog (Hh) signaling pathway plays a crucial role in preserving tissue integrity and regenerative capacity. Using animal models, researchers found that activating Hh signaling in multiple tissues such as the liver and brain enhances tissue repair and mitigates age-related functional decline. These findings suggest that targeting Hh signaling could be a promising strategy to promote healthy aging by enhancing regeneration and alleviating age-related dysfunction.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

A PI3Kδ-Foxo1-FasL signaling amplification loop rewires CD4+ T cell signaling and differentiation

Dominic P. Golec, Pamela L. Schwartzberg and colleagues (National Institute of Allergy and Infectious Diseases (NIAID)) describe a PI3 Kinase-Foxo1-FasL signaling circuit that promotes amplified signaling and rewires transcriptional and epigenetic programs driving IFN-γ and altered T helper cell differentiation in CD4+ T cells from mice expressing an activating mutant of phosphoinositide 3-kinase delta.

Immunodeficiency LymphocyteBiology

While inputs regulating CD4+ T helper (Th) cell differentiation are well defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th lineage identity remains incompletely resolved. PI3K signaling is a critical regulator of T cell function; activating mutations affecting PI3Kδ result in an immunodeficiency with multiple T cell defects. Using mice expressing activated PI3Kδ, we found aberrant expression of proinflammatory Th1 signature genes under Th2-inducing conditions, both in vivo and in vitro. This dysregulation was driven by a PI3Kδ-IL-2-Foxo1 signaling amplification loop, fueling Foxo1 inactivation, loss of Th2 lineage restriction, and extensive epigenetic reprogramming. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, normalized both Th2 differentiation and TCR signaling. BioID and imaging revealed Fas interactions with TCR signaling components, which were supported by Fas-mediated potentiation of TCR signaling that could occur in the absence of FADD. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated PI3Kδ, thereby linking two key pathways of immune dysregulation.

Immune checkpoint inhibitor–induced myocarditis is dependent on CD8 T cell–derived TNF and TNFR2 signaling

Kathrynne Warrick, Chandrashekhar Pasare et al. show that PD-1 blockade leads to de novo priming of self-reactive CD8 T cells resulting in immune related adverse events.

Immune checkpoint inhibitors (ICIs) improve cancer survival but can trigger immune-related adverse events. Among these, fulminant myocarditis is an often fatal complication with limited therapies. We developed a mouse model employing cardiomyocyte-restricted antigen expression to define how ICIs drive cardiac autoimmunity. Combined cytotoxic T cell antigen-4 (αCTLA-4) and programmed death-1 (αPD-1) blockade uniquely induced robust expansion of antigen-specific CD8 T cells, myocardial inflammation, and lethal arrhythmias. PD-1 blockade alone permitted the priming and effector differentiation of naive autoreactive CD8 T cells, whereas concomitant CTLA-4 inhibition amplified cardiac pathology. Unexpectedly, myocardial injury was independent of perforin-mediated cytotoxicity but critically depended on T cell–derived TNF, which promoted myeloid recruitment, cytokine production, and arrhythmogenesis. Genetic ablation of CD8 T cell–derived tumor necrosis factor (TNF) or TNF receptor 2 (TNFR2) blockade prevented cardiotoxicity while preserving antitumor efficacy. These findings establish a TNF-TNFR2–driven inflammatory circuit downstream of autoreactive CD8 T cells as a central mechanism of ICI myocarditis and a strategy to uncouple cardiotoxicity from immunotherapy benefits.

Leveraging current steering and the biophysics of spike generation for cellular-resolution electrical stimulation of neurons

Vasireddy et al. provide a framework for electrical stimulation current steering using several microelectrodes to most effectively target individual neurons in a population. A biophysically inspired mathematical model fits the linear and nonlinear responses of neurons, and data-driven regression models are used to efficiently find the most selective electrical stimulation patterns.

AI Tool Sets New Standard in Diagnosing Rare Diseases

A new system, which consists of a large LLM and a network of agentic tools, outperformed several other models and human physicians [1].

Too rare to easily diagnose

Rare diseases can be notoriously hard to diagnose. Patients average over 5 years to receive a correct diagnosis, enduring repeated referrals, misdiagnoses, and unnecessary interventions in what is known in rare disease medicine as ‘the diagnostic odyssey’ [2]. These rare diseases, defined as conditions affecting fewer than 1 in 2000 people, collectively impact over 300 million people worldwide. About 7,000 distinct disorders of this type have been identified, with 80% of them being genetic in origin [3].

Modeling lipid homeostasis using stable isotope tracing and flux analysis

Online now: Wessendorf-Rodriguez et al. develop a pipeline for applying metabolic flux analysis to quantify lipid homeostasis. Lipid-MFA elucidates differences in synthesis and salvage fluxes in precision-cut lung slices harboring tumors with common driver mutations of lung adenocarcinoma. Application of Lipid-MFA reveals distinct trafficking of ceramide species into the sphingolipidome.

Convergence of aging- and rejuvenation-related epigenetic alterations on PRC2 targets

Rejuvenation of tissues in physiologically aging mice can be accomplished by long-term partial reprogramming via expression of reprogramming factors (Oct4, Sox2, Klf4, and c-Myc). To investigate the epigenetic determinants of partial reprogramming-mediated rejuvenation, we used whole-genome bisulfite sequencing to carry out unbiased comprehensive profiling of DNA methylation changes in skin from mice subjected to partial reprogramming, as well as young and untreated old controls. We found a striking convergence of age- and rejuvenation-related epigenetic alterations on targets of the Polycomb repressive complex 2 (PRC2), with increased DNA methylation level and entropy over these regions. Native ChIP demonstrated extensive loss of H3K27me3 in aged epidermis compared to young, partially overlapping regions with age- and rejuvenation-related DNA methylation changes. In addition, large H3K9me2-marked “LOCK” heterochromatin domains defined the boundaries for hypomethylated highly entropic regions during aging. These results are also supported by a likewise prominent enrichment of PRC2 targets in gene expression data, suggesting that PRC2 activity can modulate aging and mediate tissue rejuvenation.

Electricity creates consciousness

Are we thinking about consciousness in the wrong way?

Nick Lane is an multi-award-winning biochemist and an outstanding science communicator in the origins of life field. He is a Professor of Evolutionary Biochemistry at University College London.

Tap the link to watch his talk now.

How could calcium ions rushing through a membrane generate the taste of coffee, the smell of a rose or the feeling of love? Join celebrated biochemist, Nick Lane, as he argues that the deep logic of life is at root an electrical phenomenon.’His theories are ingenious, breathtaking in scope, and challenging in every sense’ — The Guardian.

Radiation dose constraints for organs at risk in neuro-oncology; the European particle therapy network consensus

Case report: radiation-induced optic neuropathy following radiation therapy for a recurrent tuberculum sellae meningioma: a case report

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Prior to the first surgery, the patient experienced progressive visual loss, resulting in a visual acuity of 20/200 in her right eye, and visual field loss in the temporally and lower 2 quadrants. Her vision was described as normal in the left eye prior to surgery. Visual function improved after surgery, and after 3 months visual acuity in the patient’s right eye was assessed to be 20/40. Despite the successful initial surgery, a tumor recurrence was detected 4 years later. At this time point, the patient had reduced vision and a progressive visual field loss in her right eye. After the second surgery, her visual acuity was 20/60 in her right eye and 20/22.5 in the left eye. The right visual field was substantially reduced, especially in the lower 2 quadrants.

Based on recurrent disease, high probability of microscopic residual tumor remnants, and progressive loss of visual function, the patient was offered postoperative radiation therapy delivered with photons. Radiation therapy was administered 4 months following the last surgical procedure, and a conservative fractionation of 1.8 Gy in 29 fractions, with a total dose of 52.2 Gy, was chosen to keep anterior visual pathway doses below what is considered safe (Table 1) according to the European Particle Therapy Network Consensus. These standards recommend doses below 55 Gy to 0.03 cm3 (D 0.03cc) to the chiasm and the optic nerves.1 For the chiasm, the maximum dose (D max) was 53.7 Gy and the mean dose (D mean) was 51.7 Gy. The right optic nerve had a D max of 53.3 Gy and a D mean of 48.8 Gy, whereas the left optic nerve had a D max of 52.3 Gy and a D mean of 30.5 Gy. Radiation therapy dose distribution is shown in Figure 3. After radiation therapy, the patient reported minor improvement in visual function. Unfortunately, 7 to 8 months later her visual function again deteriorated over only a few weeks. Both eyes were affected, and deterioration was most pronounced in her left eye, with only finger counting possible and nearly total visual field loss. In the right eye, visual acuity was 20/60, with a substantially reduced visual field, especially in the lower 2 quadrants.

RION is primarily a diagnosis of exclusion, with tumor recurrence being the most important differential diagnosis. Tumor progression often results in a slower course of visual loss than RION.2 The patient’s vision loss was painless and rapid in onset, and radiological findings were bilateral and not consistent with neoplastic progression. Although MRI findings are nonspecific in RION-affected patients, neuro-ophthalmological examinations and clinical course/timing pointed to RION as the most likely cause of the patient’s visual loss. Systemic steroids in high doses were administered for 2 weeks before gradual tapering off, without any improvement in visual function. As a last effort to improve visual function, it was decided to try bevacizumab 7.5 mg/kg every 3 weeks. Treatment was well tolerated, with no reported side effects.

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