Gladstone Institutes

Cullin-5 RING E3 ligase limits CD8⁺ T-cell persistence and effector responses during chronic antigen stimulation

Abstract T-cell exhaustion limits durable antitumor responses and remains a barrier to adoptive cell therapies (ACT) in solid tumors. To identify regulators of T-cell persistence, we performed genome-wide CRISPR knockout screens in primary human CD8⁺ T cells expressing an NY-ESO-...

Disruption of the CRL5 ubiquitin ligase complex enhances engineered T-cell persistence under chronic tumor antigen exposure

Abstract Engineered T-cell therapies are limited by progressive dysfunction under chronic tumor antigen exposure, and genetic perturbation of negative regulators has emerged as a promising strategy to sustain effector activity. We reanalyzed a genome-wide CRISPR knockout screen i...

Modeling human neurodegeneration with iPSCs: opportunities, limitations, and the challenge of aging

Most neurodegenerative diseases reflect patient-specific combinations of polygenic risk variants interacting with aging and environmental factors, rather than a single causative mutation. Phase III clinical trial failure rates for neurodegenerative indications exceed 95%, reflect...

Large-scale prospective evaluation of co-folding across hundreds of Mac1–ligand complexes and three virtual screens

Abstract Accurate prediction of ligand-bound protein complexes and ranking them by affinity are central problems in drug discovery. While deep learning co-folding methods can help address these challenges, their evaluation has been hampered by the difficulties in assessing indepe...

Exploring transcriptomic and genomic latent variable correction approaches in differential expression analysis

Abstract Background Differential expression analysis is a central tool for studying the biological processes altered in human diseases via transcriptomic signatures. However, transcriptomic datasets are systematically confounded by latent variables from two distinct sources: unme...

Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid...

Single-cell atlas of transcriptomic vulnerability across brain disorders

Abstract Neurodegenerative and neuropsychiatric diseases impose a considerable societal and public health burden. However, our understanding of the molecular mechanisms underlying these highly complex conditions remains limited 1,2 . Here, to gain deeper insights into the aetiolo...

Personalized single-cell transcriptomics reveals molecular diversity in Alzheimer’s disease

Alzheimer’s disease (AD) is highly heterogeneous and driven by diverse molecular and cellular mechanisms. Functional genomics investigates these mechanisms from genetic variants to gene expression and regulation. We performed personalized functional genomics analysis on populatio...

AI-based characterization of Alzheimer’s disease phenotypes from population-scale single-cell data

The complexity of Alzheimer’s disease (AD) manifests in diverse clinical phenotypes, including cognitive impairment and neuropsychiatric symptoms. However, the etiology of these phenotypes remains elusive. To address this, the PsychAD project generated a population-level single-n...

Single-nucleus atlas of cell-type specific genetic regulation in the human brain

Abstract Genetic risk variants for common diseases are predominantly located in non-coding regulatory regions and modulate gene expression. Although bulk tissue studies have elucidated shared mechanisms of regulatory and disease-associated genetics, the cellular specificity of th...

Single-nucleus transcriptome-wide association study of human brain disorders

Abstract Common brain disorders impose a substantial health burden, but localizing their genetic risk in the brain remains challenging 1 . Although genome-wide association studies have identified numerous loci associated with neuropsychiatric and neurodegenerative disorders, many...

Lifespan single-cell transcriptomic atlas of the human prefrontal cortex

The human brain undergoes profound changes from early development through late adulthood, shaping cognition, behaviour and vulnerability to disease1,2. Understanding how these changes are organized within specific brain regions and cell types is essential for interpreting normal...

A noncontiguous code for RNA-guided DNA recognition at the origin of CRISPR-Cas

CRISPR-Cas provides RNA-mediated adaptive immunity, but how its first RNA-guided effector arose is unclear. In this study, we report the discovery of Viral Interference Programmable Repeat (VIPR) systems consisting of a Vipr protein ancestral to the earliest CRISPR-Cas effectors...

VIPR RNA-guided DNA recognition by noncontiguous geometric triplex formation

Viral interference programmable repeat (VIPR) systems use a noncontiguous code for RNA-guided transcriptional silencing. How the Vipr protein and a VIPR RNA (vrRNA) comprising alternating GGY and NN segments achieve precise DNA targeting is unknown. Here, we present 21 cryo–elect...

Buying Time: T cells and Delayed HIV Rebound After Treatment Interruption

Charles R Crain, Gaurav D Gaiha, Rajesh T Gandhi; Buying Time: T cells and Delayed HIV Rebound After Treatment Interruption, The Journal of Infectious Dise

Metagenome-scale modeling to assess microbiome metabolic complementarity for precision microbiota transplantation therapies

Fecal microbiota transplantation (FMT) holds therapeutic promise beyond recurrent Clostridioides difficile infection, but clinical outcomes remain unpredictable, in part because existing computational models do not fully capture the metabolic compatibility between donor and recip...

Artificial Intelligence and the Prospects for Net-Zero Energy and Net-Zero Carbon Buildings: A Science Mapping Analysis Using Digital Twins and Geographic Information Systems

This study explores the relationship between Artificial Intelligence (AI) and net-zero carbon buildings (NZCBs) and net-zero energy buildings (NZEBs) over the last decade. A thematic evolution has been observed in this research area, shifting from conventional optimization toward...

P1.047. Therapeutic Endoscopy as Essential Regional Care: Outcomes From an Australian Centre

Abstract Topic Benign Disease: Other Background Providing therapeutic endoscopy in regional centres offers substantial benefits by enabling minimally invasive gastrointestinal interventions closer to home. This reduces travel burden, improves timely access to specialist care, and...

Genome folding and nuclear speckles converge to orchestrate fibroblast activation

Fibroblasts adopt diverse cell states in response to inductive cues to maintain tissue homeostasis. We leveraged this cell-state plasticity to define how genome organization contributes to changes in cellular identity. We show that TGF-β reconfigures topologically associating dom...

Human spinal interneurons repair the injured rat spinal cord through synaptic integration

Spinal cord injury (SCI) results in irreversible disruption of motor, sensory, and autonomic circuits with no approved reparative treatment to restore lost function. Endogenous V2a spinal interneurons (SpINs) have been implicated as a key component in recovery post-SCI, but the i...