Publications by Year: 2026

Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels. 007 targets an N332gp120 glycan-independent V3 epitope, a site of the HIV-1 envelope protein (Env) vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryogenic electron microscopy structure revealed contacts with the V3 324GD/NIR327 motif and interactions with N156gp120 and N301gp120 glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332gp120 glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs. Bivalent 007 IgG was more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1ADA-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007's potential for HIV-1 prevention, therapy, functional cure and vaccine design.

DOT1L and Menin are essential cofactors for the oncogenic activity of MLL fusion proteins (MLL-FPs) in leukaemia. However, the mechanisms underpinning the therapeutic effects of their inhibitors remain unclear. Here we identify a critical role for the non-canonical Polycomb repressive complex 1.1 (PRC1.1) in mediating the cellular responses to DOT1L and Menin inhibitors. Menin inhibition induces PRC1.1-dependent deposition of H2AK119ub to silence a subset of MLL-FP targets, whereas DOT1L inhibition results in a genome-wide increase in H2AK119ub. We show that enhanced PRC1.1 activity arises specifically from the progressive loss of DOT1L-mediated H3K79 methylation, independent of MLL-FP displacement or transcriptional repression. This regulatory crosstalk is conserved across cell types and is driven by direct biochemical antagonism between H3K79 methylation and PRC1 activity. Together, our findings establish DOT1L as a component of transcriptional memory co-opted in leukaemia and suggest it serves as the missing link balancing the opposing forces of the MLL-Polycomb axis.

Explosive outbursts, often referred to as "rage attacks," affect a significant number of individuals with Tourette syndrome (TS) and chronic tic disorders (CTDs), and are associated with increased disorder-related morbidity and psychosocial impairment. Tic severity, psychiatric comorbidity, psychosocial and other factors appear relevant. This chapter provides an overview of the phenomenology, possible neurobiologic and environmental underpinnings, and evaluation and treatment of explosive outbursts in TS. Existing literature on explosive outbursts, rage attacks, impulsive anger and aggression, and episodic dyscontrol in TS/CTD was reviewed and summarized. Explosive outbursts are common transdiagnostic symptoms and occur with increased frequency in individuals with TS/CTD. The etiology of these symptoms in TS/CTD is still unknown, appears multifactorial, and may reflect factors that are intrinsic to tic disorders, associated with their common neuropsychiatric comorbidities, and/or extrinsic influences. At present, evidence-based treatments for explosive outbursts in TS/CTD are limited. There remains an urgent need to advance the investigation of these disabling symptoms in TS/CTD. Use of consistent terminology and standardized assessment tools for studying and treating explosive outbursts in TS and CTDs are much needed.

RATIONALE: Opioid withdrawal is a serious obstacle to self-initiated abstinence, and previous experiences of opioid withdrawal may exacerbate the severity of subsequent incidences.

METHODS: To study the impact of repeated opioid withdrawal episodes, we compared male and female mice after one or five cycles of fentanyl exposure and withdrawal. We selectively expressed hemagglutinin-tagged ribosomes (RiboTag) in microglia of transgenic mice to immunoprecipitate and sequence RNA actively undergoing translation (the "translatome") from striatal microglia during fentanyl withdrawal. Key changes were confirmed by RTqPCR of RiboTag RNA.

RESULTS: Repeated bouts of fentanyl treatment and withdrawal impacted striatal microglia much more than a single cycle of fentanyl followed by withdrawal. Multiple withdrawal cycles reduced ramification of microglial processes, suggesting a more reactive cell state, and induced more severe behavioral withdrawal signs in mice. Five cycles of fentanyl exposure and withdrawal increased the expression of gene networks associated with innate immunity signaling. Indeed, 100% of the genes associated with the "microglia core sensome", were upregulated after five cycles of withdrawal.

CONCLUSIONS: Together these results suggest that mouse striatal microglia initiate a proinflammatory response following five, but not one, opioid exposure and withdrawal experiences and suggest that drug therapies targeting microglial innate immune responses may mitigate the severe withdrawal associated with repeated opioid tolerance and withdrawal.

Thetis cells (TCs) are a recently identified lineage of RORγt+ antigen-presenting cells comprising four subsets, TC I to TC IV, including a tolerogenic subset (TC IV) that instructs tolerance to gut microbiota and food antigens1-6. A developmental wave of TCs during early life creates a crucial window of opportunity for establishing intestinal tolerance1,5. The ontogeny of TCs and the cues that shape their abundance and heterogeneity remain unknown, however, limiting efforts to harness their therapeutic potential. Here we identify a population of RORγt+ progenitors, termed Thetis-lymphoid tissue inducer progenitors (TLPs), that give rise to the immediate TC progenitor (TCP) and the lymphoid tissue inducer (LTi) progenitor (LTiP), and identify PU.1 as the transcription factor that governs TC fate. Despite transcriptional similarity to myeloid-derived conventional dendritic cells, we show that TCs descend from the common lymphoid progenitor. Deletion of the plasmacytoid dendritic cell (pDC) lineage-determining transcription factor TCF4 expands TLPs and TCs, indicating a shared developmental branch with pDCs. TLPs are enriched in fetal liver, but, unlike LTi cells, TCs emerge postnatally, indicating that developmentally timed environmental cues promote TCP differentiation. We identify one such cue, RANKL provision by lymphoid tissue organizer cells, that is essential for TC I differentiation. Together, these findings define the ontogeny of TCs and the transcription factors that promote TC differentiation and heterogeneity, facilitating future investigations of these enigmatic cells and their therapeutic potential for tolerance induction in food allergy and autoimmunity.

Articular cartilage is crucial for joint function; however, it has limited regenerative capacity when damaged, a hallmark of many rheumatic diseases. Non-invasive imaging is essential for early diagnosis, therapeutic monitoring and prognostication. MRI remains the reference standard, offering detailed assessment of both morphological and compositional cartilage changes. Technological advances, including high-resolution and compositional MRI techniques such as T2 mapping, T1ρ, delayed gadolinium-enhanced MRI of cartilage, sodium imaging, diffusion imaging and ultra-short echo-time imaging, enable early detection of matrix alterations that precede structural breakdown. CT arthrography, although it involves radiation, serves as a valuable alternative when MRI is contra-indicated, offering high performance in the detection and evaluation of cartilage surface lesions. Emerging modalities, such as ultrasonography and PET, offer additional functional insights but are currently limited in scope. Artificial intelligence is poised to transform cartilage imaging through accelerated acquisition, automated segmentation, improved interpretation and enhanced efficiency, with growing clinical adoption. Advanced cartilage imaging will probably have an increasingly important role in clinical rheumatology, particularly for the optimization of individualized management of cartilage pathology.

Medical artificial intelligence (AI) tools, including clinical language models, vision-language models and multimodal health record models, are used to summarize clinical notes, answer questions and support decisions. Their adaptation to new populations, specialties or care settings often relies on fine-tuning, prompting or retrieval from external knowledge bases. These strategies can scale poorly and risk contextual errors-outputs that appear plausible but miss critical patient or situational information. We envision context switching as an emergent solution. Context switching adjusts model reasoning at inference, without retraining. Generative models can tailor outputs to patient biology, care setting or disease. Multimodal models can switch between notes, laboratory results, imaging and genomics, even when some data are missing or delayed. Agent models can coordinate tools and roles based on task and user context. In each case, context switching enables medical AI to adapt across specialties, populations and geographies. This approach requires advances in data design, model architectures and evaluation frameworks, and establishes a foundation for medical AI that scales to an infinite number of contexts, while remaining reliable and suited to real-world care.