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Sutherland, R.

Publications and source records attributed to Sutherland, R..

3 recordsLinked to original sources

The curse of dimensionality in motor cortex

Understanding how motor cortex generates movement is a foundational challenge in neuroscience. Unsupervised dimensionality reduction techniques, such as principal component analysis (PCA), are widely used to transform high-dimensional neural recordings into a compact, low-dimensional space. The dimensionality of this space--that is, the number of principal components needed to explain a fixed fraction of variance--is broadly assumed to be an intrinsic property of the underlying neural dynamics, potentially modulated by task complexity. Here, by comparing con-strained reaching and unconstrained naturalistic behaviors recorded from the same animal on the same day, we show that this assumption breaks down in two distinct ways. First, across four non-human primates, the dominant axes of low-dimensional neural activity separate behavioral contexts rather than movement kinematics, with neural activity shifting rapidly between task-specific regions of state space at task transitions. Notably, traditional dimensionality metrics are insensitive to movement complexity across tasks. Instead, unsupervised dimensionality scales with the number of recorded neurons, exhibiting non-saturating growth up to 1000 simultaneously recorded electrodes, a pattern that holds across PCA, factor analysis, shared variance component analysis, and nonlinear autoencoders. This scaling has direct consequences for decoding: while decoders trained on unsupervised subspaces improve only modestly with electrode count, super-vised methods leverage additional electrodes to separate neural states from a vanishingly small fraction of total variance (<10% at 1000 electrodes). Together, these results challenge current views on cortical dimensionality, reveal a greater-than-appreciated role for behavioral context in shaping motor cortical activity, and motivate careful consideration of computational methods as experimental data volumes scale.

neuroscience↗

PTPN2-KO CAR-T Cells Demonstrate Enhanced Effector Function, CNS Infiltration, and Toxicity in a Non-Human Primate CAR-T Model

B-cell targeting CAR-T cell therapies achieve high remission rates, yet durable responses occur in fewer than 40% of patients. Deletion of negative T-cell regulators, such as PTPN2, a key inhibitor of TCR and cytokine signaling, represents a promising strategy to enhance the efficacy of CAR-T cells. While transfer of PTPN2 knockout (KO) T cells has demonstrated antitumor benefits in murine models, its impact on human-derived CAR-T cells and, importantly, the associated in vivo efficacy and toxicity remain unclear. Here, we demonstrate that PTPN2-KO human CD19 CAR-T cells exhibit enhanced cytokine production, cytotoxicity, TCR and CAR affinity and signaling, leading to superior in vitro elimination of leukemic cells with low CD19 expression. To assess in vivo efficacy and toxicity, we performed a dose-escalation study using a non-human primate (NHP) model of B-cell-targeting CD20 CAR-T cell therapy. We demonstrated that PTPN2-KO CD20 CAR-T cells exhibited superior in vivo expansion and B-cell depletion compared to WT CAR-T cells, in a dose-dependent manner. At the highest dose level, CAR-T expansion was associated with increased toxicities, particularly ICANS, compared to PTPN2 WT CD20 CAR-T cells driven by enhanced CNS-infiltration. Transcriptional profiling revealed a dominant effector and proliferative signature, with cytotoxic CNS-infiltrating CD8+ PTPN2-KO CAR-T cells implicated in ICANS pathogenesis. This study details the comprehensive evaluation of PTPN2-KO CAR-T cells in an immunocompetent model, demonstrating their enhanced on-target functionality, while highlighting increased toxicity risks, underscoring the need for rigorous preclinical assessment of potent genetic modifications in CAR-T therapy. Key pointsO_LIPTPN2-KO CAR-T cells exhibit enhanced effector function C_LIO_LIIn a dose escalation study in rhesus macaques, PTPN2-KO mediated enhanced proliferation and CNS infiltration was associated with increased ICANS C_LI

immunology↗

CIS calibrates GM-CSF signalling strength to regulate macrophage polarization via a STAT5-IRF8 axis

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the ability to differentiate macrophages (MOs) with opposing functions, namely proinflammatory M1-like and immunosuppressive M2-like. Despite the importance and opposing functional outcomes of these processes, the intrinsic mechanism that regulates the functional polarization of MOs under GM-CSF signaling remains elusive. Here we show that GM-CSF induced MOs polarisation resulted in the expression of the Cytokine-inducible SH2-containing protein (CIS), and that CIS deficiency diverted differentiation of monocytes into immunosuppressive M2-like MOs expression. CIS deficiency resulted in the hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting the downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss and gain of function approaches highlighted IRF8 as a critical instructor of the M1-like polarisation program. In vivo, CIS deficiency led to skewing to M2-like macrophages, which induced strong Th2 immune responses characterised by the development of severe experimental asthma. Collectively, we reveal a CIS-censored mechanism interpreting the opposing actions of GM-CSF in MO differentiation and uncovering its role in controlling allergic inflammation.

immunology↗