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Gaines, J.

Publications and source records attributed to Gaines, J..

3 recordsLinked to original sources

Modeling framework disentangles cerebellar mechanisms in speech feedback control, revealing trade-offs reshaped by degeneration

A central challenge in systems neuroscience is understanding how computational mechanisms--including those implemented within a single brain region--interact to produce behavior. For example, prior work in the literature attributes many computational functions to the cerebellum, but these functions have been tested in isolation and it remains unclear how they jointly contribute to motor control. Here, we test several established hypotheses of cerebellar function: internal modeling, timing of movement dynamics, sensory-error processing, delay processing, and multimodal integration. We first formalize these functions as mechanistic parameters within a computational model of speech motor control. We then use this formalism to investigate the relative contribution of each function to the abnormal speech corrective response seen in adults with cerebellar degeneration during perturbed auditory feedback. We find the following functions explain most of the behavioral differences: internal modeling, timing of movement dynamics, and multimodal integration. We also show that the key mechanisms have a trade-off relationship, and that cerebellar degeneration modulates those trade-off strengths and boundaries. These results both elaborate the mechanistic function of the cerebellum in speech feedback control and, more broadly, demonstrate the promise of using this paradigm to simultaneously test competing theories of neural function underlying behavior.

neuroscience↗

Damaged glomeruli in proliferative pediatric lupus nephritis exhibit a C5a-C5aR1 induced fibrotic transcriptional program

Lupus nephritis (LN) is a leading cause of morbidity in pediatric systemic lupus erythematosus (pSLE) due to suboptimal kidney remission rates and the sequelae of prolonged intensive immunosuppressive therapy. LN is patchy, with some glomeruli severely damaged while others remain histologically unaffected in the same kidney. Using spatial transcriptomic technology, we interrogated microanatomic transcriptional differences between histologically damaged and unaffected glomeruli in pSLE LN to understand local drivers of renal injury. Despite SLE being a disease of Type I interferon (IFN), IFN gene response does not associate with local glomerular damage. Rather, damage associates with a transcriptional module of higher expression of myeloid cell markers, C5AR1 (encoding the receptor for complement component 5a [C5a]), early complement components, and fibrosis genes. Bulk RNA-sequencing of C5a stimulated human monocyte-derived-macrophages revealed upregulation of tissue-remodeling and fibrosis-related pathways reversible by the C5aR1 inhibiting drug avacopan. These same C5a-inducible fibrosis genes were significantly upregulated in histologically damaged versus unaffected LN glomeruli providing a mechanistic link between C5a-C5aR1 signaling and early fibrosis in proliferative lupus nephritis. Our data provide insight into an understudied connection between complement activation and fibrosis relevant in SLE and likely other inflammatory diseases of complement activation.

immunology↗

Antiretroviral treatment does not prevent extrapulmonary tuberculosis during SIV/Mtb co-infection in macaques

Co-infection with both HIV and M. tuberculosis (Mtb) results in disseminated tuberculosis (TB) and accelerated progression of HIV. Despite greater access to antiretroviral treatment (ART), it remains unclear whether suppression of HIV replication protects against severe Mtb infection. Here, using a macaque model of SIV/Mtb coinfection, we investigated whether treatment of SIV infection with ART influenced control of a subsequent Mtb challenge compared to SIV infected macaques who were not treated with ART. Using a macaque model of simian immunodeficiency virus (SIV)-Mtb co-infection, macaques were first infected with SIVB670, SIVB670 with ART, or saline followed by a low-dose Mtb inoculation with serial clinical, microbiological, PET CT imaging, and immunologic assessments. At necropsy, gross pathology, viremia, bacterial burden, and immunologic parameters were compared. SIV-TB animals had greater gross pathology and total bacterial burden than TB only and SIV/ART/TB groups. However, despite normal blood CD4 counts and undetectable SIV RNA, SIV/ART/TB macaques showed similar clinical parameters and extrapulmonary involvement as SIV/TB animals. Analysis of barcoded-Mtb suggests ART control of SIV replication does not prevent Mtb extrapulmonary dissemination. These data indicate that people living with HIV on ART remain at high risk of bacterial dissemination and extrapulmonary TB disease, particularly when methods to identify extrapulmonary disease are inconsistent. This highlights the importance of understanding the mechanism of extrapulmonary spread and disease severity in HIV/TB co-infected individuals.

immunology↗