Biology subjects

Linke, A.

Publications and source records attributed to Linke, A..

6 recordsLinked to original sources

bioRxiv2025

Brain function in language and associated networks in non- or minimally verbal children

Language is universal in humans, develops robustly in infancy, and is rarely absent entirely in aphasia following strokes. Non- or minimally verbal children, in whom language has not developed by school-age in either production or comprehension, thus provide an unparalleled window into the human brain when it is deprived of language function. Yet insights from functional MRI are absent. Here we report results from a first study of intrinsic connectivity in 9 non- or minimally verbal children with autism spectrum disorder (nvASD) scanned under sedation with propofol along with 8 typically developing children (scanned awake), using resting-state (rs) fMRI. We targeted both functional (FC) and anatomically constrained, generative effective connectivity (GEC) in the speech and language networks, the insula and associated networks, and the hippocampus. Identical analyses were applied to an independent rsMRI dataset of healthy adults scanned both under propofol and while awake, to evaluate sedation confounds. NvASDs compared to their neurotypical peers showed a widespread pattern of hypoconnectivity in auditory speech perception, frontotemporal, and semantic processing regions, which extended further to the insula, and the hippocampus. GEC results selectively replicated these patterns, which correlated with autism diagnostic observation schedule (ADOS) behavioral scores within the nvASD group. This hypoconnectivity pattern extended neither to the adults scanned under propofol, nor to the visual cortex used as control region in nvASD, suggesting that this pattern of results could not be explained by sedation. Together, this first evidence from intrinsic connectivity reveals a broad pattern of underconnectivity across key cognitive networks, which provides a neural correlate for the significant breakdown of language-related cognitive functions in this population.

neuroscience↗

bioRxiv2025

Improved Source Localization of Auditory Evoked Fields using Reciprocal BEM-FMM

The precise localization of auditory evoked fields (AEFs) from magnetoencephalography (MEG) data is very important for the functional understanding of the auditory cortex in medicine and cognitive neuroscience. The numerical solution of the field equations in the human head using the boundary element method (BEM) is a powerful tool for achieving this. We hypothesized that the spatial resolution of the BEM is crucial for the achievable accuracy. However, in classical BEM (as implemented, e.g., in MNE-Python), very high resolutions are impractical due to the associated prohibitive computational effort. In contrast, our recently introduced reciprocal boundary element fast multipole method (reciprocal BEM-FMM) allows for hitherto unprecedented spatial resolution. In this work, we apply our reciprocal BEM-FMM technique for source estimation to localize AEFs, and we compare our results with the source estimates produced using a 3-layer BEM model (standard BEM) via MNE-Python. We first validate our methodology through comparison of source estimates of simulated N1m components of AEFs using a receiver operating characteristic (ROC) measure. While we obtain ROC measures of about 80% for the standard BEM, reciprocal BEM-FMM reaches about 90%, a significant statistical improvement. We then apply this methodology to analyze the source estimates of experimental data obtained from a cohort of 7 participants subjected to binaural auditory stimulation. Using a dispersion measurement to quantify the focality of localized sources, we find improvements upwards of 30% using reciprocal BEM-FMM over the standard BEM. Analyses from both simulated and experimental data show localization of AEFs using high-resolution reciprocal BEM-FMM is significantly better in terms of accuracy and focality than those estimates of the low-resolution standard BEM. We therefore recommend using the high-resolution reciprocal BEM-FMM to utilize high spatial anatomical precision for the modeling of neural activity.

neuroscience↗

bioRxiv2023

SOS1 inhibition enhances the efficacy of and delays resistance to G12C inhibitors in lung adenocarcinoma

Clinical effectiveness of KRAS G12C inhibitors (G12Cis) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. We found that targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 both enhanced the potency of and delayed resistance to G12Ci treatment, but the extent of SOS1i effectiveness was modulated by both SOS2 expression and the specific mutational landscape. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. Survival of drug-tolerant persister (DTP) cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) that drive therapeutic resistance. G12Ci drug tolerant persister cells showed a 2-3-fold enrichment of TICs, suggesting that these could be a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressor KEAP1 limits the clinical effectiveness of G12Cis, and KEAP1 and STK11 deletion increased TIC frequency and accelerated the development of acquired resistance to G12Ci in situ. SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. These data suggest that SOS1i could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations. SignificanceThe SOS1 inhibitor BI-3406 both inhibits intrinsic/adaptive resistance and targets drug tolerant persister cells to limit the development of acquired resistance to clinical KRASG12C inhibitors in lung adenocarcinoma cells.

cancer biology↗

bioRxiv2022

Transcriptional and clonal characterization of cytotoxic CD8+ T cells in crescentic glomerulonephritis

Crescentic glomerulonephritis (cGN), most often caused by anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, is an aggressive form of immune-mediated kidney disease and represents an important cause of end-stage renal failure. Although it is known that T cells infiltrate the kidney in cGN, their precise role in autoimmune kidney disease remains to be fully elucidated. By performing single-cell analysis, we identified activated, clonally expanded CD8+ T cells with a cytotoxic gene expression profile in the kidneys of patients with ANCA-associated cGN. Using an experimental model of cGN, we demonstrated that clonally expanded murine CD8+ T cells highly expressed the cytotoxic molecule granzyme B. Moreover, lack of CD8+ T cells or granzyme B resulted in an ameliorated course of cGN. This was associated with reduced cleaved caspase-3 induction in renal tissue cells. Our data indicate that clonally expanded cytotoxic CD8+ T cells have a previously unrecognized pathogenic function in aggravating immune-mediated kidney disease.

immunology↗

bioRxiv2019

Category-Selective Visual Regions Have Distinctive Signatures of Connectivity in Early Infancy

The development of the ventral visual stream is shaped both by an innate proto-organization and by experience. The fusiform face area (FFA), for example, has stronger connectivity to early visual regions representing the fovea and lower spatial frequencies. In adults, category-selective regions in the ventral stream (e.g. the FFA) also have distinct signatures of connectivity to widely distributed brain regions, which are thought to encode rich cross-modal, motoric, and affective associations (e.g., tool regions to the motor cortex). It is unclear whether this long-range connectivity is also innate, or if it develops with experience. We used MRI diffusion-weighted imaging with tractography to characterize the connectivity of face, place, and tool category-selective regions in neonates (N=445), 1-9 month old infants (N=11), and adults (N=14). Using a set of linear-discriminant classifiers, category-selective connectivity was found to be both innate and shaped by experience. Connectivity for faces was the most developed, with no evidence of significant change in the time period studied. Place and tool networks were present at birth but also demonstrated evidence of development with experience, with tool connectivity developing over a more protracted period (9 months). Taken together, the results support an extended proto-organizon to include long-range connectivity that could provide additional constraints on experience dependent development.

neuroscience↗

bioRxiv2017

Differences in the spatial and temporal patterns of head motion during MRI of adults and infants

AimHead motion has a profound effect on MRI, and will contaminate comparisons of function or structure between groups that move differently. This work compares adults and infants. Infants might move differently for physical, physiological and cognitive reasons, but so far these differences have not been quantified.\n\nMethodsThe spatial modes and total magnitude of motion in the MRI scanner were measured (N=211). The effects of group (infant vs. adult) and stimulation paradigm (auditory vs. visual) were evaluated.\n\nResultsSpatial modes of motion were found to be distinct between infant and adult groups. Infants had less anterior-posterior translational motion, but greater motion in other dimensions, often with complex multi-axis patterns. In magnitude distribution, sleeping infants often remained more still than adults, but when movement did occur it was more extreme and abrupt. Two groups of adults presented with different stimulation showed similar shapes of motion.\n\nConclusionThe spatial modes and magnitude distribution of motion differed substantially between groups, and must be considered carefully as a confound in comparisons of structure or function. The abruptness and magnitude of movement suggests that for infants relative to adults post-processing strategies such as de-noising are likely to be more effective than prospective motion correction.\n\nKey notesO_LIQuantified the spatial and temporal distribution of motion during MRI in 211 adults and neonates\nC_LIO_LIThe different spatial modes in adults and infants were visualized and statistically contrasted\nC_LIO_LIThe magnitude of motion had \"heavier tails\" in infants, with more still periods, and more large movements, than adults.\nC_LI

neuroscience↗