Biology subjects

Linke, M.

Publications and source records attributed to Linke, M..

7 recordsLinked to original sources

bioRxiv2026

Early Vision Shapes Recurrent Processing in the Human Visual Cortex

Recurrent processing involves feedforward, feedback and lateral connections and is thought to allow efficient visual processing. Anatomical and behavioral studies in humans have suggested that feedback connections mature later in development than feedforward connections and thus were proposed to depend to a larger degree on experience. In order to isolate feedforward from feedback activity and to investigate the role of early visual experience, we assessed seven individuals with reversed congenital cataracts and nine sighted controls using an "occlusion paradigm" with 7T magnetic resonance imaging (Smith & Muckli, 2010): Grayscale images of scenes were presented with the lower right quadrant covered by a white rectangle. We examined whether information about category (beaches, buildings, highways) and individual scenes could be extracted from early visual region vertices (V1 - V3) associated with the occluded quadrant of the visual field, in the absence of bottom-up visual input. This was achieved by decoding individual category or scene context utilizing a linear support vector machine. In addition, bidirectional information flow was assessed using connective field modeling. While both groups showed successful decoding of scene and category from vertices receiving bottom-up visual input, the accuracy was higher in normally sighted individuals than in individuals with reversed congenital cataracts. When bottom-up input was removed, decoding of categories remained successful in both groups, but decoding of individual scenes was only possible in normally sighted control individuals. Connective field modeling results indicated a less precise alignment of feedforward and feedback processing during visual stimulation in individuals with reversed congenital cataracts. These findings suggest that early visual experience is crucial for the refinement of feedback activity which in turn is crucial for well-tuned feedforward processing.

neuroscience↗

bioRxiv2026

16p11.2 Copy Number Variation Alters Genome Architecture and Transcriptional Regulation During Neurodevelopment

Microdeletions and microduplications in 16p11.2 are responsible for a spectrum of neurodevelopmental disorders (NDDs) with partially reciprocal and overlapping symptoms. However, the clinical variability in 16p11.2 microduplication patients is significantly greater than that in patients carrying a microdeletion. Here, we use iPSCs derived from members of a family carrying a 16p11.2 microduplication and model neurodevelopment through in vitro differentiation into neural progenitor cells (NPCs) and neurons. The analysis is complemented by reanalysis of publicly available data from 16p11.2 microdeletion patients. Transcriptome analysis revealed MAPK3-centered hubs of upregulated genes in the microduplication-carrying and downregulated in the microdeletion-carrying cells, indicating that MAPK3 is a central driver of 16p11.2 Copy Number Variation (CNV) pathology. While genes within the 16p11.2 region showed about a two-fold reduction in expression in cells carrying the microdeletion, their expression levels in microduplication-derived NPCs and neurons, but not in iPSCs, were elevated to a degree much higher than expected. This observation was accompanied by a substantial number of dysregulated genes unrelated to the genes in the critical region or their interaction networks. To further investigate whether altered chromatin organization may accompany these transcriptional changes, we generated Hi-C data from patient and control iPSCs and NPCs. This revealed increased chromatin contacts within the duplicated 16p11.2 region in patient-derived iPSCs, while genome-wide compartment analysis showed that increased compartments preferentially co-occurred with upregulated differentially expressed genes, particularly in NPCs. Together, these findings suggest that 16p11.2 microduplication may influence gene expression through both local dosage-dependent mechanisms and broader, differentiation-associated changes in chromatin organization. Our data support a model in which CNV-associated genome architecture changes may modulate transcriptional dysregulation and contribute to the variable neurodevelopmental phenotypes associated with 16p11.2 rearrangements.

pathology↗

bioRxiv2025

Single-cell chromatin landscape and DNA methylation patterns reveal shared molecular programs in human tumor and non-tumor tissue CCR8+ Treg cells

Regulatory T (Treg) cells, a subset of CD4+ T cells, play a crucial role in immunoregulation. Notably, CCR8-expressing Treg cells in tissues also contribute to organ homeostasis and repair. To determine whether these tissue-regenerative programs are active in the tumor microenvironment, we employed single-cell chromatin accessibility and genome-wide DNA methylation analyses to investigate CCR8+ tissue Treg cells isolated from human tumor and adjacent tumor-free tissues. Our findings indicate that CCR8+ tissue Treg cells from tumor and corresponding tumor-free tissues exhibit a high degree of similarity, suggesting that the tumor microenvironment may harbor highly activated tissue Treg cells. This observation was consistent across various tumor types and origins, including primary tumors and metastases. Using quantitative proteomics, we identified several candidate factors associated with the regenerative and suppressive programs of Treg cells, which may serve as potential reservoir of druggable targets for future therapeutic interventions.

immunology↗

bioRxiv2024

Visual and auditory object representations in ventral visual cortex after restoring sight in humans

Visual category-selective representations in human ventral occipital temporal cortex (VOTC) seem to emerge early in infancy. Surprisingly, the VOTC of congenitally blind humans features category-selectivity for auditory and haptic objects. Yet it has been unknown whether VOTC would show category-selective visual responses if sight were restored in congenitally blind humans. Assuming competition for synaptic space during development, cross-modal activation of VOTC as a consequence of congenital blindness might interfere with visual processing in sight-recovery individuals. To test this hypothesis, we investigated adults who had suffered a transient phase of congenital blindness due to bilateral dense cataracts before their sight was restored by cataract-removal surgery. In a functional magnetic resonance imaging (fMRI) study, participants watched movies of faces, scenes, body parts and other objects in the visual condition, while in the auditory condition they listened to the corresponding sounds. The most prominent group difference was the reduced face-selectivity in individuals with reversed congenital cataracts compared to age- and sex-matched normally-sighted individuals. In addition, a double dissociation was found: only sight-recovery individuals demonstrated significant decoding accuracy of visual categories based on auditory category representations in VOTC, while only normally-sighted individuals VOTC decoded auditory categories based on visual category representations. The present results uncovered the neural mechanisms of previously observed face processing impairments in individuals with reversed congenital blindness. We suggest that lower face-selectivity in the sight recovery group might arise from selective deficits in the cortical representation of the central visual field in lower-tier visual areas. Additionally, we speculate that in higher-order visual areas cross-modal activity might facilitate - rather than interfere - with visual functional recovery after congenital blindness.

neuroscience↗

bioRxiv2024

Direct RNA sequencing (RNA004) allows for improved transcriptome assessment and near real-time tracking of methylation for medical applications

Direct RNA sequencing (DRS) is a nanopore-based technique for analyzing RNA in its native form, promising breakthroughs in diagnostics and biomarker development. Coupled to RNA002 sequencing chemistry, its clinical implementation has been challenging due to low throughput, low accuracy, and lack of large-scale RNA-modification models. In this study, we evaluate the improvements achieved by pairing the latest RNA004 chemistry with novel modified-base-calling models for pseudouridine and N6-methyladenosine using diverse RNA samples from cell lines, synthetic oligos, and human blood. Finally, we present the first clinical application of DRS by confirming the loss of RNA methylation in a patient carrying truncating mutations in the methyltransferase METTL5. Conclusively, the combined use of RNA004 chemistry with the base-calling models significantly improved the throughput, accuracy, and site-specific detection of modifications. From this perspective, we offer an outlook on the potential suitability of DRS for use in routine diagnostics, the first comprehensive benchmark of human peripheral blood and quality assessments of RNA therapeutics.

bioinformatics↗

bioRxiv2023

Nanopore adaptive sampling of a metagenomic sample derived from a human monkeypox case

In 2022, a series of human monkeypox cases in multiple countries led to the largest and most widespread outbreak outside the known endemic areas. Genomic surveillance is of utmost importance to control such outbreaks. To this end, we performed Nanopore Whole Genome Sequencing of a local monkeypox sample on a PromethION 24. Adaptive sampling was applied for in silico depletion of the human host genome, allowing for the enrichment of low abundance viral DNA without a priori knowledge of sample composition. Nanopore sequencing allowed for high viral genome coverage, tracking of sample composition during sequencing, strain determination, and preliminary assessment of mutational pattern. Nanopore sequencing is a highly versatile method to characterize a virus in real-time without pre-sequencing target enrichment.

microbiology↗

bioRxiv2017

Harnessing optogenetics to probe sub-cellular mechanics

The mechanics of the actin cytoskeleton regulates cell morphogenesis during essential physiological processes. While cellular contractility is known to be largely RhoA-dependent, the process by which localized biochemical signals are translated into cell-level responses is not well understood. Here we combine optogenetic control of RhoA in space and time, live cell imaging and traction force microscopy to investigate the dynamics of actomyosin-based force generation in adherent fibroblasts. Local activation of RhoA not only stimulates local recruitment of actin and myosin, but also leads to increased traction forces outside the activation region that rapidly propagate across the cell via stress fibers and drive actin flow towards the region of heightened RhoA. Surprisingly, the flow reverses direction when local RhoA activation stops. We identify zyxin as a regulator of stress fiber mechanics, as stress fibers are fluid-like without flow reversal in its absence. These experimental data are used to constrain a physical model, which demonstrates that stress fibers are elastic-like, even at time scales exceeding turnover of constituent proteins. Such molecular control of actin mechanics likely plays critical roles in regulation of morphogenic events.

biophysics↗