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Biology subjects

Stark, J.

Publications and source records attributed to Stark, J..

6 recordsLinked to original sources

Tree-to-cycle transition scale characterizes trade-off between dissipation and construction cost in adaptive transport networks

Biological transport networks range from tree-like to highly reticulated architectures, which have been proposed to reflect different balances between viscous dissipation and metabolic cost. This balance cannot currently be inferred from structure: available descriptors either discard edge width entirely or preserve it only as a hierarchical decomposition that has not been mapped to the dissipation--cost trade-off. Here we introduce the tree-to-cycle transition scale, a single number given by the radius of the thickest edge outside the maximum spanning tree, which we interpret as the highest cost a network accepts for redundancy. We compute it for networks adapting to spatially correlated load fluctuations, whose correlation length sets their position on the Pareto front. The transition scale decreases linearly with dissipation and increases linearly with metabolic cost. Its scatter is largest in the regime where some networks end up off the front, and adding a growth term removes the scatter but splits the correlation into two branches. A single quantity read off the static network architecture thus characterizes where a network sits on the Pareto front, and is sensitive to the trajectory the network took through the optimization landscape. This suggests a route to comparing observed networks, for example leaf venations across species or growth conditions, by the trade-off they realize.

biophysics↗

Molecular characterization of MRI/CYREN reveals the Ku binding mode and the role of multimerization in stimulating the activity of NHEJ in DNA repair

Mammalian cells primarily repair DNA double-strand breaks through non-homologous end joining (NHEJ), a pathway that requires the Ku heterodimer, DNA-PKcs, XRCC4 complexed with DNA Ligase 4, and XLF as core components. In addition, several auxiliary proteins are involved in the regulation of NHEJ, whose importance has been underscored recently. Among them, MRI, also known as CYREN, is one of the most important auxiliary proteins. Despite its importance, the structural properties of MRI remain poorly characterized. In this study, we used solution NMR spectroscopy combined with cellular experiments to investigate two isoforms of human MRI (MRI1 and MRI2) at the residue level. Our findings reveal that both isoforms are predominantly disordered, and that the APLF-like Ku-binding motif (A-KBM) of MRI undergoes folding upon binding to the von Willebrand A domain of Ku80 (Ku80vWA). Moreover, an evolutionarily dominant leucine-to-methionine substitution in A-KBM significantly increases binding affinity for Ku80vWA by over 30 times without impacting cellular NHEJ efficiency. Importantly, we identified here a domain that drives MRI multimerization that is required for efficient NHEJ in cellular assays. This work further deciphers the increasingly recognized functional roles of disordered protein regions of the NHEJ machinery.

biophysics↗

Prolonged TGF-β locks NK cells in a dysfunctional state through persistent epigenetic remodeling of IRF, T-bet and EOMES binding sites

TGF-{beta} signaling is a major regulator of immune cell differentiation and function, yet whether prolonged signaling can durably imprint dysfunctional immune states independently of continued pathway engagement remains unclear. Here, we identify signal duration as a critical determinant of human natural killer (NK) cell fate: short-term TGF-{beta} exposure induces largely reversible transcriptional, chromatin and functional changes, whereas prolonged exposure establishes persistent effector dysfunction independent of continued signaling. Mechanistically, prolonged TGF-{beta} drives durable loss of chromatin accessibility at effector-associated regulatory elements, particularly those enriched for IRF, EOMES, and T-bet binding motifs, resulting in stable restriction of NK cell effector programs despite reversibility of active histone marks. In contrast, tissue residency-associated programs remain largely reversible, revealing that distinct NK cell fate programs differ fundamentally in their susceptibility to epigenetic fixation downstream of the same cytokine signal. SMAD4 CUT&RUN and knockout experiments further demonstrate that canonical TGF-{beta} signaling acts primarily through rewiring of upstream transcriptional regulatory networks rather than direct targeting of effector loci. Finally, NK cells from patients with hepatocellular carcinoma recapitulate key functional and epigenetic features of the persistent TGF-{beta}-associated state defined in vitro. Together, these findings identify signal duration as a critical determinant of TGF-{beta}-driven cell fate and demonstrate that prolonged TGF-{beta} exposure can induce epigenetically stabilized dysfunctional states that persist after signal withdrawal, with important implications for therapeutic strategies aimed at reversing chronic TGF-{beta}-mediated dysfunction.

immunology↗

Morphogen gradients are regulated by porous media characteristics of the developing tissue

Long-range morphogen gradients have been proposed to form by morphogen diffusion from a localized source to distributed sinks in the target tissue. The role of the complex tissue geometry in this process is, however, less well understood and has not been explicitly resolved in existing models. Here, we numerically reconstruct pore-scale 3D geometries of zebrafish epiboly from light-sheet microscopy images. In these high-resolution 3D geometries, we simulate Fgf8a gradient formation in the tortuous extracellular space. Our simulations show that when realistic embryo geometries are considered, a source-diffusion-degradation mechanism with additional binding to extracellular matrix polymers is sufficient to explain self-organized emergence and robust maintenance of Fgf8a gradients. The predicted normalized gradient is robust against changes in source and sink rates but sensitive to changes in the pore connectivity of the extracellular space, with lower connectivity leading to steeper and shorter gradients. This demonstrates the importance of considering realistic geometries when studying morphogen gradients. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/588250v2_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@66c705org.highwire.dtl.DTLVardef@1943009org.highwire.dtl.DTLVardef@1dda6dcorg.highwire.dtl.DTLVardef@f5db66_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

Airway injury induces alveolar epithelial and mesenchymal responses mediated by macrophages

Airway injury activates local progenitors and stimulates cell-cell interactions to restore homeostasis, but it is unknown how distal niches are impacted. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar and immune responses. Single-cell transcriptomics and in vivo validation of mouse models of airway-specific epithelial injury revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific injury or ablation. Myeloid cells exhibited altered gene expression after club cell loss and were detectable in the bronchoalveolar lavage fluid. The AT2 cell proliferative response was reliant on alveolar macrophages (AMs) exhibiting an injury-induced gene expression program. Overall, these results demonstrate that acute airway damage can trigger myeloid-mediated lung alveolar responses that may contribute to disease susceptibility or dysfunction.

cell biology↗

Conserved lipid and small molecule modulation of COQ8 reveals regulation of the ancient UbiB family

Human COQ8A (ADCK3) and Saccharomyces cerevisiae Coq8p (collectively COQ8) are UbiB family proteins essential for mitochondrial coenzyme Q (CoQ) biosynthesis. However, the biochemical activity of COQ8 and its direct role in CoQ production remain unclear, in part due to lack of known endogenous regulators of COQ8 function and of effective small molecules for probing its activity in vivo. Here we demonstrate that COQ8 possesses evolutionarily conserved ATPase activity that is activated by binding to membranes containing cardiolipin and by phenolic compounds that resemble CoQ pathway intermediates. We further create an analog-sensitive version of Coq8p and reveal that acute chemical inhibition of its endogenous activity in yeast is sufficient to cause respiratory deficiency concomitant with CoQ depletion. Collectively, this work defines lipid and small molecule modulators of an ancient family of atypical kinase-like proteins and establishes a chemical genetic system for further exploring the mechanistic role of COQ8 in CoQ biosynthesis.

biochemistry↗