Publications

Human biology is rooted in highly specialized cell types programmed by a common genome, 98% of which is outside of genes. Genetic variation in the enormous noncoding space is linked to the majority of disease risk. To address the problem of linking these variants to expression changes in primary human cells, we introduce ExPectoSC, an atlas of modular deep-learning-based models for predicting cell-type-specific gene expression directly from sequence. We provide models for 105 primary human cell types covering 7 organ systems, demonstrate their accuracy, and then apply them to prioritize relevant cell types for complex human diseases. The resulting atlas of sequence-based gene expression and variant effects is publicly available in a user-friendly interface and readily extensible to any primary cell types. We demonstrate the accuracy of our approach through systematic evaluations and apply the models to prioritize ClinVar clinical variants of uncertain significance, verifying our top predictions experimentally.

Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, deficiency of coenzyme Q (CoQ), mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells results in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (under chow and high fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial Ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

The cell nucleus is enveloped by a complex membrane, whose wrinkling has been implicated in disease and cellular aging. The biophysical dynamics and spectral evolution of nuclear wrinkling during multicellular development remain poorly understood due to a lack of direct quantitative measurements. Here we characterize the onset and dynamics of nuclear wrinkling during egg development in the fruit fly when nurse cell nuclei increase in size and display stereotypical wrinkling behaviour. A spectral analysis of three-dimensional high-resolution live-imaging data from several hundred nuclei reveals a robust asymptotic power-law scaling of angular fluctuations consistent with renormalization and scaling predictions from a nonlinear elastic shell model. We further demonstrate that nuclear wrinkling can be reversed through osmotic shock and suppressed by microtubule disruption, providing tunable physical and biological control parameters for probing the mechanical properties of the nuclear envelope. Our findings advance the biophysical understanding of nuclear membrane fluctuations during early multicellular development.

Coarsening of two-phase systems is crucial for the stability of dense particle packingssuch as alloys, foams, emulsions, or supersaturated solutions. Mean field theoriespredict an asymptotic scaling state with a broad particle size distribution. Aqueousfoams are good model systems for investigations of coarsening-induced structures,because the continuous liquid as well as the dispersed gas phases are uniform andisotropic. We present coarsening experiments on wet foams, with liquid fractionsup to their unjamming point and beyond, that are performed under microgravity toavoid gravitational drainage. As time elapses, a self-similar regime is reached wherethe normalized bubble size distribution is invariant. Unexpectedly, the distributionfeatures an excess of small roaming bubbles, mobile within the network of jammedlarger bubbles. These roaming bubbles are reminiscent of rattlers in granular materials(grains not subjected to contact forces). We identify a critical liquid fraction흓∗, abovewhich the bubble assembly unjams and the two bubble populations merge into a singlenarrow distribution of bubbly liquids. Unexpectedly,흓∗is larger than the randomclose packing fraction of the foam흓rcp. This is because, between흓rcpand흓∗, the largebubbles remain connected due to a weak adhesion between bubbles. We present modelsthat identify the physical mechanisms explaining our observations. We propose a newcomprehensive view of the coarsening phenomenon in wet foams. Our results shouldbe applicable to other phase-separating systems and they may also help to control theelaboration of solid foams with hierarchical structures

The forces which orient the spindle in human cells remain poorly understood due to a lack of direct mechanical measurements in mammalian systems. We use magnetic tweezers to measure the force on human mitotic spindles. Combining the spindle’s measured resistance to rotation, the speed it rotates after laser ablating astral microtubules, and estimates of the number of ablated microtubules reveals that each microtubule contacting the cell cortex is subject to ∼1 pN of pulling force, suggesting that each is pulled on by an individual dynein motor. We find that the concentration of dynein at the cell cortex and extent of dynein clustering are key determinants of the spindle’s resistance to rotation, with little contribution from cytoplasmic viscosity, which we explain using a biophysically based mathematical model. This work reveals how pulling forces on astral microtubules determine the mechanics of spindle orientation and demonstrates the central role of cortical dynein clustering.

Surface tension at cavity walls can play havoc with the mechanical properties of perforated soft solids when the cavities are filled with a fluid. This study is an investigation of the macroscopic elastic properties of elastomers embedding spherical cavities filled with a pressurized liquid in the presence of surface tension, starting with the linearization of the fully nonlinear model and ending with the enhancement properties of the linearized model when many such liquid filled cavities are present.

Incomplete labels are common in multi-task learning for biomedical applications due to several practical difficulties, e.g., expensive annotation efforts by experts, limit of data collection, different sources of data. A naive approach to enable joint learning for partially labeled data is adding self-supervised learning for tasks without ground truths by augmenting an input image and forcing the multi-task model to return the same outputs for both the input and augmented images. However, the partially labeled setting can result in imbalanced learning of tasks since not all tasks are trainable with ground truth supervisions for each data sample. In this work, we propose a multi-task curriculum learning method tailored for partially labeled data. For balanced learning of tasks, our multitask curriculum prioritizes less performing tasks during training by setting different supervised learning frequencies for each task. We demonstrate that our method outperforms standard approaches on one biomedical and two natural image datasets. Furthermore, our learning method with partially labeled data performs better than the standard multi-task learning methods with fully labeled data for the same number of annotations.

Blastomere instance segmentation is important for analyzing embryos’ abnormality. To measure the accurate shapes and sizes of blastomeres, their amodal segmentation is necessary. Amodal instance segmentation aims to recover an object’s complete silhouette even when the object is not fully visible. For each detected object, previous methods directly regress the target mask from input features. However, images of an object under different amounts of occlusion should have the same amodal mask output, making it harder to train the regression model. To alleviate the problem, we propose to classify input features into intermediate shape codes and recover complete object shapes. First, we pre-train the Vector Quantized Variational Autoencoder (VQ-VAE) model to learn these discrete shape codes from ground truth amodal masks. Then, we incorporate the VQ-VAE model into the amodal instance segmentation pipeline with an additional refinement module. We also detect an occlusion map to integrate occlusion information with a backbone feature. As such, our network faithfully detects bounding boxes of amodal objects. On an internal embryo cell image benchmark, the proposed method outperforms previous state-of-the-art methods. To show generalizability, we show segmentation results on the public KINS natural image benchmark. Our method would enable accurate measurement of blastomeres in In Vitro Fertilization (IVF) clinics, potentially increasing the IVF success rate.

Sensation of light is essential for all organisms. The eye-less nematode Caenorhabditis elegans detects UV and blue light to evoke escape behavior. The photosensor LITE-1 absorbs UV photons with an unusually high extinction coefficient, involving essential tryptophans. Here, we modeled the structure and dynamics of LITE-1 using AlphaFold2-multimer and molecular dynamics (MD) simulations and performed mutational and behavioral assays in C. elegans to characterize its function. LITE-1 resembles olfactory and gustatory receptors from insects, recently shown to be tetrameric ion channels. We identified residues required for channel gating, light absorption, and mechanisms of photo-oxidation, involving a likely binding site for the peroxiredoxin PRDX-2. Furthermore, we identified the binding pocket for a putative chromophore. Several residues lining this pocket have previously been established as essential for LITE-1 function. A newly identified critical cysteine pointing into the pocket represents a likely chromophore attachment site. We derived a model for how photon absorption, via a network of tryptophans and other aromatic amino acids, induces an excited state that is transferred to the chromophore. This evokes conformational changes in the protein, possibly leading to a state receptive to oxidation of cysteines and, jointly, to channel gating. Electrophysiological data support the idea that LITE-1 is a photon and H2O2-coincidence detector. Other proteins with similarity to LITE-1, specifically C. elegans GUR-3, likely use a similar mechanism for photon detection. Thus, a common protein fold and assembly, used for chemoreception in insects, possibly by binding of a particular compound, may have evolved into a light-activated ion channel.

Under a sufficiently large load, a solid material will flow via rearrangements, where particles change neighbors. Such plasticity is most easily described in the athermal, quasistatic limit of zero temperature and infinitesimal loading rate, where rearrangements occur only when the system becomes mechanically unstable. For disordered solids, the instabilities marking the onset of rearrangements have long been believed to be fold instabilities, in which an energy barrier disappears and the frequency of a normal mode of vibration vanishes continuously. Here, we report that there exists another, anomalous, type of instability caused by the breaking of a “stabilizing bond,” whose removal creates an unstable vibrational mode. For commonly studied systems, such as those with harmonic finite-range interparticle interactions, such “discontinuous instabilities” are not only inevitable, they often dominate the modes of failure. Stabilizing bonds are a subset of all the bonds in the system and are prevalent in disordered solids generally. Although they do not trigger discontinuous instabilities in systems with vanishing stiffness at the interaction cutoff, they are, even in those cases, local indicators of incipient mechanical failure. They therefore provide an accurate structural predictor of instabilities not only of the discontinuous type but of the fold type as well.