Publications

Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer’s Disease. An important mechanism of Aβ clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as Aβ. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade Aβ oligomers due to a phagolysosome dysfunction. An Alzheimer’s mouse model containing phospho-deficient PS1 show severe Aβ accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer’s -associated phenotypes.

Malignancy in cancer is a consequence of the progressive accumulation of mutations in a tumor, with profound implications for drug selection and treatment. However, in human studies, inter-patient variability obscures molecular signatures of tumor progression because patients usually present with a single mammary tumor. In contrast, dogs frequently exhibit multiple naturally occurring mammary tumors in the same individual. Moreover, canine mammary tumors (CMTs) and human breast cancer have similar histopathological profiles and clinical presentation. We leverage the CMT model to elucidate genome-wide molecular changes clinically relevant in human breast cancer, focusing on signals underlying tumor development. We develop a robust, generally applicable, computational analysis framework (FREYA) for analysis of CMTs for comparative oncology. Using FREYA, we RNA profile 89 samples from 16 dogs, and demonstrate that CMTs recapitulate human breast cancer subtypes. We then extract molecular profiles of breast cancer progression at three distinct stages (normal, pre-malignant and malignant) and identify signatures of gene expression reflective of tumor progression. Focusing on the transitions to malignancy, we identify transcriptional patterns and biological pathways specific to malignant tumors and distinct from those characterizing pre-malignant tumors or normal tissue. We find that human breast cancer patients whose tumors exhibit strong CMT malignancy signatures have significantly decreased survival, indicative of the importance of the tumor progression processes identified in CMTs to human breast cancer prognosis. Altogether, our comprehensive genomic characterization demonstrates that CMTs are a powerful translational model of breast cancer, providing insights that inform our understanding of tumor development in humans. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we publicly share all of our data and provide FREYA, a robust data processing pipeline and statistical analyses framework, at freya.flatironinstitute.org.

Transferring knowledge between species is challenging: different species contain distinct proteomes and cellular architectures, which cause their proteins to carry out different functions via different interaction networks. Many approaches to proteome and biological network functional annotation use sequence similarity to transfer knowledge between species. These similarity-based approaches cannot produce accurate predictions for proteins without homologues of known function, as many functions require cellular or organismal context for meaningful function prediction. In order to supply this context, network-based methods use protein-protein interaction (PPI) networks as a source of information for inferring protein function and have demonstrated promising results in function prediction. However, the majority of these methods are tied to a network for a single species, and many species lack biological networks. In this work, we integrate sequence and network information across multiple species by applying an IsoRank-derived network alignment algorithm to create a meta-network profile of the proteins of multiple species. We then use this integrated multispecies meta-network as input features to train a maxout neural network with Gene Ontology terms as target labels. Our multispecies approach takes advantage of more training examples, and more diverse examples from multiple organisms, and consequently leads to significant improvements in function prediction performance. Further, we evaluate our approach in a setting in which an organism’s PPI network is left out, using other organisms’ network information and sequence homology in order to make predictions for the left-out organism, to simulate cases in which a newly sequenced species has no network information available.

Animal embryos are patterned by a handful of highly conserved inductive signals. Yet, in most cases, it is unknown which pattern features (i.e., spatial gradients or temporal dynamics) are required to support normal development. An ideal experiment to address this question would be to “paint” arbitrary synthetic signaling patterns on “blank canvas” embryos to dissect their requirements. Here, we demonstrate exactly this capability by combining optogenetic control of Ras/extracellular signal-related kinase (ERK) signaling with the genetic loss of the receptor tyrosine-kinase-driven terminal signaling patterning in early Drosophila embryos. Blue-light illumination at the embryonic termini for 90 min was sufficient to rescue normal development, generating viable larvae and fertile adults from an otherwise lethal terminal signaling mutant. Optogenetic rescue was possible even using a simple, all-or-none light input that reduced the gradient of Erk activity and eliminated spatiotemporal differences in terminal gap gene expression. Systematically varying illumination parameters further revealed that at least three distinct developmental programs are triggered at different signaling thresholds and that the morphogenetic movements of gastrulation are robust to a 3-fold variation in the posterior pattern width. These results open the door to controlling tissue organization with simple optical stimuli, providing new tools to probe natural developmental processes, create synthetic tissues with defined organization, or directly correct the patterning errors that underlie developmental defects.

Self-diffusion in dense rod suspensions are subject to strong geometric constraints because of steric interactions. This topological effect is essentially anisotropic when rods are nematically aligned with their neighbors, raising considerable challenges in understanding and analyzing their impacts on the bulk physical properties. Via a classical Doi-Onsager kinetic model with the Maier-Saupe potential, we characterize the long-time rotational Brownian diffusivity for dense suspensions of hard rods of finite aspect ratios, based on quadratic orientation autocorrelation functions. Furthermore, we show that the computed nonmonotonic scalings of the diffusivity as a function of volume fraction can be accurately predicted by an alternative tube model in the nematic phase.

The famous Arrhenius equation is well motivated to describe the temperature dependence of chemical reactions but has also been used for complicated biological processes. Here, we evaluate how well the simple Arrhenius equation predicts complex multistep biological processes, using frog and fruit fly embryogenesis as two canonical models. We find the Arrhenius equation provides a good approximation for the temperature dependence of embryogenesis, even though individual developmental stages scale differently with temperature. At low and high temperatures, however, we observed significant departures from idealized Arrhenius Law behavior. When we model multistep reactions of idealized chemical networks we are unable to generate comparable deviations from linearity. In contrast, we find the single enzyme GAPDH shows non-linearity in the Arrhenius plot similar to our observations of embryonic development. Thus, we find that complex embryonic development can be well approximated by the simple Arrhenius Law and propose that the observed departure from this law results primarily from non-idealized individual steps rather than the complexity of the system.

The double-helical topology of DNA molecules observed at room temperature in the absence of any external loads can be disrupted by increasing the bath temperature or by applying tensile forces, leading to spontaneous strand separation known as DNA melting. Here, continuum mechanics of a 2D birod is combined with statistical mechanics to formulate a unified framework for studying both thermal melting and tensile force induced melting of double-stranded molecules: it predicts the variation of melting temperature with tensile load, provides a mechanics-based understanding of the cooperativity observed in melting transitions, and reveals an interplay between solution electrostatics and micromechanical deformations of DNA which manifests itself as an increase in the melting temperature with increasing ion concentration. This novel predictive framework sheds light on the micromechanical aspects of DNA melting and predicts trends that were observed experimentally or extracted phenomenologically using the Clayperon equation.

Current estimates of COVID-19 prevalence are largely based on symptomatic, clinically diagnosed cases. The existence of a large number of undiagnosed infections hampers population-wide investigation of viral circulation. Here, we use longitudinal wastewater analysis to track SARS-CoV-2 dynamics in wastewater at a major urban wastewater treatment facility in Massachusetts, between early January and May 2020. SARS-CoV-2 was first detected in wastewater on March 3. Viral titers in wastewater increased exponentially from mid-March to mid-April, after which they began to decline. Viral titers in wastewater correlated with clinically diagnosed new COVID-19 cases, with the trends appearing 4-10 days earlier in wastewater than in clinical data. We inferred viral shedding dynamics by modeling wastewater viral titers as a convolution of back-dated new clinical cases with the viral shedding function of an individual. The inferred viral shedding function showed an early peak, likely before symptom onset and clinical diagnosis, consistent with emerging clinical and experimental evidence. Finally, we found that wastewater viral titers at the neighborhood level correlate better with demographic variables than with population size. This work suggests that longitudinal wastewater analysis can be used to identify trends in disease transmission in advance of clinical case reporting, and may shed light on infection characteristics that are difficult to capture in clinical investigations, such as early viral shedding dynamics.

We demonstrate that an achiral stretching force transforms disk-shaped colloidal membranes composed of chiral rods into twisted ribbons with handedness opposite the preferred twist of the rods. Using an experimental technique that enforces torque-free boundary conditions we simultaneously measure the force-extension curve and the ribbon shape. An effective theory that accounts for the membrane bending energy and uses geometric properties of the edge to model the internal liquid crystalline degrees of freedom explains both the measured force-extension curve and the force-induced twisted shape.

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10−4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10−5). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1–5.0, P = 5.4 × 10−3). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1–1.2, P = 8.8 × 10−5). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.