A meta-analysis of the gut microbiome in inflammatory bowel disease patients identifies disease-associated small molecules.

Changes in the gut microbiome have been associated with several human diseases, but the molecular and functional details underlying these associations remain largely unknown. Here, we performed a multi-cohort analysis of small molecule biosynthetic gene clusters (BGCs) in 5,306 metagenomic samples of the gut microbiome from 2,033 Inflammatory Bowel Disease (IBD) patients and 833 matched healthy subjects and identified a group of Clostridia-derived BGCs that are significantly associated with IBD. Using synthetic biology, we discovered and solved the structures of six fatty acid amides as the products of the IBD-enriched BGCs.

Tapioca: a platform for predicting de novo protein-protein interactions in dynamic contexts.

Protein-protein interactions (PPIs) drive cellular processes and responses to environmental cues, reflecting the cellular state. Here we develop Tapioca, an ensemble machine learning framework for studying global PPIs in dynamic contexts. Tapioca predicts de novo interactions by integrating mass spectrometry interactome data from thermal/ion denaturation or cofractionation workflows with protein properties and tissue-specific functional networks.

To be or not to be: orb, the fusome and oocyte specification in Drosophila.

In the fruit fly Drosophila melanogaster, two cells in a cyst of 16 interconnected cells have the potential to become the oocyte, but only one of these will assume an oocyte fate as the cysts transition through regions 2a and 2b of the germarium. The mechanism of specification depends on a polarized microtubule network, a dynein dependent Egl:BicD mRNA cargo complex, a special membranous structure called the fusome and its associated proteins, and the translational regulator orb. In this work, we have investigated the role of orb and the fusome in oocyte specification.

Long Timescales, Individual Differences, and Scale Invariance in Animal Behavior.

The explosion of data on animal behavior in more natural contexts highlights the fact that these behaviors exhibit correlations across many timescales. However, there are major challenges in analyzing these data: records of behavior in single animals have fewer independent samples than one might expect. In pooling data from multiple animals, individual differences can mimic long-ranged temporal correlations; conversely, long-ranged correlations can lead to an overestimate of individual differences.

Efficient prime editing in two-cell mouse embryos using PEmbryo.

Using transient inhibition of DNA mismatch repair during a permissive stage of development, we demonstrate highly efficient prime editing of mouse embryos with few unwanted, local byproducts (average 58% precise edit frequency, 0.5% on-target error frequency across 13 substitution edits at 8 sites), enabling same-generation phenotyping of founders. Whole-genome sequencing reveals that mismatch repair inhibition increases off-target indels at low-complexity regions in the genome without any obvious phenotype in mice.

Short-term hypercaloric carbohydrate loading increases surgical stress resilience by inducing FGF21.

Dietary restriction promotes resistance to surgical stress in multiple organisms. Counterintuitively, current medical protocols recommend short-term carbohydrate-rich drinks (carbohydrate loading) prior to surgery, part of a multimodal perioperative care pathway designed to enhance surgical recovery. Despite widespread clinical use, preclinical and mechanistic studies on carbohydrate loading in surgical contexts are lacking.

Global WWTP Microbiome-based Integrative Information Platform: From experience to intelligence.

Domestic and industrial wastewater treatment plants (WWTPs) are facing formidable challenges in effectively eliminating emerging pollutants and conventional nutrients. In microbiome engineering, two approaches have been developed: a top-down method focusing on domesticating seed microbiomes into engineered ones, and a bottom-up strategy that synthesizes engineered microbiomes from microbial isolates. However, these approaches face substantial hurdles that limit their real-world applicability in wastewater treatment engineering.

mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b.

In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood.

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration.

Rational strain design with minimal phenotype perturbation.

Devising genetic interventions for desired cellular phenotypes remains challenging regarding time and resources. Kinetic models can accelerate this task by simulating metabolic responses to genetic perturbations. However, exhaustive design evaluations with kinetic models are computationally impractical, especially when targeting multiple enzymes.

Scale invariance in early embryonic development.

The body plan of the fruit fly is determined by the expression of just a handful of genes. We show that the spatial patterns of expression for several of these genes scale precisely with the size of the embryo. Concretely, discrete positional markers such as the peaks in striped patterns have absolute positions along the anterior-posterior axis that are proportional to embryo length, with better than 1% accuracy.

The value of information gathering in phage-bacteria warfare.

Phages-viruses that infect bacteria-have evolved over billions of years to overcome bacterial defenses. Temperate phage, upon infection, can "choose" between two pathways: lysis-in which the phage create multiple new phage particles, which are then liberated by cell lysis, and lysogeny-where the phage's genetic material is added to the bacterial DNA and transmitted to the bacterial progeny. It was recently discovered that some phages can read information from the environment related to the density of bacteria or the number of nearby infection attempts.

Developmental basis of SHH medulloblastoma heterogeneity.

Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development.

Interpretable neural architecture search and transfer learning for understanding CRISPR-Cas9 off-target enzymatic reactions.

Finely tuned enzymatic pathways control cellular processes, and their dysregulation can lead to disease. Developing predictive and interpretable models for these pathways is challenging because of the complexity of the pathways and of the cellular and genomic contexts. Here we introduce Elektrum, a deep learning framework that addresses these challenges with data-driven and biophysically interpretable models for determining the kinetics of biochemical systems.

Natural history of Ebola virus disease in rhesus monkeys shows viral variant emergence dynamics and tissue-specific host responses.

Ebola virus (EBOV) causes Ebola virus disease (EVD), marked by severe hemorrhagic fever; however, the mechanisms underlying the disease remain unclear. To assess the molecular basis of EVD across time, we performed RNA sequencing on 17 tissues from a natural history study of 21 rhesus monkeys, developing new methods to characterize host-pathogen dynamics. We identified alterations in host gene expression with previously unknown tissue-specific changes, including downregulation of genes related to tissue connectivity.

Developmental transcriptomes predict adult social behaviours in the socially flexible sweat bee, Lasioglossum baleicum.

Natural variation can provide important insights into the genetic and environmental factors that shape social behaviour and its evolution. The sweat bee, Lasioglossum baleicum, is a socially flexible bee capable of producing both solitary and eusocial nests. We demonstrate that within a single nesting aggregation, soil temperatures are a strong predictor of the social structure of nests.

Mapping protein states and interactions across the tree of life with co-fractionation mass spectrometry.

We present CFdb, a harmonized resource of interaction proteomics data from 411 co-fractionation mass spectrometry (CF-MS) datasets spanning 21,703 fractions. Meta-analysis of this resource charts protein abundance, phosphorylation, and interactions throughout the tree of life, including a reference map of the human interactome. We show how large-scale CF-MS data can enhance analyses of individual CF-MS datasets, and exemplify this strategy by mapping the honey bee interactome.

Peak-agnostic high-resolution cis-regulatory circuitry mapping using single cell multiome data.

Single same cell RNAseq/ATACseq multiome data provide unparalleled potential to develop high resolution maps of the cell-type specific transcriptional regulatory circuitry underlying gene expression. We present CREMA, a framework that recovers the full cis-regulatory circuitry by modeling gene expression and chromatin activity in individual cells without peak-calling or cell type labeling constraints. We demonstrate that CREMA overcomes the limitations of existing methods that fail to identify about half of functional regulatory elements which are outside the called chromatin 'peaks'.

Mechanical constraints to unbound expansion of on semi-solid surfaces.

How bacterial cells colonize new territory is a problem of fundamental microbiological and biophysical interest and is key to the emergence of several phenomena of biological, ecological, and medical relevance. Here, we demonstrate how bacteria stuck in a colony of finite size can resume exploration of new territory by aquaplaning and how they fine tune biofilm viscoelasticity to surface material properties that allows them differential mobility. We show how changing local interfacial forces and colony viscosity results in a plethora of bacterial morphologies on surfaces with different physical and mechanical properties.

The permissive binding theory of cancer.

The later stages of cancer, including the invasion and colonization of new tissues, are actively mysterious compared to earlier stages like primary tumor formation. While we lack many details about both, we do have an apparently successful explanatory framework for the earlier stages: one in which genetic mutations hold ultimate causal and explanatory power. By contrast, on both empirical and conceptual grounds, it is not currently clear that mutations alone can explain the later stages of cancer.

RNA structure modulates Cas13 activity and enables mismatch detection.

The RNA-targeting CRISPR nuclease Cas13 has emerged as a powerful tool for applications ranging from nucleic acid detection to transcriptome engineering and RNA imaging. Cas13 is activated by the hybridization of a CRISPR RNA (crRNA) to a complementary single-stranded RNA (ssRNA) protospacer in a target RNA. Though Cas13 is not activated by double-stranded RNA (dsRNA) , it paradoxically demonstrates robust RNA targeting in environments where the vast majority of RNAs are highly structured.