By Luis Linares-Otoya, Jaden D. Shirkey, Bhuwan Khatri Chhetri, Amira Mira, Abhishek Biswas, Samuel L. Neff, Maria V. Linares-Otoya, Ye Chen, Julio V. Campos-Florian, Mayar L. Ganoza-Yupanqui, Philip D. Jeffrey, Frederick M. Hughson & Mohamed S. Donia

Considerable advances have been made in characterizing bioactive molecules secreted by bacteria, yet the regulatory elements controlling their production remain largely understudied. Here we identify and characterize the N-acyl-cyclolysine (ACL) system—a cell-density-dependent chemical signalling system specific to and widespread in the phylum Bacteroidota (formerly Bacteroidetes)—and show that it regulates the expression of co-localized operons encoding diverse secreted molecules. Using genetic and biochemical analyses, combined with structural studies of a key biosynthetic enzyme, AclA, we elucidate the molecular structure of various ACLs and their complete biosynthetic pathway involving l-lysine acylation and ATP-dependent cyclization. Furthermore, we find that secreted ACLs are sensed by a dedicated transcription factor, AclR, resulting in the expression of associated operons and the autoinduction of ACL biosynthesis. Moreover, we show that different Bacteroidota strains produce structurally diverse ACLs and encode transcription factors with varying ligand specificities. Finally, we find that the acl circuit is widely distributed and transcribed in human gut and oral microbiome samples, with clear evidence for an active role in regulating associated operons under host colonization conditions. Understanding the function of the ACL system in different contexts has the potential to reveal details about the biology, ecology and chemistry of the Bacteroidota and how members of this phylum interact with their environments and hosts.

Read the paper: https://www.nature.com/articles/s41586-025-09418-9

By Jiayu Zhang, Elizabeth C. Chavez, Melina Winkler, Jianche Liu, Sebastian Carver, Aaron E. Lin, Abhishek Biswas, Tomokazu Tamura, Anna Tseng, Danyang Wang, Aaron Benhamou, Aoife K. O’ Connell, Mao Matsuo, Jack E. Norton, Devin Kenney, Britt Adamson, Ralph E. Kleiner, Benjamin Burwitz, Nicholas A. Crossland, Florian Douam & Alexander Ploss

The live-attenuated yellow fever 17D vaccine strain differs genetically only minimally from its virulent parent. However, it remains unclear which sequence differences lead to virulence or attenuation. Here we demonstrate, using SHAPE-MaP, that these mutations do not induce global RNA structure changes and show that protein sequence mutations are mostly responsible for the phenotypic differences between 17D and virulent YFV. Using a highly modular, combinatorial genetic approach, we identified key mutations in the envelope (E) and non-structural 2A (NS2A) proteins that increase 17D’s ability to spread and enhance host antiviral responses. Introducing these mutations into infectious clones of virulent YFV genomes results in viral attenuation in vitro and in two mouse models. Collectively, our results define the genetic basis for 17D attenuation and highlight a potentially general approach for creating live-attenuated vaccines by introducing mutations resulting in similar phenotypic changes in other pathogenic viruses.

Read the paper: https://www.nature.com/articles/s41564-025-02047-y

We’re excited to announce the publication of a new paper, Ten Simple Rules for Catalyzing Collaborations and Building Bridges between Research Software Engineers (RSEs) and Software Engineering Researchers (SERs), authored by Nasir Eisty, Jeffrey Carver, Johanna Cohoon, Ian Cosden, Carole Goble, and Samuel Grayson.

Published in IEEE Computing in Science & Engineering (CiSE), this work emerged from discussions at a Dagstuhl Seminar and addresses a critical but often overlooked opportunity in the research software ecosystem: fostering collaboration between RSEs and SERs.

While both communities share a passion for improving software in research, they often operate in distinct environments, with different vocabularies, incentives, and expectations. This paper offers ten actionable rules designed to bridge those gaps, encouraging meaningful, sustained partnerships that combine practical experience with theoretical insight.

By working together, RSEs and SERs can drive innovation in tools, practices, and infrastructure, ultimately advancing the quality and impact of scientific research.

Read the preprint: https://arxiv.org/abs/2506.03012

Published version: https://ieeexplore.ieee.org/document/11003859

By Leybova L, Biswas A, Sharan R, Trejo BM, Kim K, Soto-Muniz Y, Jones RA, Phillips BK, Devenport D.

The bending of simple cellular sheets into complex three-dimensional (3D) forms requires developmental patterning cues to specify where deformations occur, but how positional information directs morphological change is poorly understood. Here, we investigate how morphogen signaling and cell fate diversification contribute to the morphogenesis of murine hair placodes, in which collective cell movements transform radially symmetric primordia into bilaterally symmetric tubes. Through live imaging and 3D volumetric reconstructions, we demonstrate that Wnt and Shh establish radial patterns of cell fate, cell morphology, and movement within developing placodes. Cell fate diversity at different radial positions provides unique and essential contributions to placode morphogenesis. Further, we show that downstream of radial patterning, gradients of classical cadherin expression are required for efficient epithelial rearrangements. Given that the transformation of epithelial discs into 3D tubes is a common morphological motif used to shape diverse organ primordia, mechanisms of radially patterned morphogenesis are likely highly conserved across evolution.

Read the paper: https://doi.org/10.1016/j.devcel.2024.09.022

By Hayden Nunley, Binglun Shao, David Denberg, Prateek Grover, Jaspreet Singh, Maria Avdeeva, Bradley Joyce, Rebecca Kim-Yip, Abraham Kohrman, Abhishek Biswas, Aaron Watters, Zsombor Gal, Alison Kickuth, Madeleine Chalifoux, Stanislav Y. Shvartsman, Lisa M. Brown, Eszter Posfai

For investigations into fate specification and morphogenesis in time-lapse images of preimplantation embryos, automated 3D instance segmentation and tracking of nuclei are invaluable. Low signal-to-noise ratio, high voxel anisotropy, high nuclear density, and variable nuclear shapes can limit the performance of segmentation methods, while tracking is complicated by cell divisions, low frame rates, and sample movements. Supervised machine learning approaches can radically improve segmentation accuracy and enable easier tracking, but they often require large amounts of annotated 3D data. Here, we first report a previously unreported mouse line expressing near-infrared nuclear reporter H2B-miRFP720. We then generate a dataset (termed BlastoSPIM) of 3D images of H2B-miRFP720-expressing embryos with ground truth for nuclear instances. Using BlastoSPIM, we benchmark seven convolutional neural networks and identify Stardist-3D as the most accurate instance segmentation method. With our BlastoSPIM-trained Stardist-3D models, we construct a complete pipeline for nuclear instance segmentation and lineage tracking from the eight-cell stage to the end of preimplantation development (>100 nuclei). Finally, we demonstrate the usefulness of BlastoSPIM as pre-train data for related problems, both for a different imaging modality and for different model systems.

Read the paper: https://doi.org/10.1242/dev.202817

By Berggren KA, Sinha S, Lin AE, Schwoerer MP, Maya S, Biswas A, Cafiero TR, Liu Y, Gertje HP, Suzuki S, Berneshawi AR, Carver S, Heller B, Hassan N, Ali Q, Beard D, Wang D, Cullen JM, Kleiner RE, Crossland NA, Schwartz RE, Ploss A.

Modification of RNA with N⁶-methyladenosine (m⁶A) has gained attention in recent years as a general mechanism of gene regulation. In the liver, m⁶A, along with its associated machinery, has been studied as a potential biomarker of disease and cancer, with impacts on metabolism, cell cycle regulation, and pro-cancer state signaling. However these observational data have yet to be causally examined in vivo. For example, neither perturbation of the key m⁶A writers Mettl3 and Mettl14, nor the m⁶A readers Ythdf1 and Ythdf2 have been thoroughly mechanistically characterized in vivo as they have been in vitro. To understand the functions of these machineries, we developed mouse models and found that deleting Mettl14 led to progressive liver injury characterized by nuclear heterotypia, with changes in mRNA splicing, processing and export leading to increases in mRNA surveillance and recycling.

Read the paper: https://doi.org/10.1101/2024.06.17.599413

By Maureen Cetera, Rishabh Sharan, Gabriela Hayward-Lara, Brooke Phillips, Abhishek Biswas, Madalene Halley, Evalyn Beall, Bridgett vonHoldt, Danelle Devenport

The planar cell polarity (PCP) pathway collectively orients cells with respect to a body axis. Hair follicles of the murine epidermis provide a striking readout of PCP activity in their uniform alignment across the skin. Here, we characterize, from the molecular to tissue-scale, PCP establishment in the rosette fancy mouse, a natural variant with posterior-specific whorls in its fur, to understand how epidermal polarity is coordinated across the tissue. We find that rosette hair follicles emerge with reversed orientations specifically in the posterior region, creating a mirror image of epidermal polarity. The rosette trait is associated with a missense mutation in the core PCP gene Fzd6, which alters a consensus site for N-linked glycosylation, inhibiting its membrane localization. Unexpectedly, the Fzd6 trafficking defect does not block asymmetric localization of the other PCP proteins. Rather, the normally uniform axis of PCP asymmetry rotates where the PCP-directed cell movements that orient follicles are reversed, suggesting the PCP axis rotates 180°. Collectively, our multiscale analysis of epidermal polarity reveals PCP patterning can be regionally decoupled to produce posterior whorls in the rosette fancy mouse.

Read the paper: https://doi.org/10.1242/dev.202078

By Yongzhen Liu, Thomas R. Cafiero, Debby Park, Abhishek Biswas, Benjamin Y. Winer, Cheul H. Cho, Yaron Bram, Vasuretha Chandar, Aoife K. O’ Connell, Hans P. Gertje, Nicholas Crossland, Robert E. Schwartz & Alexander Ploss

Hepatitis B virus (HBV) only infects humans and chimpanzees, posing major challenges for modeling HBV infection and chronic viral hepatitis. The major barrier in establishing HBV infection in non-human primates lies at incompatibilities between HBV and simian orthologues of the HBV receptor, sodium taurocholate co-transporting polypeptide (NTCP). Through mutagenesis analysis and screening among NTCP orthologues from Old World monkeys, New World monkeys and prosimians, we determined key residues responsible for viral binding and internalization, respectively and identified marmosets as a suitable candidate for HBV infection. Primary marmoset hepatocytes and induced pluripotent stem cell-derived hepatocyte-like cells support HBV and more efficient woolly monkey HBV (WMHBV) infection. Adapted chimeric HBV genome harboring residues 1–48 of WMHBV preS1 generated here led to a more efficient infection than wild-type HBV in primary and stem cell derived marmoset hepatocytes. Collectively, our data demonstrate that minimal targeted simianization of HBV can break the species barrier in small NHPs, paving the path for an HBV primate model.

Read the paper: https://www.nature.com/articles/s41467-023-39148-3

By Robert LeDesma, Brigitte Heller, Abhishek Biswas, Stephanie Maya, Stefania Gili, John Higgins, Alexander Ploss

Hepatitis E virus (HEV) is an RNA virus responsible for over 20 million infections annually. HEV’s open reading frame (ORF)1 polyprotein is essential for genome replication, though it is unknown how the different subdomains function within a structural context. Our data show that ORF1 operates as a multifunctional protein, which is not subject to proteolytic processing. Supporting this model, scanning mutagenesis performed on the putative papain-like cysteine protease (pPCP) domain revealed six cysteines essential for viral replication. Our data are consistent with their role in divalent metal ion coordination, which governs local and interdomain interactions that are critical for the overall structure of ORF1; furthermore, the ‘pPCP’ domain can only rescue viral genome replication in trans when expressed in the context of the full-length ORF1 protein but not as an individual subdomain. Taken together, our work provides a comprehensive model of the structure and function of HEV ORF1.

Read the paper: https://doi.org/10.7554/eLife.80529