Biology subjects

Goodman, J.

Publications and source records attributed to Goodman, J..

7 recordsLinked to original sources

bioRxiv2026

Collateral Sensitivity Strongly Connected Components in Real-World Clinical Surveillance Data: Retrospective Detection of Evolutionary Traps in WHO Priority Pathogens

Collateral sensitivity (CS) - acquisition of resistance to one antibiotic inducing hypersensitivity to another - offers an evolutionary trap for multidrug-resistant pathogens. A strongly connected component (SCC) in the directed CS graph represents a closed cycle in which every drug is reachable from every other via successive CS edges. Prior evidence for CS SCCs derives from in vitro experiments; whether such structures exist in clinical surveillance data has not been tested. We mined 104,337 antibiotic susceptibility records from BV-BRC spanning four WHO critical-priority pathogens (Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa; 18,821 unique isolates), applying Fisher's exact test with Benjamini-Hochberg FDR correction to all ordered antibiotic pairs, Tarjan's algorithm for SCC detection, and permutation testing (n = 1,000). A 3-node SCC in K. pneumoniae - imipenem, meropenem, tetracycline - met every criterion: empirical p = 0.001, bidirectional carbapenem-tetracycline edges at OR = 1.81-1.82 (q < 0.002, n > 850 per edge), tetracycline-specific relative to tigecycline, and stable across independent year bands. It does not survive stratification by clonal lineage. Assigning MLST sequence types to 5,276 of 5,382 genomes and pooling the same contingency tables by Cochran-Mantel-Haenszel gives within-lineage odds ratios of 0.93 and 0.95 (CMH p = 0.73 and 0.80), with confidence intervals excluding the unadjusted estimate. The two dominant strata pull in opposite directions (ST307, OR = 1.26; ST258, OR = 0.67). Permuting sequence-type labels 300 times while preserving stratum sizes leaves the odds ratio at a median of 1.76, so the collapse is attributable to lineage specifically rather than to stratification; de novo re-typing from genome sequence agreed with the assignments used in 32 of 33 isolates. The crude association is therefore confounded by clonal structure: carbapenem-resistant and tetracycline-resistant phenotypes co-occur because they are carried by different successful lineages, not because resistance to one induces susceptibility to the other. We report this as a negative result with a reusable control. Two larger clinical collateral-sensitivity analyses have been published without lineage adjustment, and the permutation test used here distinguishes genuine confounding from stratification artefact at negligible cost.

microbiology↗

bioRxiv2026

Synthetic germ granules reveal a direct role of Vasa/DDX4 in RNA localization and translational activation

AbstractCytoplasmic RNA granules, including stress granules, P bodies, neuronal RNA granules, and germ granules, are essential for RNA storage and regulation across a wide range of organisms. However, dissecting the contributions of individual factors to granule function is challenging because of the interdependence of components in vivo. This is especially true for DEAD-box helicases, common regulators of mRNA granules, whose specific contributions remain unclear. In this study, we developed a synthetic approach to de novo generate germ granules, enabling us to identify the minimal machinery needed for RNA localization and translational activation. Using a self-assembling PopTag-based scaffold derived from Caulobacter fused to the RNA-binding domain (RBD) of the germplasm organizer Oskar, we found that the recruitment of endogenous germ granule mRNAs (nanos and pgc) depended on the DDX4 protein Vasa. By employing orthogonal RNA tethering approaches, we demonstrate that Vasa is both necessary and sufficient for localized mRNA translation. Consistent with these findings, acute depletion of Vasa from endogenous germ granules specifically reduced Nanos translation without affecting mRNA localization, confirming Vasa as a core factor linking RNA recruitment to localized translational activation. These in vivo reconstitution experiments reveal a two-component module in which a scaffold RBD and the Vasa helicase, but not other DEAD-box helicases, enable RNP condensates to accumulate specific RNAs and promote their translation. Overall, our study uncovers previously unrecognized functions of an RNA helicase within ribonucleoprotein condensates and demonstrates the power of synthetic biology to analyze complex biomolecular condensates in living organisms.

developmental biology↗

bioRxiv2025

A microfluidics-based platform enables discovery of gametogenicrejuvenation factors in Saccharomyces cerevisiae

During mitotic growth, Saccharomyces cerevisiae cells age by dividing asymmetrically producing young daughter cells while retaining age-associated damage in the mother cell, which will eventually become senescent. Gametogenesis naturally and fully resets precursor cell lifespan, even for replicatively aged cells. However, the mechanisms responsible for gametogenic rejuvenation remain elusive. This is, in part, due to the existing methods to quantify replicative lifespan resetting in this context, which are limited to low-throughput and labor-intensive approaches. Here, we introduce a high-throughput microfluidic-based assay that allows systematic characterization of factors required for gametogenic rejuvenation in S. cerevisiae. With this technique, we show that we can sensitively measure a wide range of gamete replicative lifespans that are consistent with known short and long-lived mutants. Excitingly, using this technique, we report Atg39 and Atg40, receptors involved in selective autophagy of the ER, as the first identified molecular determinants of gametogenic rejuvenation. We anticipate that this novel technique will enable systematic identification of additional molecular factors that drive gametogenic rejuvenation.

molecular biology↗

bioRxiv2025

Pln1 Mediates Lipid Droplet-Vacuole Tethering During Microlipophagy Saccharomyces cerevisiae

Lipid droplets (LDs) are dynamic organelles that undergo growth or degradation depending on the metabolic state of the cell. One form of LD degradation is autophagy-mediated, referred to as lipophagy. Here, we demonstrate that Pln1, a perilipin located on the surface of LDs in Saccharomyces cerevisiae, previously known for its role in LD biogenesis, is essential for lipophagy. Pln1 facilitates the docking of cytosolic LDs to vacuoles, the lysosome-like organelles responsible for LD degradation, under various nutrient conditions. Molecular dissection of Pln1 revealed that the N-terminal PAT (Perilipin (PLN1), Adipophilin (PLN2), and TIP47 (PLN3)) domain and a hydrophobic region are critical for the localization and binding of LDs to vacuoles. Site-specific mutagenesis within the PAT domain identified a semi-hydrophobic LD Interacting Motif (LIM), which is vital for this interaction. Furthermore, an intrinsically disordered region (IDR) near the center of Pln1 is required for efficient LD-vacuole tethering. These findings support a model in which Pln1 bridges LDs and vacuoles by simultaneously interacting with both organelles. Notably, deleting PLN1 did not impair survival during prolonged nitrogen starvation and enhanced viability in autophagy-defective (atg8{Delta}) cells, suggesting that balancing Pln1-mediated LD biogenesis and lipophagy is crucial for yeast survival under starvation conditions.

cell biology↗

bioRxiv2025

APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction

APOE4 is the leading genetic risk factor for Alzheimers disease, and chronic stress is a leading environmental risk factor. Studies suggest that APOE4 confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimers onset and progression. Whether and how APOE4-mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and Alzheimers pathology, remains unexplored. Using a combination of in vivo and in vitro experiments in humanized APOE4 and APOE3 knockin mice and primary hippocampal neurons from these animals, we investigate whether and how APOE4 confers sensitivity to glucocorticoids, the main stress hormones. We find that a major hallmark of stress/glucocorticoid-induced brain damage, tau pathology (i.e., tau accumulation, hyperphosphorylation, and spreading) is exacerbated in APOE4 versus APOE3 mice. Moreover, APOE4 animals exhibit underlying mitochondrial dysfunction and enhanced glucocorticoid receptor activation in the hippocampus, factors that likely contribute to tau pathogenesis in both the presence and absence of stress/glucocorticoids. Supporting this concept, we show that opening of the mitochondrial permeability transition pore drives mitochondrial dysfunction and tau pathology in APOE4 mice, and that pharmacological inhibition of pore opening is protective against ApoE4-mediated mitochondrial damage, tau phosphorylation and spreading, and downstream hippocampal synapse loss. These findings shed light on the mechanisms of stress vulnerability in APOE4 carriers and identify the mitochondrial permeability transition pore as a potential therapeutic target for ameliorating Alzheimers pathogenesis in this population.

neuroscience↗

bioRxiv2024

Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex

Adipogenin (Adig) is an evolutionarily conserved microprotein and is highly expressed in adipose tissues and testis. Here, we identify Adig as a critical regulator for lipid droplet formation in adipocytes. We determine that Adig interacts directly with seipin, leading to the formation of a rigid complex. We solve the structure of the seipin/Adig complex by Cryo-EM at 2.98[A] overall resolution. Surprisingly, seipin can form two unique oligomers, undecamers and dodecamers. Adig selectively binds to the dodecameric seipin complex. We further find that Adig promotes seipin assembly by stabilizing and bridging adjacent seipin subunits. Functionally, Adig plays a key role in generating lipid droplets in adipocytes. In mice, inducible overexpression of Adig in adipocytes substantially increases fat mass, with enlarged lipid droplets. It also elevates thermogenesis during cold exposure. In contrast, inducible adipocyte-specific Adig knockout mice manifest aberrant lipid droplet formation in brown adipose tissues and impaired cold tolerance.

cell biology↗

bioRxiv2019

Free water in white matter differentiates MCI and AD from control subjects

Recent evidence show that neuroinflammation plays a role in many neurological diseases including mild cognitive impairment (MCI) and Alzheimers disease (AD), and that free water (FW) modeling from clinically acquired diffusion MRI (DTI-like acquisitions) can be sensitive to this phenomenon. This FW index measures the fraction of the diffusion signal explained by isotropically unconstrained water, as estimated from a bi-tensor model. In this study, we developed a simple FW processing pipeline that uses a safe white matter (WM) mask without gray matter (GM)/CSF partial volume contamination (WMsafe) near ventricles and sulci. We investigated if FW inside the WMsafe mask, including and excluding areas of white matter damage such as white matter hyperintensities (WMHs) as shown on T2 FLAIR, computed across the whole white matter could be indicative of diagnostic grouping along the AD continuum. After careful quality control, 81 cognitively normal controls (NC), 103 subjects with MCI and 42 with AD were selected from the ADNIGO and ADNI2 databases. We show that MCI and AD have significantly higher FW measures even after removing all partial volume contamination. We also show, for the first time, that when WMHs are removed from the masks, the significant results are maintained, which demonstrates that the FW measures are not just a byproduct of WMHs. Our new and simple FW measures can be used to increase our understanding of the role of inflammation-associated edema in AD and may aid in the differentiation of healthy subjects from MCI and AD patients.

neuroscience↗