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bioRxiv2026

A Mechanistic Account of Dedifferentiation in the Aging Visual System

To uncover the mechanisms of age-related dedifferentiation, we simulated neural degradation in a computational model of the ventral visual stream. Severing connections or adding noise, whether in inferotemporal cortex (IT) or upstream, reduced IT differentiation, indicating that dedifferentiation need not originate locally. Degrading peripheral V1, which preferentially drove place-selective IT neurons, selectively reduced place differentiation, a candidate mechanism for the stronger place dedifferentiation reported in aging.

neuroscience↗
bioRxiv2026

Exploratory positional differences in observed CDRH2 lineage-state transitions following HIV-1 germline-targeting vaccination

Background: Germline-targeting HIV-1 vaccination recruits VRC01-class B-cell precursors, but the positional patterns of observed longitudinal B-cell receptor lineage-state changes remain incompletely described. We compared CDRH2 profiles between homologous and heterologous boosting regimens using published IAVI G002 data. Methods: Participant-specific Week-8 lineages were prospectively matched to Week-24 observations. Germline-to-nongermline changes in sampled lineage-modal residues were evaluated at seven IGHV1-2*02 CDRH2 positions using participant-balanced, mean-centered profiles and exact participant-label permutation inference. Sampling-depth and sorting-probe sensitivity analyses assessed observability. A separate participant-held-out benchmark evaluated antibody-language-model representations for predicting observed Week-24 lineage detection. Results: The CDRH2 analysis included 332 lineages, 15 participants, 2,179 eligible lineage-position observations, and 241 observed state changes. The regional profile statistic was 0.027066 (exact p = 0.001709; six-region adjusted q = 0.010256), with descriptive differences at V-relative positions 51, 54, and 55. Most eligible longitudinal observations had one assessable cell per visit. In seven Group-1 participants, Week-24 dual-probe sampling recovered 181 baseline lineages with eOD-GT8 and 143 with Cg28v2, including 60 detected by both probes. In a separate cohort of 2,739 lineages from 17 participants, IgBERT and AbLang-2 representations did not improve participant-balanced average precision over a four-feature biological baseline. Conclusions: Observed CDRH2 lineage-modal-state profiles differed between regimens in this exploratory secondary analysis. Sparse sampling, potentially probe-related ascertainment, and absent linked functional validation preclude inference about mutation timing, functional improvement, or causal booster effects.

immunology↗
bioRxiv2026

Multivalent mRNA tuberculosis vaccines protect against mycobacterial infection in zebrafish, mice and guinea pigs

Despite a century of BCG use, tuberculosis remains a leading cause of death from infectious diseases and more effective vaccines are urgently needed. Here we combined antigen discovery in zebrafish with mRNA vaccine technology to generate multivalent vaccine candidates, TUmRNA4, TUmRNA6 and TUmRNA9, encoding four, six, or nine Mycobacterium tuberculosis antigens, respectively. The vaccines were well tolerated, and induced robust antigen-specific cellular immune responses, including IFN{gamma} production and expansion of memory T-cell populations. In mice, TUmRNA4 and TUmRNA6 reduced pulmonary M. tuberculosis burden and lung pathology to levels comparable to BCG vaccination and TUmRNA6 enhanced BCG-mediated protection when used as a booster vaccine. In guinea pigs, TUmRNA9 reduced bacterial burden in the lungs, spleen, and lymph nodes and decreased pulmonary lesions. These findings demonstrate that protective antigens identified in zebrafish can be translated into effective multivalent mRNA vaccines and establish a framework for tuberculosis vaccine development across multiple preclinical models.

immunology↗
bioRxiv2026

Biochemical reassessment of the activation of PANK1 by SGLT2 inhibitors

Although SGLT2 inhibitors (SGLT2i) show cardiovascular benefits in addition to glycemic control, their molecular target for cardiovascular effect remains unclear. A recent study reported that two SGLT2i, empagliflozin and dapagliflozin, directly activate pantothenate kinase 1 (PANK1), which mediate their cardioprotective effect. PANK1 phosphorylates pantothenate with ATP to yield 4'-phosphopantothenate and ADP, representing the rate-limiting enzyme of coenzyme A (CoA) biosynthesis. We therefore reassessed this claim using purified recombinant human PANK1. The malachite green assay detected free inorganic phosphate (Pi) but neither ADP nor 4'-phosphopantothenate and its signals do not reflect PANK1 activity. In the ADP-Glo assay, empagliflozin and dapagliflozin did not stimulate PANK1 under either basal conditions or acetyl-CoA feedback inhibition, while the activator PZ-2891 enhanced the activity of PANK1. These results show that SGLT2i do not directly activate PANK1, challenging the proposed PANK1-dependent cardioprotection mechanism.

biochemistry↗
bioRxiv2026

Longitudinal miRNA-mRNA Profiling Reveals Network Reorganization in Preeclampsia

Background: Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity. Temporal dynamics of molecular dysregulation across pregnancy remain poorly understood. We performed longitudinal RNA sequencing of maternal whole blood to characterize miRNA-mRNA regulatory network evolution in PE. Methods: Whole-blood samples from early (M1: 10-18 weeks) and late pregnancy (M2: 32-38 weeks) were analyzed from 43 PE cases and 106 normotensive controls, including 109 paired samples (36 PE cases, 73 controls). Differential expression, temporal classification, pathway enrichment, and miRNA-mRNA network integration were performed. Placental expression support was assessed using internal RNA-seq and public databases. Key miRNA-mRNA interactions were experimentally validated in HTR-8/SVneo trophoblast cells. Results: PE exhibited marked temporal reorganization of miRNA-mRNA networks, with strongly opposing temporal effect sizes across overlapping miRNA and mRNA features (Spearman {rho} = -0.82, P < 0.0001). PI3K/AKT/mTORC1 signaling showed biphasic reversal (NES = +1.46, FDR = 0.028 at M1; NES = -1.64, FDR = 0.025 at M2), and heme-metabolism programs showed progressive suppression (2.1-fold NES intensification; FDR < 0.05 at both timepoints). Network analysis identified 29 high-confidence biphasic miRNA-mRNA pairs, including convergent targeting of ADGRA2 by three miRNAs and HSD17B1 by three miRNAs. miR-101-3p overexpression reduced DEPP1 mRNA (~40%) and protein (~26%) in trophoblast cells (P < 0.01), supporting a FOXO-DEPP1 axis. Blood-derived pairs showed pathway convergence with placental VGLL3-centered programs (PI3K/AKT, FOXO, TGF-{beta}, trophoblast differentiation). Conclusions: PE is associated with predominantly stage-specific or biphasic miRNA-mRNA network reorganization, with PI3K/AKT/mTORC1 dynamic remodeling and progressive heme-metabolism suppression. These findings support gestational-age-specific biomarker development and identify regulatory axes, including miR-101-3p [->] DEPP1, for mechanistic investigation.

genomics↗
bioRxiv2026

Reusing pipettes in Patch-seq: a foundation for automated multimodal profiling

Patch-seq is a technique for single-cell multimodal characterization. It combines whole-cell electrophysiology, single-cell transcriptomics, and morphological reconstruction in single neurons. Patch-seq morphologies are a critical bridge among cell types, genes, physiology, and large-scale connectivity platforms such as EM connectomes and single-cell-resolution projectomes. However, patch-seq experimental complexity and operator dependence limit throughput. Automation could enable scalable Patch-seq but requires procedural adaptations, including detergent-based pipette cleaning, robotic nucleus extraction and collection. The impact of these automations on Patch-seq quality has not been systematically evaluated. Here, we show that each of these modifications preserves or improves key Patch-seq outcomes. Automated nucleus extraction performs comparably to, or better than, expert manual operation, preserving key RNA and morphological metrics. Detergent-cleaned, reused pipettes supported a viable sealing success rate across multiple cleaning cycles and preserved electrophysiological quality and transcriptomic yield without introducing excess contamination. Sonication effectively allows collection of nuclear material without damaging RNA and supports subsequent pipette cleaning and reuse. Enhanced automated sealing and break-in procedures increased throughput regardless of brain region, cell type or species. Together, these results validate the core procedural adaptations required for automated Patch-seq and establish a foundation for high-throughput, standardized multimodal single-cell characterization.

neuroscience↗
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