San Diego Biomedical Research Institute

Building on our previous finding that a small fibrinogen peptide inhibits microglial repair of the hypoxia-disrupted blood-brain barrier (BBB), we directly evaluated the importance of fibrinogen in this process by studying these events in fibrinogen knockout (KO) mice. While young (4 months old) fibrinogen KO mice were still capable of mediating a vasculo-protective response to chronic mild hypoxia (CMH; 8% O2), the extent of vascular leak in these mice was much greater than wild-type (WT) mice. Consistent with this, fibrinogen KO mice displayed greatly reduced levels of hypoxia-induced microglial activation, proliferation, and aggregation around leaky blood vessels. Notably, defects in fibrinogen KO mice became more pronounced with age such that by 8-months old, a large fraction (3/8) of fibrinogen KO mice failed to survive 4 days CMH, and those that survived showed much greater loss of myelin and neurons compared to WT. Furthermore, under normoxic conditions, microglia in middle-aged (13 months old) fibrinogen KO mice were significantly less activated compared to WT, suggesting that slow fibrinogen leak across the age-weakened BBB might explain why microglia are more activated in aged mice. Finally, in vitro studies revealed that microglia readily attach to fibrinogen and that compared to other pro-adhesive ECM proteins such as fibronectin, fibrinogen promotes morphological transition into a polarized phenotype capable of greater levels of migration. Together, these observations demonstrate the importance of fibrinogen in promoting an effective microglial vasculo-protective response and suggest that pharmacological manipulation of fibrinogen-microglial interactions in the aged brain could hold therapeutic promise in the prevention or treatment of vascular dementia.

The practical realization of lithium metal batteries (LMBs)─long hailed for their high theoretical energy density─continues to be impeded by the persistent challenge of lithium dendrite formation, which compromises safety and cycling stability. In this study, we introduce 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TPP) as an electrolyte additive to suppress dendritic lithium growth. The porphyrin additive forms an in situ lithium-TPP complex at the Li metal interface, which facilitates the interfacial charge transfer and homogenizes the Li+ flux, thereby stabilizing the lithium metal deposition. Symmetric cells incorporating 20 mM TPP in a commercial electrolyte, with a thin polymeric separator that offers minimal resistance to dendritic penetration, exhibit stable cycling for over 1000 h at 0.5 mA cm–2 without short-circuiting and stable voltage response under increasing current, significantly outperforming the reference cell without the TPP-containing electrolyte, which suffers rapid short-circuit failure. Scanning electron microscopy reveals a compact lithium morphology with the TPP-modified electrolyte, while operando solid-state 7Li NMR spectroscopy during symmetric Li-cell cycling confirms the suppression of dendrite formation. Full cells using Li4Ti5O12 cathodes demonstrate 90% capacity retention over 150 cycles, with a Coulombic efficiency of 99.9%. These results highlight the potential of porphyrin-based additives in enabling safe and long-lasting lithium metal batteries, and may inspire broader exploration of molecular complexes as a dynamic interphase in next-generation energy storage systems.

Autosomal monoallelic gene expression and asynchronous replication between alleles are well-established features of imprinted genes and genes regulated by allelic exclusion. Inactivation/Stability Centers (I/SCs) are recently described autosomal loci that exhibit epigenetic regulation of allelic expression and replication timing, with differences that can be comparable to those observed between the active and inactive X chromosomes 1. Here we characterize hundreds of autosomal loci with allele-specific epigenetic regulation of replication timing and gene expression, defining them as I/SCs. I/SCs are approximately 1 megabase in size and can contain both protein-coding and noncoding genes. In different single cell derived clones, these genes may be expressed from a single allele, the opposite allele, both alleles, or not expressed at all. This stochastic, yet mitotically stable, pattern indicates that the choice of which allele is expressed is independent of parent of origin and independent of the expression status of the other allele. Similarly, alleles within I/SCs show varying replication timing, either earlier or later, that is also independent of the other allele. Additionally, we find corresponding I/SCs in the mouse genome that display conserved synteny with human I/SCs. This allele-restricted regulation creates extensive cellular mosaicism through a stable epigenetic mechanism. This mosaicism impacts numerous dosage-sensitive genes associated with human diseases such as Parkinson, epilepsy, deafness, and impaired intellectual development.

Neuroimmune signals can regulate neuronal function and affect behavior through mechanisms that are not yet fully understood. Here we investigated the action of interleukin 13 (IL-13), a cytokine that can be produced in the brain by both microglia and neurons. We show that dopamine-containing neurons in the ventral tegmental area (VTA) predominantly express the IL-13 receptor alpha 1 (IL-13Rα1) and exhibit presynaptic vesicular localization of neuronal IL-13. Exogenous application of IL-13, or its endogenous mobilization by optogenetics, reduced the activity of VTA dopaminergic neurons and opposed the stimulatory effects of nicotine on these neurons in rodents. These actions required IL-13Rα1, activation of the PI3K/AKT pathway, and functional hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Consistently, local infusion of IL-13 into the VTA markedly reduced nicotine self-administration in rodents. Collectively, these findings demonstrate that IL-13 acts in a neuromodulator-like fashion on mesolimbic dopamine neurons expressing IL-13Rα1. Our data also indicate that IL-13Rα1 signaling regulates the stimulatory actions of nicotine, suggesting a potential role for this neuronal immune signaling in reward processing and the addictive properties of nicotine.

Our study contributes to a more gender-sensitive approach to marine spatial planning, aiming for balanced, sustainable growth in the blue economy. It examined gendered ocean use patterns and their implications for equitable marine spatial planning. To document the distinct ways men and women interact with and value ocean spaces, we analyzed participatory mapping results from Ocean Use Surveys (OUS) conducted in three regions: the Maldives, the Azores, and Belize. The findings show that, globally, men dominate offshore activities like commercial fishing, whereas women’s activities are concentrated nearshore, often involving informal economic roles such as subsistence fishing, tourism, and cultural uses. Our analysis generated gender-specific heat maps highlighting areas of ocean use by sector and gender. This gender-disaggregated data revealed spatial and sectoral differences: in the Azores, women are more active in research and recreational fishing; in Belize, they engage in mariculture; and in the Maldives, they participate in more informal, small-scale, self-employed economies. We also addressed the gender gap in ocean data, a result of historic biases in data collection, which has led to undervaluing women’s contributions to the maritime economy and to gender-blind policies. The findings stress the need for gender-disaggregated data in marine planning to avoid exacerbating gender inequities and to ensure inclusive, effective policies. We recommend enhanced data practices that capture women’s oceanic contributions, advocating for mixed-gender survey teams and targeted outreach to reduce bias. Policymakers are encouraged to integrate these insights to support equitable marine governance, fostering inclusivity in ocean resource management. • In three regions studied, men and women use and value ocean space differently. • Ocean use surveys show men dominate offshore activities while women focus nearshore. • Gender-disaggregated data is vital for equitable, inclusive marine spatial planning. • Formalizing and valuing women’s nearshore roles can strengthen coastal economies.

Abstract SMC5/6 is unique amongst the Structural Maintenance of Chromosomes (SMC) complexes in its ability to repress transcription from extrachromosomal circular DNA (ecDNA), including viral genomes and plasmids. Previously, we showed that human SMC5/6 is regulated by two mutually exclusive subcomplexes—SIMC1-SLF2 and SLF1/2—the counterparts of yeast Nse5/6 (Oravcová, eLife, 2022). Notably, only SIMC1-SLF2 recruits SMC5/6 to SV40 Large T antigen (LT) foci in PML nuclear bodies (PML NBs), suggesting that these regulatory subcomplexes direct distinct roles of SMC5/6 on chromosomal versus ecDNA. However, their roles in plasmid repression remain unclear. Here, we demonstrate that SMC5/6-mediated repression of plasmid transcription depends exclusively on SIMC1-SLF2, whereas SLF1/2 is dispensable. Reinforcing its specialized role in ecDNA suppression, SIMC1-SLF2 does not participate in SMC5/6 recruitment to chromosomal DNA lesions. We further show that plasmid silencing requires a conserved interaction between SIMC1-SLF2 and SMC6, mirroring the functional relationship observed between yeast Nse5/6 and Smc6. As for viral silencing, plasmid repression depends on the SUMO pathway; however, unlike viral silencing, it does not require PML NBs. Additionally, we find that LT interacts with SMC5/6 and increases plasmid transcription to levels observed in SIMC1-SLF2-deficient cells–echoing the antagonistic roles of HBx (HBV) and Vpr (HIV-1) in viral genome repression. These findings expand the paradigm of viral antagonism against SMC5/6-mediated silencing, positioning LT as a novel player in this evolutionary tug-of-war.

Abstract Models of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Whereas gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.

Antibodies that target the gp120-gp41 interface of the HIV-1 envelope (Env) trimer comprise a commonly elicited category of broadly neutralizing antibodies (bNAbs). Here, we isolate and characterize VRC44, a bNAb lineage with up to 52% neutralization breadth. The cryoelectron microscopy (cryo-EM) structure of antibody VRC44.01 in complex with the Env trimer reveals binding to the same gp120-gp41 interface site of vulnerability as antibody 35O22 from a different HIV-1-infected donor. In addition to having similar angles of approach and extensive contacts with glycans N88 and N625, VRC44 and 35O22 derive from the same IGHV1-18 gene and share convergent mutations, indicating these two antibodies to be members of the only known highly glycan-dependent multidonor class. Strikingly, both lineages achieved almost 100% neutralization breadth against virus strains displaying high-mannose glycans. The high breadth and reproducible elicitation of VRC44 and 35O22 lineages validate germline-based methods of immunogen design for targeting the HIV-1 gp120-gp41 interface.