Publications by Year: 2026

The O1 serogroup of Vibrio cholerae has caused all cholera pandemics and for over a century V. cholerae O1 outbreak strains have been characterized by their serotype. The two V. cholerae serotypes differ by the presence (Ogawa) or absence (Inaba) of methylation of the terminal sugar on the lipopolysaccharide O1-antigen. Serotype switching often occurs during epidemics and has historically been attributed to the pathogen adapting to immune pressures. Here we address the impact of serotype on V. cholerae pathogenicity using otherwise isogenic Ogawa and Inaba versions of several clinical V. cholerae O1 isolates. Our findings indicate that O1 antigen methylation in Ogawa strains promotes V. cholerae colonization, infectivity and resistance to antimicrobial peptides. We propose that methylation of the O1 antigen elevates colonization by shielding the bacterium from cationic antimicrobial peptides at the pH of the small intestine. These observations provide insights into the biological significance of the V. cholerae O1 serotypes.

The lack of biomarkers to identify individuals at risk of asthma exacerbations remains a significant limitation to improving patient outcomes. To address this need, we analyze data from three asthma cohorts, combining up to 25 years of electronic medical records with sequential metabolomics studies, to develop and replicate a predictive model for asthma exacerbation risk. We identify asthma-associated biochemical pathways via global circulatory metabolomics and then apply targeted mass spectrometry methods to quantify selected steroids, sphingolipids, and microbial-derived metabolites. The sphingolipid-to-steroid ratios robustly associate with 5-year exacerbation risk (discovery p value = 1.63×10⁻26-0.029; replication p value = 1.89×10⁻36-0.033). Based upon these findings, we derive and replicate a simple 5-year predictive model of asthma exacerbations using 21 sphingolipid-to-steroid ratios that outperforms current clinical measures (discovery AUC = 0.90; replication AUC = 0.89). These findings underscore the value of metabolomic profiling to develop a practical, cost-effective clinical assay for asthma exacerbation risk that may improve patient care.

Recent epigenome-wide studies have identified a large number of genomic regions that consistently exhibit changes in their methylation status with aging across diverse populations, but the functional consequences of these changes are largely unknown. On the other hand, transcriptomic changes are more easily interpreted than epigenetic alterations, but previously identified age-related gene expression changes have shown limited replicability across populations. Here, we develop an approach that leverages high-resolution multi-omic data for an integrative analysis of epigenetic and transcriptomic age-related changes and identify genomic regions associated with both epigenetic and transcriptomic age-dependent changes in blood. Our results show that these multi-omic aging genes in blood are enriched for adaptive immune functions, replicate more robustly across diverse populations and are more strongly associated with aging-related outcomes compared to the genes identified using epigenetic or transcriptomic data alone. These multi-omic aging genes may serve as targets for epigenetic editing to facilitate cellular rejuvenation.

APOBEC family members play crucial roles in antiviral restriction. However, certain APOBEC3 (A3) proteins drive harmful hypermutation in humans, contributing to cancer. The cancer-associated A3 proteins are capable of transiting from the cytosol to the nucleus, where they can cause genome mutations. Here, we uncover a specific set of cellular pathways that protect genomic DNA from the major cancer-associated A3 proteins. Through genetic and proteomic screening, we identify UBR4, UBR5, and HUWE1 as key ubiquitin E3 ligases marking cancer-associated A3B and A3H-I for degradation, thereby limiting A3-driven hypermutation. Mechanistically, UBR5 and HUWE1 recognize A3s in the absence of their RNA binding partner, thus promoting proteasomal degradation of APOBEC3 protein that is not engaged in its antiviral cellular function. Depletion or mutation of the E3 ligases in cells and human cancer samples increases A3-driven genome mutagenesis. Our findings reveal that UBR4, UBR5, and HUWE1 are crucial factors in a ubiquitination cascade that maintains human genome stability.

OBJECTIVES: We aimed to describe 1) how program directors leverage data regarding applicants' race and ethnicity in the recruitment process; 2) program strategies to recruit a diverse fellowship class; and 3) perceived barriers and facilitators to the recruitment of a diverse fellowship class.

METHODS: In collaboration with the Association of Pediatric Program Directors Subspecialty Pediatrics Investigator Network, we conducted a national survey of pediatric subspecialty fellowship program directors (FPDs).

RESULTS: With 516 respondents, FPDs overwhelmingly agreed that diversity in subspecialty trainees is important and that it improves patient care. However, race and ethnicity were identified as a top factor influencing the rank list for fewer than 24% of respondents. FPDs employed several strategies to prioritize diversity in recruitment, but none were perceived as effective by more than 40% of respondents. The most prevalent facilitators for recruiting a diverse fellowship class were institutional culture and addressing diversity with applicants. Key barriers included the diversity of the applicant pool and institution's faculty.

CONCLUSIONS: Diversity in pediatric subspecialty fellowship programs is important to FPDs and is thought to improve patient care. Although strategies are being utilized to recruit URIM fellows, FPDs give only modest ratings to their effectiveness.

OBJECTIVE: Investigate whether enteral supplementation with arachidonic acid (AA) and docosahexaenoic acid (DHA), from birth to term-equivalent age (TEA), promotes brain maturation as a prespecified secondary outcome of a multicentre randomised controlled trial.

PARTICIPANTS: 206 infants born at 22-28 weeks gestational age (GA) were randomised into intervention or control groups from three university hospitals in Sweden.

INTERVENTION: The intervention group received an oil with AA (100 mg/kg/d) and DHA (50 mg/kg/d) starting at birth until 40 weeks postmenstrual age (PMA) in addition to standard nutrition. Standard-of-care infants received standard nutrition according to national guidelines.

MAIN OUTCOME AND MEASURES: MRI volumetrics were defined a priori as a secondary outcome of the trial and included total brain, white and cortical grey matter, central structures and cerebellum. Univariable and multivariable linear regression models were used for comparisons.

RESULTS: MRI data in 117 infants had sufficient quality for inclusion (n=58 intervention). Birth weight, GA at birth, sex distribution, and PMA at MRI were similar in the groups. Infants receiving intervention had significantly larger white-matter volume at TEA, as compared with standard of care, in models adjusted for GA at birth, sex, study centre and PMA at MRI (β=6.8 cm3, 95% CI 0.7 to 12.9, p=0.028). The contribution of the intervention to white-matter volume corresponded to 10 days of prolonged gestation.

CONCLUSION AND RELEVANCE: Our findings in this hypothesis-generating study suggest that AA+DHA promotes white matter growth, which may protect the developing brain in this vulnerable population.

TRIAL REGISTRATION NUMBER: NCT03201588.

How aging affects brain-body connections can be investigated through changes in the coupling between functional magnetic resonance imaging (fMRI) signals and bodily autonomic processes across the adult lifespan. Recent studies using univariate approaches have identified age-related changes in the association between fMRI signals from multiple individual brain regions and low-frequency respiratory and cardiac activity. Here, we investigate if whole-brain spatial fMRI patterns associated with low-frequency physiological processes (heart rate and respiratory volume fluctuations) present generalizable changes with age. Data from human participants of both sexes are included in the analysis. We find that chronological age can be predicted statistically beyond chance from patterns of low-frequency fMRI-physiological coupling, even after accounting for individual differences in physiological signal characteristics and brain anatomy. Notably, brain areas implicated in central autonomic regulation, including nodes within salience and ventral attention networks (e.g., insula and middle cingulate cortex), are among the strongest contributors to age prediction. Furthermore, we observe that after removing physiological effects from fMRI data, the residual blood oxygen level-dependent signal variability is still a reliable indicator of age. Together, these findings underscore the close integration between brain and body physiology and highlight this interaction as a potential biomarker of the aging process.

Our visual system can recognize patterns across many spatial scales. A fundamental assumption in visual neuroscience is that this ability relies on the putative scale-invariant properties of receptive fields (RFs) in early vision, whereby the spatial area over which a visual neuron responds is proportional to the spatial scale of information it can encode (i.e., spatial frequency, SF). In other words, the resolution of spatial sampling of a RF is assumed to be constant in the visual cortex. However, this assumption has gone untested in the human visual cortex. To address this, we leveraged model-based fMRI techniques that characterize the spatial tuning and SF preferences of cortical subpopulations sampled within a voxel across eight participants (five females, three males). We find that the voxel-wise ratio between peak SF tuning and RF size-expressed as "cycles per RF"-remains constant across visual areas V1, V2, and V3, suggesting that, at the population level, SF preferences are inversely proportional to the RF size, a tenet of scale invariance in early human vision.

In addition to providing outputs from the cerebellar cortex, Purkinje cell (PC) axon collaterals target other PCs, molecular layer interneurons (MLIs), and Purkinje layer interneurons (PLIs). It was assumed that PC collaterals to MLI synapses provide positive feedback to PCs via the PC-MLI-PC pathway, because it was thought that MLIs primarily inhibit PCs. However, it was recently shown that MLIs consist of two subtypes: MLI1s primarily inhibit PCs, whereas MLI2s mainly inhibit MLI1s and disinhibit PCs. Clarifying PC connectivity onto these MLI subtypes is vital to understanding the influence of feedback from PC collaterals. Here we use a combination of serial electron microscopy (EM) and optogenetic studies to characterize PC synapses onto MLI subtypes in mice of either sex. EM reconstructions show that PCs make 53% of their synapses onto other PCs, 32% onto PLIs, 6% onto MLI1s, and 7% onto MLI2s. Since there are far more MLI1s than MLI2s, each MLI2 is expected to receive many more synapses than each MLI1. In slice experiments, optogenetic activation of PCs evokes inhibitory currents in most MLI2s but primarily disinhibits MLI1s. We also find that candelabrum cells, a type of PLI, form many more synapses onto MLI1s than MLI2s. These findings suggest that PC-MLI synapses do not primarily disinhibit PCs and that the PC-MLI2-MLI1-PC and PC-PLI-MLI1-PC pathways might provide negative feedback to PCs that acts in concert with PC-PC synapses to counter elevations in PC firing.

The association between vaccine efficacy (VE) and force of infection (FoI) remains incompletely understood. Previous analyses have been primarily based on trial-level summary data-not accounting for the effect of time and constrained by the number of trials. Here, we leverage individual-level data from three phase 3 randomized, placebo-controlled COVID-19 vaccine trials-the COVE trial (Moderna, CoVPN3001), the AZD1222 trial (AstraZeneca, CoVPN3002), and the ENSEMBLE trial (Janssen/Johnson & Johnson, CoVPN3003)-and contemporaneous geographic-location-specific SARS-CoV-2 surveillance data from the start of the pandemic through November 14, 2021 (including the blinded follow-up periods of the trials) to conduct five cohort- and vaccine-specific analyses: COVE (U.S.), AZD1222 overall (U.S. + non-U.S.), AZD1222 U.S., ENSEMBLE overall (U.S. + non-U.S.), and ENSEMBLE U.S. In AZD1222 U.S., higher VE was associated with higher FoI (p = 0.01). In ENSEMBLE overall, lower VE was marginally associated with higher FoI (p = 0.21), further supported by a region-specific analysis. In COVE, AZD1222 overall, and ENSEMBLE U.S., no VE-FoI association was found. These findings highlighted a new perspective: the VE-FoI association appears complex, potentially influenced by FoI levels, with patterns suggesting an inverted U-shaped relationship, showing a positive association at low FoI levels and a negative association at high levels.