Faculty Bibliography

Water diffusion gives rise to micron-scale sensitivity of diffusion MRI (dMRI) to cellular-level tissue structure. Precision medicine and quantitative imaging depend on uncovering the information content of dMRI and establishing its parsimonious hardware-independent fingerprint. Based on the rotational SO(3) symmetry, we study the geometry of the dMRI signal and the topology of its acquisition, identify irreducible components and a full set of invariants for the cumulant tensors, and relate them to tissue properties. Including all kurtosis invariants improves multiple sclerosis classification in a cohort of 1189 subjects. We design the shortest acquisitions based on icosahedral vertices to determine the most used invariants in only 1-2 minutes for whole brain. Representing dMRI via scalar invariant maps with definite symmetries will underpin machine learning classifiers of pathology, development, and aging, while fast protocols will enable translation of advanced dMRI into clinic.

Nickel is a transition metal that is widely distributed in the environment. Nickel compounds are classified as Group 1 carcinogens (human carcinogens) by the International Agency for Research on Cancer (IARC). Despite extensive studies, the molecular mechanisms underlying nickel-induced carcinogenesis remain incompletely understood. Maternally Expressed Gene 3 (MEG3) is the first long non-coding RNA (lncRNA) identified as a tumor suppressor. Previous studies have shown that downregulation of MEG3 increases HIF-1α expression in human bronchial epithelial BEAS-2B cells chronically exposed to nickel. In the present study, we observed that MEG3 expression is markedly reduced in nickel-transformed cells. Dysregulation of Runt-Related Transcription Factor 2 (RUNX2) has also been implicated in multiple cancer types. Previous studies have demonstrated that RUNX2 is upregulated in nickel-induced malignantly transformed BEAS-2B cells. Consistent with these findings, we observed that chronic exposure of BEAS-2B cells to low-dose nickel increases both RUNX2 mRNA and protein expression, accompanied by elevated expression of mesenchymal markers and enhanced migratory and invasive capacities. Overexpression of MEG3 in nickel-transformed cells reduces RUNX2 protein levels and reverses the alterations of epithelial-mesenchymal transition (EMT) markers, resulting in decreased cell migration and invasion in nickel-transformed cells. Similarly, silencing RUNX2 reverses the expression of EMT markers and suppresses the migratory and invasive capacities of nickel-transformed cells. Notably, shRNA-mediated RUNX2 knockdown increases MEG3 expression, indicating reciprocal regulation between MEG3 and RUNX2 in nickel-transformed cells. Collectively, our findings demonstrate that MEG3 and RUNX2 form a reciprocally regulated signaling axis that contributes to EMT, thereby promoting migration and invasion in nickel-transformed cells. These results identify MEG3 and RUNX2 as interconnected biomarkers and potential therapeutic targets for cancer prevention and treatment, warranting further mechanistic investigation.

BACKGROUND AND OBJECTIVES/OBJECTIVE:This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS:A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS:A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION/CONCLUSIONS:This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

This practice guideline provides updated evidence-based recommendations regarding the use of pharmacologic migraine prevention in adults. A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies published through June 6, 2024, and is available in a companion publication. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. Recommendations are provided on how to decide when it is appropriate to start a pharmacologic migraine preventive medication and how to decide which migraine preventive medication to start. Recommendations address decision making on appropriate choices of migraine preventive medications in specific situations and populations, including patients with fibromyalgia, obesity, or hypertension; considerations for older adults; treatment during pregnancy and lactation; sex-related factors in choosing medications; and treatment for patients with medication overuse. Recommendations on assessment of treatment efficacy, adverse effects, and discontinuing migraine preventive medications are provided.

Chromatin-modifying complexes are critical in gene regulation, yet their proposed interactions with RNA remain poorly understood. Counter to prior models of specific recruitment, we find that WDR5, an essential subunit of the MLL1/KMT2A histone methyltransferase complex, binds RNA promiscuously. Using a stringent approach, we demonstrate that WDR5 directly engages a diverse pool of cellular RNAs, dictated primarily by RNA abundance rather than specific motifs. Equilibrium binding assays show that RNA length, rather than sequence, governs high affinity. WDR5 binds to RNA through multiple surfaces, some of which overlap with MLL1 complex subunit interfaces. Strikingly, we find that RNA binding disrupts the MLL1 complex by competitively displacing WDR5 from these critical protein-protein interactions, leading to a marked inhibition of MLL1 catalytic activity. Further experiments in human cell lines suggest that this disassembly mechanism may operate to homeostatically downregulate MLL1 complex activity, thereby integrating transcriptional activity with chromatin state.

The human sodium-citrate cotransporter NaCT imports various tri- and di-carboxylates into the cell as TCA cycle intermediates. This substrate uptake process is driven by an inward sodium gradient. The protein is a member of the divalent anion-sodium symporter (DASS) family. Whereas extensive biochemical and structural studies have been carried out for NaCT, how the substrate binding and translocation is coupled to the sodium gradient remains unclear. Here using single particle cryo-electron microscopy, we determined the structures of the human NaCT protein in three states: sodium-free, in the presence of sodium, and bound to sodium and a substrate mimicking inhibitor. These structures suggest a simultaneous binding mechanism for sodium-substrate coupling, distinct from the sequential binding, conformational selection mechanism previously observed for the bacterial DASS protein VcINDY.

Thrombotic risk in COVID-19 extends beyond acute illness, including in nonhospitalized individuals, suggesting that thrombo-inflammatory biology may persist during recovery. Longitudinal sampling with pre-infection baselines is needed to distinguish infection-associated signals from inter-individual variability and time-related drift in blood gene expression. To define coordinated, time-resolved whole-blood transcriptomic programs during SARS-CoV-2 convalescence using longitudinal within-person comparisons before and after infection, alongside COVID-19-naïve controls. Adults were sampled longitudinally with specimens collected before SARS-CoV-2 infection (T0) and at ~3 months (T1) and ~6 months (T2) post-infection; COVID-19-naïve controls were sampled across matched timepoints. COVID-19-naïve status was confirmed using a multiplex anti-nucleocapsid IgG assay spanning multiple variant antigens. Whole-blood RNA-seq (PAXgene) was analyzed with DESeq. 2 using models that incorporated time point and participant. To prioritize infection-linked changes, genes differentially expressed over time in controls were identified and excluded from comparisons between COVID-19 time points. Pathways were assessed by pre-ranked GSEA (MSigDB) and clustered with aPEAR. After excluding control-associated genes, COVID-19 convalescence remained associated with marked transcriptional remodeling (T1 vs. T0: 782 genes; T2 vs. T0: 655 genes; p < 0.05) and persistent pathway-level changes. Interferon-α and interferon-γ signatures were enriched at both T1 and T2, and a core set of interferon-associated genes remained elevated across convalescence. SARS-CoV-2 infection is followed by durable whole-blood immune-defense programs, including persistent interferon signaling, detectable up to 6 months post-infection. These sustained signatures support a model of prolonged post-infectious immune activation that may contribute to extended thromboinflammatory risk.

BACKGROUND AND OBJECTIVES/OBJECTIVE:This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS:A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS:A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION/CONCLUSIONS:This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

This practice guideline provides updated evidence-based recommendations regarding the use of pharmacologic migraine prevention in adults. A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies published through June 6, 2024, and is available in a companion publication. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. Recommendations are provided on how to decide when it is appropriate to start a pharmacologic migraine preventive medication and how to decide which migraine preventive medication to start. Recommendations address decision making on appropriate choices of migraine preventive medications in specific situations and populations, including patients with fibromyalgia, obesity, or hypertension; considerations for older adults; treatment during pregnancy and lactation; sex-related factors in choosing medications; and treatment for patients with medication overuse. Recommendations on assessment of treatment efficacy, adverse effects, and discontinuing migraine preventive medications are provided.

In the United States, Black gay, bisexual, and other men who have sex with men (BGBM) continue to face disproportionate burdens of HIV. Contributing factors include unprotected sex with multiple partners, limited awareness of HIV prevention, stigma, racism, and structural barriers to healthcare access. Biomedical prevention strategies such as pre-exposure prophylaxis (PrEP) have demonstrated effectiveness in reducing HIV transmission. However, social perceptions, stigma, and anticipated discrimination continue to influence uptake and adherence. This scoping review examined literature published between 2017 and 2024 to identify how social networks and social media shape prevention behaviors among BGBM. Guided by Social Network Theory (SNT), the review synthesized findings from 21 studies across four contexts: House Ballroom communities, social media, faith-based settings, and dating apps. Results highlight the role of culturally tailored and community-based interventions, including those delivered in religious settings, in supporting prevention uptake, while digital platforms demonstrated strong potential for outreach, testing, and linkage to care. These findings underscore the need for interventions that integrate biomedical prevention tools with culturally responsive approaches to reduce disparities and improve HIV prevention outcomes for BGBM. Findings provide suggestions for future HIV interventions for BGBM.