Faculty Bibliography

The transfer of regulatory information between distal loci on chromatin is thought to involve physical proximity, but key biophysical features of these contacts remain unclear. For instance, it is unknown how close and for how long two loci need to be in order to productively interact. The main challenge is that it is currently impossible to measure chromatin dynamics with high spatiotemporal resolution at scale. Polymer simulations provide an accessible and rigorous way to test biophysical models of chromatin regulation, yet there is a lack of simple and general methods for extracting the values of model parameters. Here we adapt the Nelder-Mead simplex optimization algorithm to select the best polymer model matching a given Hi-C dataset, using the MYC locus as an example. The model's biophysical parameters predict a compartmental rearrangement of the MYC locus in leukemia, which we validate with single-cell measurements. Leveraging trajectories predicted by the model, we find that loci with similar Hi-C contact frequencies can exhibit widely different contact dynamics. Interestingly, the frequency of productive interactions between loci exhibits a non-linear relationship with their Hi-C contact frequency when we enforce a specific capture radius and contact duration. These observations are consistent with recent experimental observations and suggest that the dynamic ensemble of chromatin configurations, rather than average contact matrices, is required to fully predict productive long-range chromatin interactions.

Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca²⁺ release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.

Widespread pain (WP) is associated with reduced function and disability. Importantly, three-fourths of the approximately 42% of U.S. adults with obesity have WP. Moreover, rates of adult obesity are higher, and WP outcomes are worse in racialized non-Hispanic Black and Hispanic/Latino/a/X groups, potentially exacerbating existing pain disparities. Bariatric surgery significantly reduces weight and improves pain. However, recurrent or unresolved pain after bariatric surgery can hinder weight loss or facilitate weight regain. The current study conducted a secondary analysis of a longitudinal study of predictors and mechanisms of weight loss after bariatric surgery to examine the point prevalence of WP and pain trajectories 24 months post surgery. Our secondary aim was to examine the association between weight loss and pain characteristics. Our exploratory aim was to longitudinally examine racial differences in pain trajectories after bariatric surgery. Our results showed that point prevalence decreased after bariatric surgery. Additionally, significant improvements in pain trajectories occurred within the first 3 months post surgery with a pattern of pain reemergence beginning at 12 months post surgery. Hispanic/Latino/a/X participants reported a higher number of painful anatomical sites before bariatric surgery, and the rate of change in this domain for this group was faster compared with the racialized non-Hispanic Black participants. These findings suggest that pain improvements are most evident during the early stages of surgical weight loss in racialized populations of adults with WP. Thus, clinicians should routinely monitor patients' weight changes after bariatric surgery as they are likely to correspond to changes in their pain experiences. PERSPECTIVE: This article presents the prevalence and pain trajectories of racialized adults with WP after surgical weight loss. Clinicians should evaluate changes in the magnitude and spatial distribution of pain after significant weight change in these populations so that pain interventions can be prescribed with greater precision.

Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.

BACKGROUND/UNASSIGNED:Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D. METHODS/UNASSIGNED: RESULTS/UNASSIGNED: CONCLUSIONS/UNASSIGNED:Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux.

OBJECTIVE:The purpose of this study was to perform a network meta-analysis of level I and II evidence comparing different management techniques to define the optimum treatment method for humeral shaft fractures (HSFs). DATA SOURCES/METHODS:A systematic review of the literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of MEDLINE, Embase, and Cochrane Library was screened from 2010 to 2023. STUDY SELECTION/METHODS:Inclusion criteria were evidence level I or II studies comparing nonoperative and/or operative repair techniques including open reduction internal fixation plate osteosynthesis (ORIF-Plate), minimally invasive percutaneous plating (MIPO), and intramedullary nail (IMN) fixation for the management of HSFs (OTA/AO 12A, B, C). DATA EXTRACTION/METHODS:The risk of bias and methodologic quality of evidence were assessed according to the guidelines designed by the Cochrane Statistical Methods Group and Cochrane Methods Bias Group. DATA SYNTHESIS/RESULTS:Network meta-analysis was conducted with a frequentist approach with a random-effects model using the netmeta package version 0.9-6 in R. RESULTS:A total of 25 studies (1908 patients) were included. MIPO resulted in the lowest complication rate (2.1%) when compared with ORIF-Plate (16.1%) [odds ratio (OR), 0.13; 95% confidence interval (CI), 0.04-0.49]. MIPO resulted in the lowest nonunion rate (0.65%) compared with all management techniques (OR, 0.28; 95% CI, 0.08-0.98), whereas Non-Op resulted in the highest (15.87%) (OR, 3.48; 95% CI, 1.98-6.11). MIPO demonstrated the lowest rate of postoperative radial nerve palsy overall (2.2%) and demonstrated a significantly lower rate compared with ORIF-Plate (OR, 0.22; 95% CI, 0.07-0.71, P = 0.02). IMN resulted in the lowest rate of deep infection (1.1%) when compared with ORIF-Plate (8.6%; P = 0.013). MIPO resulted in a significantly lower Disabilities of the Arm, Shoulder, and Hand score (3.86 ± 5.2) and higher American Shoulder and Elbow Surgeons score (98.2 ± 1.4) than ORIF-Plate (19.5 ± 9.0 and 60.0 ± 5.4, P < 0.05). CONCLUSION/CONCLUSIONS:The results from this study support that surgical management results in better postoperative functional outcomes, leads to higher union rates, reduces fracture healing time, reduces revision rate, and decreases malunion rates in patients with HSFs. In addition, MIPO resulted in statistically higher union rates, lowest complication rate, lowest rate of postoperative radial nerve palsy, and lower intraoperative time while resulting in better postoperative Disabilities of the Arm, Shoulder, and Hand and American Shoulder and Elbow Surgeons scores when compared with nonoperative and operative (ORIF and IMN) treatment modalities. LEVEL OF EVIDENCE/METHODS:Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Natural photosystems couple light harvesting to charge separation using a 'special pair' of chlorophyll molecules that accepts excitation energy from the antenna and initiates an electron-transfer cascade. To investigate the photophysics of special pairs independently of the complexities of native photosynthetic proteins, and as a first step toward creating synthetic photosystems for new energy conversion technologies, we designed C₂-symmetric proteins that hold two chlorophyll molecules in closely juxtaposed arrangements. X-ray crystallography confirmed that one designed protein binds two chlorophylls in the same orientation as native special pairs, whereas a second designed protein positions them in a previously unseen geometry. Spectroscopy revealed that the chlorophylls are excitonically coupled, and fluorescence lifetime imaging demonstrated energy transfer. The cryo-electron microscopy structure of a designed 24-chlorophyll octahedral nanocage with a special pair on each edge closely matched the design model. The results suggest that the de novo design of artificial photosynthetic systems is within reach of current computational methods.