Faculty Bibliography

INTRODUCTION/BACKGROUND:The study aimed to investigate the efficacy of autogenous iliac crest bone graft (ICBG) compared with other graft types in achieving successful fracture nonunion repair. METHODS:An institutional review board-approved retrospective review of prospectively collected data was conducted on a consecutive series of patients surgically treated for fracture nonunions at an academic medical center between September 10, 2004, and August 20, 2023. Patients were analyzed based on which bone graft type-ICBG versus alternative graft types-used during their nonunion repair. Patient demographics, injury characteristics, and surgical history were compared. Outcomes included radiographic healing, time to union, postoperative complications, and revision rate. Cohorts were compared using an independent sample Student t-test for continuous variables and chi-square or Fisher exact tests for categorical variables. One-way analysis of variance with post hoc comparisons assessed differences across treatment strategy groups. RESULTS:Five hundred fifty-six patients were treated surgically for a fracture nonunion using standard internal fixation and a "bone graft" for biologic stimulation. 57.4% of these patients were treated with autogenous ICBG; 42.6% received alternative grafts (iliac crest aspirate, allograft, bone morphogenetic, reamer-irrigation aspirator, and/or demineralized bone matrix, without autogenous cancellous iliac crest). Compared with the alternative cohort, the ICBG cohort showed greater healing success after a single nonunion surgery (95.6% ICBG versus 86.9% alternative, P < 0.001) and faster healing times (4.8 ± 2.4 months versus 7.1 ± 4.9 months, P < 0.001). Complications at the ICBG harvest site included wound infections/hematomas and iliac wing fracture. No notable differences were found in positive cultures at the time of surgery, postoperative fracture-related infection, implant failure, or neurovascular injury. DISCUSSION/CONCLUSIONS:Using autogenous ICBG in the surgical repair of fracture nonunions was associated with higher healing rates compared with alternative graft types, supporting its continued role in enhancing bone healing outcomes, even in the face of infected nonunion.

Fertility in women decreases with age, but the molecular basis for age-related, unexplained infertility remains elusive. Here, we reveal distinct transcriptome changes in oocytes and surrounding cumulus cells from women in their mid-thirties, as evidenced by notably increased transcription of ribosome genes. Additionally, meiosis genes and actin and cohesin components are downregulated in oocytes with age. Lysosomes and proteostasis are also disrupted in cumulus cells. Moreover, DNA hypomethylation and altered heterochromatin deposition at specific genomic loci are linked to increased transcription of ribosome genes. Rapamycin effectively reduces translation and promotes protein homeostasis in cumulus cells. Remarkably, short-term rapamycin allows patients who fail repeated in vitro fertilization cycles with embryo developmental arrest to achieve high-quality blastocysts that yield successful pregnancy and live birth. These data suggest a causal role for elevated transcription of ribosome genes in aging oocytes and cumulus cells and identify rapamycin as a promising treatment for age-related infertility. This study is registered at Chinese Clinical Trial Registry (ChiCTR2300069828).

Protein-protein interaction (PPI) networks are dynamically remodeled in disease, yet most systems biology approaches focus on changes in protein abundance, overlooking critical interaction-level dysfunction. Here, we present a robust, chemoproteomic method-dysfunctional Protein-Protein Interactome (dfPPI)-that enables high-throughput, systematic, disease-contextual mapping of PPI network dysfunctions in cells and primary human tissue. This method integrates chemical biology probes that selectively capture epichaperome-based interactome assemblies with label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) and network-based computational analysis, to uncover the rewiring of protein networks not apparent from transcriptomic or proteomic data alone. The dfPPI platform can be applied across disease states, species, and tissues to identify actionable nodes of dysfunction and enable high-resolution, systems-level insights into disease progression. In this protocol, we demonstrate step-by-step procedures for sample preparation, chemical probe treatment, affinity enrichment, label-free LC-MS/MS analysis, and bioinformatics workflows used to generate and interpret dfPPI datasets. This article aims to promote reproducibility and accessibility of this approach, supporting its adoption by the broader systems biology and translational research communities.

Stress-induced dinucleoside tetraphosphates (Np₄Ns, where N is adenosine, guanosine, cytosine or uridine) are ubiquitous in living organisms, yet their function has been largely elusive for over 50 years. Recent studies have revealed that RNA polymerase can influence the cellular lifetime of transcripts by incorporating these alarmones into RNA as 5'-terminal caps. Here we present structural and biochemical data that reveal the molecular basis of noncanonical transcription initiation from Np₄As by Escherichia coli and Thermus thermophilus RNA polymerases. Our results show the influence of the first two nucleotide incorporation steps on capping efficiency and the different interactions of Np₄As with transcription initiation complexes. These data provide critical insights into the substrate selectivity that dictates levels of Np₄ capping in bacterial cells.

BACKGROUND:The knee's inflammatory response to ligamentous, meniscal, and cartilage injuries is complex and incompletely understood, particularly in the setting of concomitant injuries. Recent research has highlighted the potential utility of synovial fluid biomarker analysis in identifying factors involved in the progression of posttraumatic osteoarthritis. PURPOSE/OBJECTIVE:To investigate if unique patterns of knee injury are associated with distinct synovial fluid biomarker profiles at the time of surgical intervention. STUDY DESIGN/METHODS:Cross-sectional study; Level of evidence, 3. METHODS:Patients undergoing arthroscopic knee surgery were prospectively enrolled and asked to complete the Lysholm Knee Scoring Scale and visual analog scale for pain preoperatively. Synovial fluid was aspirated from the operative knee before surgical incision, and the concentrations of 10 biomarkers of interest were quantified. Patients with intraoperative evidence of articular cartilage, meniscal, and/or anterior cruciate ligament (ACL) injury were identified and included for subsequent analysis. Biomarker concentrations were log-normalized and standardized. Principal component analysis (PCA) was performed using biomarker variables to reduce dimensionality and extract key patterns. Multivariable linear regression for each retained principal component (PC) was performed with the predictors of age, sex, body mass index, symptom duration, ACL injury, meniscal injury, and Outerbridge grade. A separate regression analysis was performed to assess relationships between PCs and patient-reported outcomes controlling for the same variables. RESULTS:= .001; β = -.199). CONCLUSION/CONCLUSIONS:Cartilage lesions exhibited a synovial fluid inflammatory profile distinct from ACL and meniscal injury at the time of knee arthroscopy. While ACL and meniscal injuries displayed a pro-inflammatory phenotype, more severe cartilage lesions were associated with a reduced presence of anti-inflammatory markers. The pro-inflammatory phenotype also independently correlated with worse baseline knee function. These findings contribute to the understanding of the pathophysiology of ligamentous, meniscal, and cartilage injuries and may aid in the identification of pathology-specific treatments to help alter the natural history of disease.

PURPOSE OF REVIEW/OBJECTIVE:Cardiovascular diseases (CVDs) are a leading cause of death worldwide. While it is well known that obesity, dyslipidemia and diabetes are major risk factors of CVD, observational clinical studies have shown that variability in body weight, circulating LDL-cholesterol (LDL-C) or glucose levels further increase this risk. The underlying mechanisms, however, leading to increased risk of CVD due to metabolic cycling are not well understood. RECENT FINDINGS/RESULTS:Recent studies have shown that metabolic cycling can cause reprogramming of immune cells and their progenitors. Weight, LDL-C, or glucose cycling induced myelopoiesis, monocytosis and/or altered immune cell functions. This resulted in a heightened immune response, ultimately worsening atherosclerosis. SUMMARY/CONCLUSIONS:Even though there are differences in how metabolic cycling is measured in clinical and basic research studies, the conclusion remains the same: metabolic cycling increases CVD severity. Some studies have highlighted the role of reprogramming of myeloid cells and their progenitors in progression of atherosclerosis due to metabolic cycling, but further research is required to better understand the mechanisms behind it.

Arrhythmogenic cardiomyopathy (ACM) is a genetically heterogeneous inherited cardiomyopathy with an estimated prevalence of 1:5000-10 000 that predisposes patients to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD). ACM diagnostic criteria and risk prediction models, particularly for arrhythmogenic right ventricular cardiomyopathy (ARVC), the most common form of ACM, are typically genotype-agnostic, but numerous studies have established clinically meaningful genotype-phenotype associations. Early signs of ACM onset differ by genotype indicating the need for genotype-specific diagnostic criteria and family screening paradigms. Likewise, risk factors for SCD vary by genetic subtype, indicating that genotype-specific guidelines for management are also warranted. Of particular importance, genotype-specific therapeutic approaches are being developed. Results from a randomized controlled trial for flecainide use in ARVC patients are currently pending. Research in a plakophilin-2-deficient mouse model suggests this antiarrhythmic drug may be particularly useful for patients with likely pathogenic or pathogenic (LP/P) PKP2 variants. Additionally, the first gene therapy clinical trials in ARVC patients harboring LP/P PKP2 variants are currently underway. This review aims to provide clinicians caring for ACM patients with an up-to-date overview of the current literature in genotype-specific natural history of disease and management of ACM patients and describe scientific advances that have led to upcoming clinical trials.

Directional interactions that generate regular coordination geometries are a powerful means of guiding molecular and colloidal self-assembly, but implementing such high-level interactions with proteins remains challenging due to their complex shapes and intricate interface properties. Here we describe a modular approach to protein nanomaterial design inspired by the rich chemical diversity that can be generated from the small number of atomic valencies. We design protein building blocks using deep learning-based generative tools, incorporating regular coordination geometries and tailorable bonding interactions that enable the assembly of diverse closed and open architectures guided by simple geometric principles. Experimental characterization confirms the successful formation of more than 20 multicomponent polyhedral protein cages, two-dimensional arrays and three-dimensional protein lattices, with a high (10%-50%) success rate and electron microscopy data closely matching the corresponding design models. Due to modularity, individual building blocks can assemble with different partners to generate distinct regular assemblies, resulting in an economy of parts and enabling the construction of reconfigurable networks for designer nanomaterials.

In recent history, human life expectancy has increased significantly, resulting in a high burden of late-life morbidity and geriatric fractures. Changes to the body as a result of aging, such as degeneration of the bone marrow, osteoblast apoptosis, and a decline in hormone production, coupled with sarcopenia, are only a few factors that predispose the elderly to fractures. In addition, these factors further complicate surgical management, as they increase the risk of fixation failure, nonunion, malunion, and wound complications. As a result, the standards of geriatric fracture fixation must account for variables that are rarely included when planning for surgery in the younger population. Operative fixation should provide a stable limb to allow for early mobilization and weight bearing, lowering the risk of medical complications. Therefore, early mobility is of the utmost importance in the setting of most fragility fractures. However, early mobility in some, such as the pelvic fragility fracture, may lead to an increased risk for bleeding and death. Geriatric fractures carry significant morbidity, mortality, and financial risk, which indicates that there should be a continuing review and understanding of the multifactorial process leading toward and treatment strategies employed after geriatric fractures. The purpose of this review is to summarize the biology of aging, the causes, effects, and treatments of sarcopenia, the current fixation strategies of geriatric fractures, and the importance of mobility in the geriatric patient.