Faculty Bibliography

The narrowest biological tubes are comprised of cells that hollow to form an intracellular lumen. Here, we examine early lumenogenesis of the C. elegans excretory cell, which branches to form an H-shaped intracellular tube spanning the length of the worm. Using genetically paralyzed embryos to freeze movement, we describe lumen initiation and branching for the first time using time-lapse fluorescence microscopy. We show that the excretory cell lumen forms through a plasma membrane invasion mechanism when a nascent lumen grows from the plasma membrane into the cytoplasm. The lumen subsequently extends along the left-right axis before branching to form anterior-posterior projections. Through a genetic screen, we identify mutations in ina-1/⍺-integrin and pat-3/β-integrin that block lumenogenesis at the anterior-posterior branching step, and we show that integrin function is required within the excretory cell. Finally, we find that the excretory cell crosses the epidermal basement membrane where anterior-posterior branches form and demonstrate that basement membrane crossing fails in integrin mutant embryos. Our findings reveal how an intracellular lumen initiates and branches and identify integrins and basement membrane as key branching regulators.

BACKGROUND:Intestinal ultrasonography (IUS) is increasingly utilised for diagnosing and monitoring IBD. Despite its cost-effectiveness, patient tolerance and suitability for serial bedside assessments, broad adoption has been limited by knowledge gaps in evidence, training and standardisation. AIMS/OBJECTIVE:To summarise key knowledge gaps in the assessment of luminal disease activity, postoperative recurrence, complications, pouch-related disorders and the use of IUS in paediatrics, contrast enhancement, elastography, as well as education, training and future applications involving artificial intelligence. METHODS:We conducted a systematic umbrella review, following PRISMA guidelines, to map the current landscape of high-quality evidence and identify gaps in IUS research relevant to IBD. We searched MEDLINE from inception to February 2025 for systematic reviews, meta-analyses and consensus statements. We extracted data from eligible studies on design, outcomes and identified research gaps. Gaps were categorised by insufficient information, bias, inconsistency or lack of relevant data. RESULTS:Sixty of 507 studies met inclusion criteria. Key gaps included lack of validated and standardised IUS activity indices for Crohn's disease and ulcerative colitis, limited evidence for IUS in post-operative recurrence, paediatric populations and perianal or pouch disease. Data on the use of contrast-enhanced ultrasound and elastography were sparse. Small sample sizes, heterogeneous designs and inadequate follow-up limited most studies. Training, competency assessment and integration of artificial intelligence remain underexplored. CONCLUSIONS:Sizable gaps persist in the evidence base for IUS in IBD. Addressing these gaps through robust, multicentre studies and consensus-driven frameworks is essential to optimise the clinical and research utility of IUS in IBD management.

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.

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.

Adipose tissue has emerged as a central regulator of human physiology, with its dysfunction driving the global rise in obesity-associated diseases, such as type 2 diabetes, cardiovascular and liver diseases, and several cancers. Once thought to be inert, adipocytes are now recognized as dynamic, responsive cells essential for energy homeostasis and interorgan communication, including the brain. Distinct adipose depots support specialized functions across development, sex, and aging. Technologies like single-cell RNA sequencing are unraveling depot-specific mechanisms, with the potential of identifying new therapeutic targets. This review highlights major scientific advancements leading to our current appreciation of the pivotal role of adipose tissue in health and disease. Many key discoveries in this field have been catalyzed by National Institutes of Health funding, particularly through the National Institute of Diabetes, Digestive and Kidney Diseases, now celebrating its 75th anniversary.

BACKGROUND:Motor stereotypies (MS) represent one of the transdiagnostic symptom dimensions identified by the NIMH Research Domain Criteria work group as relevant to psychopathology. MS are common in neurodevelopmental conditions, but they remain poorly understood, particularly in early childhood. The present study examined MS in 648 toddlers with autism spectrum disorder (autism, n = 455) and other neurodevelopmental conditions (non-autism, n = 193) and their concurrent and prospective links with other phenotypic characteristics. METHODS:Toddlers were recruited between February 2000 and October 2018 and evaluated at 24 +/- 5 months (Time 1, N = 648) and 41 +/- 6 months (Time 2, N = 455). The presence of MS was determined based on the Autism Diagnostic Observation Schedule assessment. The phenotypic measures included adaptive socialization skills, severity of social symptoms of autism, and verbal, nonverbal, and motor skills. The analysis was conducted using the general linear models while controlling for age, sex, visit year, group, and other relevant covariates. RESULTS: CONCLUSIONS:Motor stereotypies are present in toddlers with and without autism and may represent a distinct transdiagnostic dimension expressed early in development, associated with core developmental skills and, putatively, characterized by shared pathophysiology across neurodevelopmental conditions.

BACKGROUND:As the incidence of frontal fibrosing alopecia (FFA) continues to rise, there is a need for an optimal treatment algorithm for FFA. OBJECTIVE:To produce an international consensus statement on the treatment modalities and prognostic indicators of FFA. METHODS:Sixty-nine hair experts from six continents were invited to participate in a three-round Delphi process. The final stage was held as a virtual meeting facilitated via Zoom. The consensus threshold was set at ≥66%. RESULTS:Of 365 questions, expert consensus was achieved in 204 (56%) questions following completion of the three rounds. Three additional questions were included at the final meeting. The category with the strongest consensus agreement was disease monitoring (9; 100%). Questions pertaining to physical therapies achieved the least category consensus (15; 40%), followed by systemic therapy (45; 43%). LIMITATIONS/CONCLUSIONS:The study lacked sufficient representation from Africa and South America. CONCLUSION/CONCLUSIONS:SOFFIA highlights areas of agreement and disagreement among experts. Robust research is warranted to provide evidence-based treatment recommendations.

Nuclear Factor I (NFI) misexpressions in humans are associated with severe brain malformations, yet the underlying mechanisms remain poorly understood. Here we show that NFIs regulate the broad lineage progression and lifespan of radial glial progenitors (RGPs), and consequently neocortical development in a dose-dependent manner. Human cerebral organoids carrying patient-mimicking NFI mutations exhibit expression level-dependent bidirectional impairments in RGP temporal development, coinciding with patient phenotypes. In mouse models, selective removal of NFIs leads to a dramatic protraction of RGP lineage progression and lifespan, excessive progeny output, and neocortical overgrowth and abnormal folding, whereas overexpression of NFIs accelerates RGP lineage progression, resulting in developmental stage-dependent precocious productions of diverse neural progenies. Moreover, NFIs exhibit a positive auto-regulation and progressive increase in expression, and regulate distinct temporal-specific targets underlying RGP lineage progression. These results suggest that NFIs act as evolutionarily conserved key global temporal regulators of RGP lineage progression and neocortical development.

We sought to identify clinically relevant regulators of hair follicle inflammation by conducting a human genetic study of hidradenitis suppurativa (HS), a prevalent, understudied, inflammatory disease with limited effective treatments. We performed a GWAS with 6,300 cases and identified 12 independent risk loci. Epigenetic and transcriptomic analyses of HS risk variants defined cell-specific gene regulatory programs. We experimentally validated a coherent gene module defined by upregulated SOX9, CXCR4, and CD74 co-expression that maps to aberrant epithelial structures in the skin. Pharmacological inhibition of CXCR4 implicates CD74 mediated regulation of PI3K/AKT and NF-κB signaling to calibrate inflammation, proliferation and apoptosis in keratinocytes. We next used genome-wide methods to interrogate shared polygenic architecture and identified new clinically and mechanistically relevant disease associations, including another condition that involves aberrant hair follicle remodeling, male pattern hair loss. Our results point towards CXCR4-CD74 signaling in HS and hair follicle homeostasis and suggest CXCR4 blockade as a new therapeutic strategy in HS.