Faculty Bibliography

KdpFABC is an ATP-dependent membrane complex that enables prokaryotes to maintain potassium homeostasis under potassium-limited conditions. It features a unique hybrid mechanism combining a channel-like selectivity filter in KdpA with the ATP-driven transport functionality of KdpB. A key unresolved question is whether K+ ions translocate through the inter-subunit tunnel as a queue of ions or individually within a hydrated environment. Using molecular dynamics simulations, metadynamics, anomalous X-ray scattering, and biochemical assays, we demonstrate that the tunnel is predominantly occupied by water molecules rather than multiple K+ ions. Our results identify only one stable intermediate binding site for K+ within the tunnel, apart from the canonical sites in KdpA and KdpB. Free energy calculations reveal a substantial barrier (∼22 kcal/mol) at the KdpA-KdpB interface, making spontaneous K+ translocation unlikely. Furthermore, mutagenesis and functional assays confirm previous findings that Phe232 at this interface plays a key role in coupling ATP hydrolysis to K+ transport. These findings challenge previous models containing a continuous wire of K+ ions through the tunnel and suggest the existence of an as-yet unidentified intermediate state or mechanistic detail that facilitates K+ movement into KdpB.

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.

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.

Homeostasis of the nervous system is maintained by a population of resident neural stem cells (NSCs) retained in a state of reversible cell-cycle arrest called quiescence. Quiescent NSCs can resume proliferation in response to different physiological stimuli. Reactivation requires changes in gene expression, much of which is regulated at the epigenomic level. We mapped epigenomic changes in NSC chromatin during stem cell quiescence and reactivation in Drosophila in vivo. Contrary to expectations, chromatin accessibility is increased in quiescent NSCs. Surprisingly, genes crucial for cell-cycle progression are repressed while remaining within permissive H3K36me3-bound euchromatin. At the same time, genes necessary for cell-cell communication are derepressed by eviction of histone H1 and transition to an SWI/SNF-enriched active state. Our results reveal global expansion of accessible chromatin in quiescent NSCs without concomitant transcriptional activation. Strikingly, this process reverses upon reactivation, indicating that opening of chromatin is a quiescence-specific event.

The science of metabolic profiling exploits chemical compound byproducts of metabolism called metabolites¹ that explain internal biological functions, physiological health and disease, and provide evidence of external influences specific to an organism's habitat. Here we assess palaeometabolomes from fossilized mammalian hard tissues as a molecular ecological strategy to provide evidence of an ancient organism's relationship with its environment. From eastern, central and southern African Plio-Pleistocene localities of palaeoanthropological significance, we study six fossils from Olduvai Gorge, Tanzania, one from the Chiwondo Beds, Malawi, and one from Makapansgat, South Africa. We perform endogeneity assessments by analysing palaeometabolomes of palaeosols and the effects of owl digestion on rodent bones to enable prudent ecological inferences. Diagenesis is indicated by metabolites of collagenase-producing bacteria², whereas the preservation of peptides including those of collagen are identified by proteomics. Endogenous metabolites document biological functions and exogenous metabolites render environmental details including soil characteristics and woody cover, and enable annual minimum and maximum rainfall and temperature reconstructions at Olduvai Gorge, supporting the freshwater woodland and grasslands of Olduvai Gorge Bed I^3-5, and the dry woodlands and marsh of Olduvai Gorge Upper Bed II⁶. All sites denote wetter and/or warmer conditions than today. We infer that metabolites preserved in hard tissues derive from an extravasated vasculature serum filtrate that becomes entombed within developing mineralized matrices, and most probably survive palaeontological timeframes in the nanoscopic 'pool' of structural-bound water that occurs in hard tissue niches⁷.

Signaling interactions between the dermal papilla (DP) and neighboring stem cells in the hair germ (HGSCs) and bulge (BuSCs) regulate new follicle growth in the hair cycle. To study these interactions, the three populations had been profiled together by now-outdated microarrays or separately by bulk RNA-sequencing. Recent single-cell transcriptomics established signatures of DP, BuSCs and HGSCs, but low detection sensitivity limited the depth of gene expression discovery. Here, we define the transcriptomes of DP, BuSCs, HGSCs, epidermal, follicle and dermal fibroblast cells-after flow-sorting each population from four neighboring mouse back skin regions-to gain deeper insights into the unique gene expression programs of SCs and their instructive niche. With cross-comparisons of 56 whole-transcriptome measurements, we classify cell type-specific molecular signatures of enriched genes with unprecedented sensitivity. Joint analysis with signatures from 15 leading studies published in the last 20 years revealed many previously undescribed DP, BuSC and HGSC genes in mouse and human counterparts. With ligand-receptor mapping and CellChat analyses we then uncover comprehensive cell-cell communication insights. Finally, we provide a new installment of our Hair-Gel repository along with numerous signature and other gene tables for easy exploration of gene expression in hair follicle SCs and their niche.

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 & AIM/UNASSIGNED:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health issue. Identifying factors that prevent hepatic lipid accumulation could inform new MASLD prevention or treatment strategies. We previously demonstrated that adipocyte microsomal triglyceride transfer protein (MTP) regulates intracellular lipolysis by inhibiting adipose triglyceride lipase activity. The aim of this study was to investigate the impact of adipose MTP deficiency on MASLD. METHODS/UNASSIGNED: RESULTS/UNASSIGNED: CONCLUSION/UNASSIGNED:These findings highlight the importance of regulated FA flux from adipose tissue to the liver and the liver's adaptive capacity to utilize adipose-derived FAs in maintaining hepatic health. Modulation of adipocyte FA release may represent a therapeutic strategy to reduce hepatic steatosis. IMPACT AND IMPLICATIONS/UNASSIGNED:This study provides significant insights into the role of adipose-specific microsomal triglyceride transfer protein in regulating hepatic lipid metabolism and its potential implications for treating metabolic dysfunction-associated steatotic liver disease. By demonstrating that microsomal triglyceride transfer protein deficiency in adipose tissue leads to increased fatty acid oxidation and reduced hepatic steatosis through enhanced PPARα activation, the research underscores the importance of adipose-liver crosstalk in maintaining liver health. These findings suggest that targeting adipocyte fatty acid release could be a promising therapeutic strategy to mitigate hepatic lipid accumulation and combat metabolic dysfunction-associated steatotic liver disease, offering a novel approach to addressing this growing health issue.

BACKGROUND/UNASSIGNED:This study compares outcomes and complications of patients with Bado II Monteggia fracture-dislocations that required radial head fixation or replacement based upon approach to the radial head. METHODS/UNASSIGNED:A retrospective review was performed of 159 consecutive patients with proximal ulna fractures and a radial head dislocation or fracture (Monteggia Variant). Injuries were classified by Bado type. Forty-one patients with Bado II Monteggia injuries treated with either a radial head replacement or fixation with complete follow up were included. Demographics, injury information, surgical details, and follow up information including elbow range of motion (ROM) and complications were collected. A trans-osseous posterior (TOP) approach working through the ulna fracture to address the radial head first was used in 19 patients, while 22 patients had their radial head treated via a separate lateral (Kocher) interval after ulnar fixation. Ulnar plate fixation was performed for all patients. Comparisons were made using independent t-tests. RESULTS/UNASSIGNED:Forty-one Monteggia lesions treated through TOP (19, 46 %) or Kocher (22, 64 %) approaches underwent a radial head replacement (33, 80.5 %) or fracture repair (8, 19.5 %) with a mean final follow-up of 15.3 months. At all post-operative visits, groups displayed similar rates of functional elbow ROM. At latest follow-up rates of patient-reported pain, ultimate elbow ROM, time to radiographic healing were equivalent. No significant differences were observed in ulna non-union, joint malalignment, post-operative nerve injury, post-operative infection, heterotopic ossification, incidence of hardware failure, patient-reported pain, and rate of removal of symptomatic hardware. Sub-analysis of radial head replacement versus fixation revealed equivalent percentage of patients with full ROM at each post-operative time point. CONCLUSION/UNASSIGNED:For Bado II Monteggia fracture-dislocations, the surgical approach to the radial head-TOP versus Kocher-does not influence ultimate patient outcomes or complication rates. Radial head replacement and fixation provide comparable results. LEVEL OF EVIDENCE/UNASSIGNED:III.

Understanding the molecular mechanisms driving lineage decisions and differentiation during development is challenging in complex systems with a diverse progenitor pool, such as the mammalian cerebellum. Importantly, how different transcription factors cooperate to generate neural diversity and the gene regulatory mechanisms that drive neuron production, especially during the late stages of cerebellum development, are poorly understood. We used single cell RNA-sequencing (scRNA-seq) to investigate the developmental trajectories of Nestin-expressing progenitors (NEPs) in the neonatal mouse cerebellum. We identified FOXO1 as a key regulator of NEP-to-inhibitory neuron differentiation, acting directly downstream of ASCL1. Genome occupancy and functional experiments using primary NEP cultures showed that both ASCL1 and FOXO1 regulate neurogenesis genes during differentiation while independently regulating proliferation and survival, respectively. Furthermore, we demonstrated that WNT signalling promotes the transition from an ASCL1+ to a FOXO1+ cellular state. Finally, the role of WNT signalling in promoting neuron production via FOXO1 is conserved in primary human NEP cultures. By resolving how cerebellar inhibitory neurons differentiate, our findings could have implications for cerebellar disorders such as spinocerebellar ataxia, where these cells are overproduced.