Faculty Bibliography

Auxins are a group of phytohormones that control plant growth and development. Their crucial role in plant physiology has inspired development of potent synthetic auxins that can be used as herbicides. Phenoxyacetic acid derivatives are a widely used group of auxin herbicides in agriculture and research. Despite their prevalence, the identity of the transporters required for distribution of these herbicides in plants is both poorly understood and the subject of controversial debate. Here we show that PIN-FORMED auxin transporters transport a range of phenoxyacetic acid herbicides across the membrane. We go on to characterize the molecular determinants of substrate specificity using a variety of different substrates as well as protein mutagenesis to probe the binding site. Finally, we present cryogenic electron microscopy structures of Arabidopsis thaliana PIN8 bound to either 2,4-dichlorophenoxyacetic acid or 4-chlorophenoxyacetic acid. These structures represent five key states from the transport cycle, allowing us to describe conformational changes associated with the transport cycle. Overall, our results reveal that phenoxyacetic acid herbicides use the same export machinery as endogenous auxins and exemplify how transporter binding sites undergo transformations that dictate substrate specificity. These results provide a foundation for future development of novel synthetic auxins and for precision breeding of herbicide-resistant crop plants.

Adipose tissue (AT) is a complex connective tissue with a high relative proportion of adipocytes, which are specialized cells with the ability to store lipids in large droplets. AT is found in multiple discrete depots throughout the body, where it serves as the primary repository for excess calories. In addition, AT has an important role in functions as diverse as insulation, immunity and regulation of metabolic homeostasis. The Human Cell Atlas Adipose Bionetwork was established to support the generation of single-cell atlases of human AT as well as the development of unified approaches and consensus for cell annotation. Here, we provide a first roadmap from this bionetwork, including our suggested cell annotations for humans and mice, with the aim of describing the state of the field and providing guidelines for the production, analysis, interpretation and presentation of AT single-cell data.

Like many organisms, the roundworm Caenorhabditis elegans incorporates an assessment of environmental quality into its reproductive strategy. C. elegans hermaphrodites release fertilized eggs into food-rich environments but retain them in the absence of food. Here, we report the discovery of a neural circuit required for the modulation of reproductive behavior by food sensing. A mutation that electrically silences the AVK interneurons uncouples egg laying from detection of environmental food cues. We find that AVK activity inhibits egg laying, and AVKs themselves are inhibited by dopamine released from food-sensing neurons. AVKs express a large number of structurally and functionally diverse neuropeptides. Coordination of food-sensing and reproductive behavior requires a subset of AVK neuropeptides that converge on a small ensemble of premotor neurons that coexpress their cognate receptors. Modulation of C. elegans reproductive behavior, therefore, requires a cascade of neuromodulatory signals that uses disinhibition and combinatorial neuropeptide signals to activate reproductive behavior when food is sensed.

The continuity of a species depends on germ cells. Germ cells are different from all the other cell types of the body (somatic cells) as they are solely destined to develop into gametes (sperm or egg) to create the next generation. In this review, we will touch on 4 areas of embryonic germ cell development in Drosophila melanogaster: the assembly and function of germplasm, which houses the determinants for germ cell specification and fate and the mitochondria of the next generation; the process of pole cell formation, which will give rise to primordial germ cells (PGCs); the specification of pole cells toward the PGC fate; and finally, the migration of PGCs to the somatic gonadal precursors, where they, together with somatic gonadal precursors, form the embryonic testis and ovary.

Microsporidia are single-celled intracellular parasites that cause opportunistic diseases in humans. Encephalitozoon intestinalis is a prevalent human-infecting species that invades the small intestine. Macrophages are potential reservoirs of infection, and dissemination to other organ systems is also observed. The macrophage response to infection and the developmental trajectory of the parasite are not well studied. Here we use single cell RNA sequencing to investigate transcriptional changes in both the parasite and the host during E. intestinalis infection of human macrophages in vitro. The parasite undergoes large transcriptional changes throughout the life cycle, providing a blueprint for parasite development. While a small population of infected macrophages mount a response, most remain transcriptionally unchanged, suggesting that the majority of parasites may avoid host detection. The stealthy microsporidian lifestyle likely allows these parasites to harness macrophages for replication. Together, our data provide insights into the host response in primary human macrophages and the E. intestinalis developmental program.

OBJECTIVES/OBJECTIVE:To determine the most common reason for 30-day readmission following hospitalization for hip fractures. METHODS:Design: A retrospective review. SETTING/METHODS:Single academic medical center that includes a Level 1 Trauma Center. PATIENT SELECTION CRITERIA/UNASSIGNED:Included were all patients operatively treated for hip fractures (OTA 31) between October 2014 and November 2023. Patients that died during their initial admission were excluded. OUTCOME MEASURES AND COMPARISONS/UNASSIGNED:Patient demographics, hospital quality measures, outcomes and readmission within 30-days following discharge for each patient were reviewed. 30-day readmission reason was recorded and correlation analysis was performed. RESULTS:A total of 3,032 patients were identified with a mean age of 82.1 years and 70.5% of patients being female. The 30-day readmission cohort was 2.6 years older (p<0.001) and 8.8% more male patients (p=0.027), had 0.5 higher CCI (p<0.001), 0.3 higher ASA class (p<0.001) and were 9.2% less independent at the time of admission (p= 0.003). Hemiarthroplasty procedure (32.7% vs. 24.1%) was associated with higher 30-day readmission compared to closed percutaneous screw fixation (4.5% vs. 8.8%) and cephalomedullary nail fixation (52.2% vs. 54.4%, p<0.001). Those readmitted by 30-days developed more major (16.7% vs. 8.0%) (p<0.001) and minor (50.5% vs. 36.4%) (p<0.001) complications during their initial hospitalization and had a 1.5 day longer LOS during their first admission (p<0.001). Those discharged home were less likely to be readmitted within 30-days (20.7% vs. 27.6%, (p=0.008). Multivariate regression revealed increasing ASA class (O.R. 1.47, p=0.002) and pre-injury ambulatory status (O.R. 1.42, p=0.007) were most associated with increased 30-day readmission. The most common reason for readmission was pulmonary complications (17.1% of complications) including acute respiratory failure, COPD exacerbation and pneumonia. CONCLUSION/CONCLUSIONS:Thirty-day readmission following hip fracture was associated with older, sicker patients with decreased pre-injury ambulation status. Hemiarthroplasty for femoral neck fracture was also associated with readmission. The most common reason for 30-day readmission following hip fracture was pulmonary complications. LEVEL OF EVIDENCE/METHODS:Prognostic Level III.

Aging populations worldwide face an increasing burden of age-related chronic conditions, necessitating a deeper understanding of the underlying mechanisms. Purine metabolism has emerged as a crucial player in the pathophysiology of aging, affecting various tissues and organs. Dysregulation of purine metabolism, particularly alterations in extracellular adenosine levels and adenosine receptor signaling, contributes to age-related musculoskeletal problems, cardiovascular diseases, inflammation, and impaired immune responses. Changes in purine metabolism are associated with diminished tissue repair and regeneration, altered bone density, and impaired muscle regeneration. Mechanistically, age-related alterations in purine metabolism involve reductions in extracellular adenosine production, impaired autocrine signaling, and dysregulated expression of CD73 and CD39. Targeting adenosine receptors, such as A_2A and A_2B receptors, emerges as a promising therapeutic approach to mitigate age-related conditions, including sarcopenia, obesity, osteoarthritis, and impaired wound healing. Since we cannot reverse time, understanding the intricate molecular interplay between purine metabolism and aging-related pathologies holds significant potential for developing novel therapeutic strategies to improve the health and quality of life of aging populations. In this review, we compile the findings related to purine metabolism during aging in several tissues and organs and provide insights into how these signals can be manipulated to circumvent the deleterious effects of the passage of time on our body.

Our brains integrate sensory, cognitive and internal state information with memories to extract behavioral relevance. Cortico-hippocampal interactions likely mediate this interplay, but underlying circuit mechanisms remain elusive. Unlike the entorhinal cortex-to-hippocampus pathway, we know little about the organization and function of the hippocampus-to-cortex feedback circuit. Here we report in mice, two functionally distinct parallel hippocampus-to-entorhinal cortex feedback pathways: the canonical disynaptic route via layer 5 and a novel monosynaptic input to layer 2/3. Circuit mapping reveals that hippocampal input predominantly drives excitation in layer 5 but feed-forward inhibition in layer 2/3. Upon repetitive pairing with cortical layer 1 inputs, hippocampal inputs undergo homosynaptic potentiation in layer 5, but induce heterosynaptic plasticity and spike output in layer 2/3. Behaviorally, hippocampal inputs to layer 5 and layer 2/3 support object memory encoding versus recall, respectively. Two-photon imaging during navigation reveals hippocampal suppression reduces spatially tuned cortical axonal activity. We present a model, where hippocampal feedback could iteratively shape ongoing cortical processing.

Astrocytes are a highly abundant glial cell type and perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogeneous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of the brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: myocilin (Myoc). We show that glia limitans superficialis astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from zebrafish, rodents, and non-human primates to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.