Faculty Bibliography

Prediction of future events is essential for guiding effective actions in dynamic environments. Studies on the neural mechanisms for time-forward predictions have typically used stimuli with relatively simple statistical regularities. Here, we investigated time-forward predictions using stimuli containing statistical regularities similar to those found in natural auditory stimuli. Using intracranial EEG recordings in neurosurgical patients, we found that prediction signals were primarily carried by low-frequency activity across widespread cortical regions, including sensory, parietal, and frontal areas. Prediction-error (PE) signals were found in both low- and high-frequency activity, with high-frequency components localized mainly to sensory areas. Contrary to previous hypotheses, prediction and PE signals did not show a clear spatial or spectral segregation. Directed connectivity between brain regions decreased over the course of the stimulus sequence as predictability increased, except for pathways originating from the parietal cortex. These results reveal integrative and distributed predictive processing and highlight the dorsal auditory pathway in time-forward prediction.

Following their engagement toward differentiation, tissue stem cells often transit through a precursor state that is difficult to define because of its transient nature; similarly, the precise role of lineage precursors in the implementation of tissue architecture and function is unknown. In the present work, we used two mouse models of deficient feedback regulation to characterize precursors of the pituitary corticotrope lineage that regulates the stress response. Both the POMC knockout and adrenalectomized mouse models develop glucocorticoid deficiency and compensatory accumulation of corticotrope precursors that have so far eluded characterization. We found that pre-corticotrope differentiation depends on the lineage-specific factor Tpit and is repressed by glucocorticoids. We identified brain-derived neurotrophic factor (BDNF) as the signal that engages pituitary stem cells toward differentiation in these models as well as in normal pituitary development. A glucocorticoid-sensitive BDNF autocrine loop active in pre-corticotropes turns these cells into signaling hubs for maintenance of pituitary-adrenal homeostasis.

Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE₂), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE₂ suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE₂-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.

PURPOSE/UNASSIGNED:To compare a strategy utilizing testing to guide treatment, also known as selective therapy, to a strategy of initiating interventions without testing, termed empiric therapy, on urinary supersaturation of calcium oxalate and calcium phosphate. MATERIALS AND METHODS/UNASSIGNED:In this single-center trial, adult individuals with recurrent idiopathic calcium stone disease were randomized to either an empiric or selective strategy. Participants received 24-hour urine testing at baseline, 4 weeks, and 8 weeks. Treatment in the empiric arm was comprised of dietary and fluid counseling and pharmacologic treatment with indapamide and potassium citrate irrespective of 24-hour urine results. For the selective arm, diet and pharmacologic treatments, which included indapamide, potassium citrate, and/or allopurinol, were tailored based on urine testing at baseline and 4 weeks. The primary outcome was urinary supersaturation of calcium oxalate and calcium phosphate at 8 weeks. RESULTS/UNASSIGNED:= 0.58). Similarly, there were no significant differences at 8 weeks in urine volume and pH, or in excretion of calcium, oxalate, citrate, uric acid, and sodium. CONCLUSIONS/UNASSIGNED:In this short-term trial among individuals at high-risk for stone recurrence, there was no statistically significant difference in the urinary stone risk comparing an empiric versus selective strategy for kidney stone prevention.

Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.

OBJECTIVE:To evaluate cannabidiol (CBD) in pediatric patients with autism spectrum disorder (ASD), fluent verbal language and an estimated full-scale IQ of 80 or above. BACKGROUND:Preliminary evidence suggests CBD may ameliorate challenges associated with ASD. Whether CBD benefits pediatric ASD without accompanying intellectual or language impairment remains unknown. METHODS:, 100 mg/mL) at 3, 6, or 9 mg/kg/day using a Bayesian optimal interval dosing design. The primary endpoint was the CBD dose associated with the highest response rate (i.e., Clinical Global Impression Scale-Improvement [CGI-I] score = 1 or 2) on a target symptom domain designated individually based on informant report, standardized scales, and clinical observation. Secondary endpoints were effect sizes of changes from baseline in measures assessing ASD core and associated symptoms, and global functioning. Adverse events (AEs) were assessed weekly. Plasma CBD levels and clinical labs were obtained at the final visit. RESULTS:= 1.36, 95% CI [0.78-1.93]).Of 222 reported AEs, 27 unique AEs were considered treatment-related. Most AEs (93%) were mild and expected (82%); none was severe. The most frequent related AEs were increased salivation (30%), increased sleep duration (39%), sleepiness/sedation (26%), increased dream activity (35%), and polyuria (22%). Vital signs, physical exams, weight, liver function tests, and complete blood counts were unaffected. CBD plasma levels did not correlate with response. CONCLUSIONS:In this preliminary study, CBD was well tolerated; AEs were mild-moderate. Mean SRS2-T and subscores decreased significantly with large effect sizes, shifting from the severe to the moderate range. CLINICAL TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier NCT03900923.

The role of genetic testing for kidney stone formers remains incompletely resolved. The purpose of this paper is to review the role of genetics in kidney stone disease and provide guidance on the utility of genetic testing to overall reduce the burden of the disease for our patients. Genetic testing is a send-out laboratory test for most medical centers in the United States. However, access to such testing has been easier with options for genetic kit delivery to health care offices and even conveniently to patients' homes. The rise of genetic testing in medicine has advanced the field of nephrology in general and kidney stones specifically. It is our aim to provide basic knowledge on the approach to kidney stone disease to physicians, especially nephrologists and nephrology fellows, while also considering the appropriateness of genetic testing.

Urolithiasis is increasingly common, with rising rates driven by obesity, diabetes and metabolic syndrome. Patients with cancer have additional, unique risks of stone formation owing to effects on fluid and electrolyte balance, systemic cancer therapies, tumour lysis syndrome and anatomical alterations after urinary diversion or nephrectomy. Moreover, urolithiasis itself has been linked to increased rates of renal cell carcinoma, urothelial carcinoma and bladder cancer, potentially mediated by chronic inflammation, recurrent infections and shared metabolic or environmental factors. Management in this setting is complex and must be individualized. Percutaneous nephrolithotomy achieves the highest stone-free rates in patients with altered urinary tract anatomy, whereas retrograde intrarenal surgery and shock wave lithotripsy have more selective roles. Preventive strategies focus on thorough metabolic evaluation, hydration optimization and addressing cancer-specific risk factors such as hypercalcaemia, acidosis and chronic urinary stasis. Despite these insights, data on the epidemiology, mechanistic underpinnings and optimal management of urolithiasis in patients with cancer remain limited. Prospective studies are needed to clarify causal relationships, refine preventive strategies and develop evidence-based treatment algorithms for this growing and complex population.

Larry Young had a huge impact on the study of neuropeptides and social behavior. Here I give an autobiographical perspective on how Larry and his work influenced the field and my own career.