Vanderbilt University

Endophenotypes (intermediate phenotypes) are traits hypothesized to represent genetic risk for disorders such as OCD. However, it is unclear if disgust conditioning abnormalities may function as an OCD endophenotype. The present study sought to examine the extent which disgust conditioning abnormalities characterize OCD in a manner that is consistent with an endophenotype. Participants with OCD (n=30), first-degree relatives (n=27), and unrelated age-matched healthy controls (n=25) completed a disgust conditioning task in which one neutral food item (conditioned stimulus; CS+) was followed by disgusting videos of individuals vomiting (unconditioned stimulus; US) and another neutral food item (CS-) was not reinforced with the disgusting video. Following this acquisition phase, there was an extinction phase in which both CSs were presented unreinforced. As predicted, the CS+ was rated as significantly more disgusting than the CS- after two blocks of acquisition and this pattern was eliminated after extinction. Although no group differences emerged as a function of the CS+ compared to the CS-, the OCD group reported statistically significantly higher disgust ratings to both CSs during acquisition (but not at habituation or extinction) than relatives and controls. However, relatives and controls did not significantly differ from each other. Additionally, disgust proneness explained the group difference between those with and without OCD in disgust responding to both CSs at acquisition. These findings suggest a readiness for disgust conditioning in OCD that may be the product of heightened disgust proneness but provide no evidence that it functions as an endophenotype.

We revisit string theoretic derivations of black hole entropy and argue that their enabling structures do not persist in realistic cosmologies. We formalize this as the Thermodynamic Split Conjecture (TSC) which is the statement that in any UV complete quantum gravity, black hole and cosmological horizon thermodynamics are generically inequivalent. The BKE criterion is then formulated to formalize this approach while we also discuss ways to falsify the conjecture. Finally, we propose an observational scaling test which is centered around comparisons of data native entropy proxies from tomographic maps to the Bekenstein-Hawking prediction S ∝ H − 2 ( z ) . The framework both sharpens when and why the area law holds and provides a roadmap towards a UV complete description of cosmological horizon entropy.

Intensive care unit (ICU) clinicians respond to over 900 alarms per day, resulting in sensory overload that leads to delayed and inaccurate clinician responses. Integrating vital signs into object-based visual displays has been shown to yield quicker and more accurate responses than standard ICU alarm displays. We designed a ring-based visual alarm system that integrates heart rate (HR), blood pressure (BP), and peripheral oxygen sat-uration (SpO2) and evaluated its effectiveness using a virtual reality (VR) testing environment. VR offers significant advantages over traditional setups, notably by providing highly controlled, immersive, and replicable testing en-vironments. This display was compared against an existing graph-based dis-play that had been previously proven more effective than standard numerical ICU alarms. Using an HTC VIVE Pro Eye headset, we created controlled virtual environments to test participant speed and accuracy in identifying simulated clinical events. Tests were conducted with the graph-based, ring-based, and both displays shown, using head orientation software to determine which display participants viewed. When shown individually, the ring-based display had 33% higher accuracy and a 1.00s faster mean response time than the graph-based dis-play. When both displays were present, subjects viewed the ring-based dis-play 82.2% of the time. Display location in the visual field had no significant impact on performance. The ring-based display yielded improved alarm identification accuracy and response time compared to the graph-based alarm display. VR provided a robust, controlled method for testing medical interfaces. Future work should implement eye-tracking into alarm evaluation. This work's end goal is to combine our visual alarm with auditory alarms to create a multi-sensory alarm system.

Military surgical residency programs face unique challenges in preparing residents for the operational demands of combat casualty care. Over the past decade, significant educational innovations have been implemented to improve clinical competence and deployment readiness. To evaluate advancements in U.S. military surgical residency training between 2015 and 2025, focusing on educational interventions and their impact on resident preparedness across multiple domains of surgical education. A systematic review of literature from PubMed and Scopus was performed using defined MeSH and keyword criteria. Studies were included if they evaluated educational interventions involving surgical residents in U.S. military GME programs, reporting outcomes such as competency, readiness, or skill acquisition. Fifteen studies met inclusion criteria. Key innovations included simulation-based training in trauma, OB/GYN, and urology; deployment readiness curricula; live tissue and cadaveric courses; mentorship frameworks; and the integration of research platforms for skill sustainment. These interventions led to measurable improvements in confidence, performance, and readiness indices across residency programs. The past decade has seen a paradigm shift in military surgical education. Evidence based innovations are helping to align training with future operational demands, but further standardization and longitudinal outcomes research are needed.

Cardiac involvement is a major cause of morbidity in systemic lupus erythematosus (SLE). Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is elevated in SLE, but its contribution to lupus-associated cardiac injury is unclear. We investigated the role of TWEAK/Fn14 signaling in SLE-related cardiomyopathy and its potential as a biomarker and therapeutic target. Serum TWEAK, inflammatory cytokines, autoantibodies, and oxidative stress markers were measured in 242 SLE patients and 66 age- and sex- matched controls, with correlation to echocardiographic, electrocardiographic, and myocardial enzyme findings. Cardiac pathology and redox signaling were assessed in pristane-induced lupus models using wild-type and Fn14-deficient mice by histopathology, immunoblotting, immunofluorescence, and quantitative proteomics. Direct effects of TWEAK on mitochondrial oxidative stress, antioxidant signaling, and apoptosis were examined in primary cardiomyocytes isolated from lupus-prone MRL/lpr mice. Serum TWEAK levels were significantly elevated in patients with SLE and were highest in those with cardiac abnormalities compared with healthy controls. TWEAK correlated positively with malondialdehyde, 8-hydroxy-2' -deoxyguanosine, disease activity, and inflammatory cytokines, and inversely with superoxide dismutase. Elevated baseline TWEAK predicted new cardiac abnormalities during follow-up and declined with clinical improvement. In lupus mice, Fn14 deficiency reduced cardiac reactive oxygen species accumulation, restored Nrf2/HO-1 antioxidant signaling, attenuated histopathological injury, and preserved cardiac function. In vitro, TWEAK induced mitochondrial superoxide production, suppressed Nrf2 signaling, and promoted apoptosis in lupus-prone cardiomyocytes. TWEAK/Fn14 signaling drives oxidative stress- mediated cardiomyocyte injury in SLE and represents a promising biomarker and therapeutic target for lupus-associated cardiac damage.

Dopamine is a monoamine neurotransmitter that regulates neuronal activity and synaptic transmission. While dopaminergic activity is known to suppress action potential-dependent glutamate release in certain brain regions, the modulatory effect of dopaminergic tone on spontaneous glutamate release is unclear. Here, we used primary rat ventral tegmental area-cortex co-cultures to assess how decreased dopaminergic tone affects spontaneous synaptic glutamate release using whole-cell patch-clamp electrophysiology. We found that an acute decrease in dopaminergic tone increases the frequency of spontaneous glutamate release, driven by a surge in basal presynaptic calcium. This presynaptic calcium surge results from disinhibition of voltage-gated calcium channels (VGCCs) due to reduced Gβγ subunit activity downstream of D2 receptor signaling. While acute reduction in dopaminergic tone has robust presynaptic effects, chronic reduction results in homeostatic synaptic plasticity, characterized by postsynaptic insertion of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, a process known as synaptic upscaling. Notably, chronic antagonism of both D1 and D2 receptors using selective antagonists, as well as long-term treatment with first- and second-generation antipsychotics haloperidol, chlorpromazine, olanzapine, clozapine, and aripiprazole, promoted robust synaptic upscaling. These findings reveal a novel mechanism of action for antipsychotic medications and suggest that antipsychotics do not solely act on counteracting hyperdopaminergia, but also tune glutamatergic neurotransmission by activating homeostatic plasticity mechanisms.

Isobutanol is a fusel alcohol that can be produced microbially for use as a biofuel or upgraded into sustainable aviation fuel (SAF). A key enzyme in the isobutanol biosynthetic pathway is 2-ketoacid decarboxylase (KDC), which irreversibly decarboxylates 2-ketoisovalerate (KIV) to yield isobutyraldehyde. However, many previously characterized KDC enzymes also act promiscuously on other 2-ketoacids, (e.g., pyruvate) to produce a related aldehyde (e.g., acetaldehyde). This unwanted side reaction is especially important when isobutanol is produced in Saccharomyces cerevisiae (S. cerevisiae) because it leads to pyruvate being diverted to ethanol. In order to make S. cerevisiae a strict isobutanologen, a KDC enzyme that is specific for KIV must be deployed. In this study, we used a combination of cell-based and in vitro enzyme assays to investigate KDC substrate specificity, characterizing a large set of homologs for KIV, pyruvate, and phenylpyruvate (PPV) activity. A diverse range of substrate specificities was discovered, and some previously uncharacterized KDCs were revealed to have high KIV activity and low pyruvate activity. Multi-site saturation mutagenesis (SSM) of one of these KDCs identified mutants with increased KIV activity, while maintaining low levels of pyruvate activity. In a KIV bioconversion experiment, bioprospected and engineered KDCs allowed similar KIV consumption to when using the previously characterized Lactococcus lactis KdcA, though with some ethanol also produced. The KDCs identified here show promise for production of isobutanol and other alcohols derived from 2-ketoacids, and the dataset of newly characterized KDCs can inform future efforts to understand and engineer substrate specificity in KDCs.