Faculty Bibliography

Obstructive sleep apnea (OSA) exerts pathogenic effects through a combination of sleep fragmentation (SF) and intermittent hypoxia (IH). The mechanisms through which sleep disruption impacts memory might arise by investigating disruption of specific sleep stages and, when such disruption occurs through OSA, by evaluating the individual contributions of SF and IH. Given region-specific EEG slow activity during non-REM sleep has been associated with overnight declarative, motor and spatial memory formation, we investigated the effects of disrupting slow wave sleep (SWS) on a virtual maze navigation task. Thirty three participants (24 male, 56 years old [range 28-68 years] with OSA (baseline AHI4%>20/hour) who were habitually well-treated and adherent to CPAP completed 3 timed trials on a 3D spatial maze before and after polysomnographically (PSG) recorded sleep. We restricted CPAP withdrawal to SWS through real-time monitoring of the PSG under three conditions: 1) stable-SWS on therapeutic CPAP, 2) SWS-CPAP withdrawal containing SF and IH, and 3) SWS-CPAP withdrawal with supplemental oxygen containing SF with reduced IH. SWS-specific CPAP withdrawal (with or without supplemental oxygen) did not significantly impact EEG slow oscillation or spatial navigational memory, despite effectively reducing %SWS and SWS bout length. Greater regional EEG slow oscillation (0.6-1Hz), but not delta (1-4Hz) activity, was associated with improvements in overnight memory during stable SWS in the CPAP condition. These observations suggest that slow oscillations may be important for overnight memory processing, and sleep disruptions of sufficient magnitude to reduce slow oscillations may be required to capture demonstrable change in spatial navigation performance.

BACKGROUND/UNASSIGNED:The informed consent process has traditionally taken place in person. The introduction of electronic consent (eConsent) has made remote consenting processes possible. Use of eConsent has increased since the COVID-19 pandemic. It has streamlined the process of consenting patients and has been shown to benefit the research study team and participants. ECONSENT IN THE KETAMINE ANALGESIA FOR LONG-LASTING PAIN RELIEF AFTER SURGERY KALPAS STUDY/UNASSIGNED:The KALPAS study is a multicenter, double-blind, randomized controlled study investigating the effectiveness of ketamine in reducing chronic post-mastectomy pain in women undergoing mastectomy for oncologic indication. The study uses a two-part consent form consisting of a master consent with information applicable to all sites and site-specific information. All potential participants receive the full two-part consent form for review. When signing the eConsent, however, all potential participants are provided with a concise summary of the informed consent document, an approach not widely used by multicenter studies. eConsent has been noted to be beneficial to research staff when trying to gather informed consent from participants who live far away from the hospital, want to include their family and friends, and for researchers who can approach patients outside of their clinical appointments. CONCLUSION/UNASSIGNED:The ability to consent patients remotely has allowed for a flexible workflow within sites and a more patient-centric process that focuses on including loved ones in the discussion and scheduling time to speak to a principal investigator. Demand for eConsent will likely continue in the post-COVID era, and use of a concise summary can allow for a more efficient consenting process.

Cis-regulatory elements (CREs), such as enhancers and promoters, are fundamental regulators of gene expression and, across different cell types, the MYC locus utilizes a diverse regulatory architecture driven by multiple CREs. To better understand differences in CRE function, we perform pooled CRISPR inhibition (CRISPRi) screens to comprehensively probe the 2.8 Mb topologically-associated domain containing MYC in 6 human cancer cell lines with nucleotide resolution. We map 32 CREs where inhibition leads to changes in cell growth, including 8 that overlap previously identified enhancers. Targeting specific CREs decreases MYC expression by as much as 60%, and cell growth by as much as 50%. Using 3-D enhancer contact mapping, we find that these CREs almost always contact MYC but less than 10% of total MYC contacts impact growth when silenced, highlighting the utility of our approach to identify phenotypically-relevant CREs. We also detect an enrichment of lineage-specific transcription factors (TFs) at MYC CREs and, for some of these TFs, find a strong, tumor-specific correlation between TF and MYC expression not found in normal tissue. Taken together, these CREs represent systematically identified, functional regulatory regions and demonstrate how the same region of the human genome can give rise to complex, tissue-specific gene regulation.

Cardiomyopathies represent a diverse group of heart diseases that can be broadly classified into ischemic and nonischemic etiologies, each requiring distinct diagnostic approaches. Noninvasive imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), play a pivotal role in the diagnosis, risk stratification, and prognosis of these conditions. This paper reviews the characteristic CT and MRI findings associated with ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM), focusing on their ability to provide detailed anatomical, functional, and tissue characterization. In ICM, CT and MRI reveal myocardial scarring, infarct size, and coronary artery disease, while MRI further distinguishes tissue viability through late gadolinium enhancement (LGE). Conversely, nonischemic cardiomyopathies demonstrate a wide array of findings, with MRI's LGE pattern analysis being particularly critical for identifying specific subtypes, such as restrictive, hypertrophic, or dilated cardiomyopathies. By comparing the strengths and limitations of these modalities, this paper highlights their complementary roles in improving diagnostic accuracy, risk stratification, prognosis, and therapeutic decision making in both ischemic and nonischemic cardiomyopathies.

OBJECTIVES/OBJECTIVE:To provide a level-adjusted correction to the current standard relating anatomical cochlear place to characteristic frequency (CF) in humans, and to re-evaluate anatomical frequency mismatch in cochlear implant (CI recipients considering this correction. It is proposed that a level-adjusted place-frequency function may represent a more relevant tonotopic benchmark for CIs in comparison to the current standard. DESIGN/METHODS:The present analytical study compiled data from 15 previous animal studies that reported isointensity responses from cochlear structures at different stimulation levels. Extracted outcome measures were CFs and centroid-based best frequencies at 70 dB SPL input from 47 specimens spanning a broad range of cochlear locations. A simple relationship was used to transform these measures to human estimates of characteristic and best frequencies, and nonlinear regression was applied to these estimates to determine how the standard human place-frequency function should be adjusted to reflect best frequency rather than CF. The proposed level-adjusted correction was then compared with average place-frequency positions of commonly used CI devices when programmed with clinical settings. RESULTS:The present study showed that the best frequency at 70 dB SPL (BF70) tends to shift away from CF. The amount of shift was statistically significant (signed-rank test z = 5.143, p < 0.001), but the amount and direction of shift depended on cochlear location. At cochlear locations up to 600° from the base, BF70 shifted downward in frequency relative to CF by about 4 semitones on average. Beyond 600° from the base, BF70 shifted upward in frequency relative to CF by about 6 semitones on average. In terms of spread (90% prediction interval), the amount of shift between CF and BF70 varied from relatively no shift to nearly an octave of shift. With the new level-adjusted place-frequency function, the amount of anatomical frequency mismatch for devices programmed with standard-of-care settings is less extreme than originally thought and may be nonexistent for all but the most apical electrodes. CONCLUSIONS:The present study validates the current standard for relating cochlear place to CF, and introduces a level-adjusted correction for how best frequency shifts away from CF at moderately loud stimulation levels. This correction may represent a more relevant tonotopic reference for CIs. To the extent that it does, its implementation may potentially enhance perceptual accommodation and speech understanding in CI users, thereby improving CI outcomes and contributing to advancements in the programming and clinical management of CIs.

Methionine aminopeptidase 2 (MetAP2) plays an important role in the regulation of protein synthesis and post-translational processing. Preclinical/clinical applications of MetAP2 inhibitors for the treatment of various diseases have been explored because of their antiangiogenic, anticancer, antiobesity, antidiabetic, and immunosuppressive properties. However, the effects of MetAP2 inhibitors on CNS diseases are rarely examined despite the abundant presence of MetAP2 in the brain. Previously, we synthesized a novel boron-containing MetAP2 inhibitor, BL6, and found that it suppressed angiogenesis and adipogenesis yet improved glucose uptake. Here, we studied the anti-inflammatory effects of BL6 in SIM-A9 microglia and in a mouse model of Alzheimer's disease generated by the intracerebroventricular (icv) injection of streptozotocin (STZ). We found that BL6 reduced proinflammatory molecules, such as nitric oxide, iNOS, IL-1β, and IL-6, together with phospho-Akt and phospho-NF-κB p65, which were elevated in lipopolysaccharide (LPS)-activated microglial SIM-A9 cells. However, the LPS-induced reduction in Arg-1 and CD206 was attenuated by BL6, suggesting that BL6 promotes microglial M1 to M2 polarization. BL6 also decreased glial activation along with a reduction in phospho-tau and an elevation in synaptophysin in the icv-STZ mouse model. Thus, our experiments demonstrate an anti-neuroinflammatory action of BL6, suggesting possible clinical applications of MetAP2 inhibitors for brain disorders in which neuroinflammation is involved.

Aggression is an evolutionarily conserved behaviour that controls social hierarchies and protects valuable resources. In mice, aggressive behaviour can be broken down into an appetitive phase, which involves approach and investigation, and a consummatory phase, which involves biting, kicking and wrestling¹. Here, by performing an unsupervised weighted correlation network analysis on whole-brain FOS expression in mice, we identify a cluster of brain regions, including hypothalamic and amygdalar subregions and olfactory cortical regions, that are highly co-activated in male but not in female aggressors. The posterolateral cortical amygdala (COApl)-an extended olfactory structure-was found to be a hub region, on the basis of the number and strength of correlations with other regions in the cluster. Our data also show that oestrogen receptor 1 (Esr1)-expressing cells in the COApl (COApl^Esr1) exhibit increased activity during attack behaviour and during bouts of investigation that precede an attack, in male mice only. Chemogenetic or optogenetic inhibition of COApl^Esr1 cells in male aggressors reduces aggression and increases pro-social investigation without affecting social reward and reinforcement behaviour. We further show that COApl^Esr1 projections to the ventromedial hypothalamus and central amygdala are necessary for these behaviours. Collectively, these data suggest that, in aggressive males, COApl^Esr1 cells respond specifically to social stimuli, thereby enhancing their salience and promoting attack behaviour.

Current models of eye movement control propose that motor neurons responsible for moving the eyes contribute to all eye movements, regardless of context. A recent study in larval zebrafish has instead identified specialized neural circuits, including subtypes of motor neurons, for two different types of fast eye movement, one for exploration and the other for hunting.

For COVAIL recipients of a coronavirus disease 2019 (COVID-19) Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.