The Boonshoft School of Medicine (formerly known as Wright State University School of Medicine) is the medical school at Wright State University. The School is located in Dayton, Ohio, and serves the Miami Valley region of southwestern Ohio. Instead of operating a university-based hospital for clinical training, Wright State is affiliated with six major teaching hospitals in the Greater Dayton area and has formal affiliation agreements with more than 25 other health care institutions in the Miami Valley.Admission to Wright State University's School of Medicine is competitive among the many students who apply; in 2019, 6,182 students applied for admission to the school, and 119 matriculated.The Boonshoft School of Medicine is accredited by the Liaison Committee on Medical Education (LCME).
The small molecule SR8278 was initially identified as an antagonist of the REV-ERB (reverse c-ERBAa) nuclear receptor proteins, which play important roles in metabolism and circadian rhythms. Though SR8278 has been shown to have beneficial physiological effects in a variety of different preclinical disease contexts, its impact on gene expression and cell proliferation in keratinocytes has not previously been examined. We therefore carried out an RNA-seq analysis and found that genes involved in the G1/S transition of the cell cycle were significantly impacted by SR8278 treatment, and these effects were confirmed at both the RNA and protein level by RT-qPCR and Western blotting, respectively. Cell proliferation assays showed that SR8278 slowed cell growth but did not induce genotoxic stress or apoptosis. Finally, the use of CRISPR/Cas9 genome editing and siRNA-mediated disruption of REV-ERB gene expression showed that the loss of the REV-ERB proteins did not impact the effect of SR8278 on gene expression and cell proliferation. We conclude that the anti-proliferative effects of SR8278 are not mediated by the REV-ERB proteins, and, thus, care should be taken when interpreting studies involving this compound unless complementary genetic approaches are also shown, particularly in studies involving cell proliferation.
Abstract The time of day of UV exposure impacts both erythema and cancer development. To investigate whether UV-relevant clock-controlled gene expression can be modulated pharmacologically, we treated human skin explants with a combination of a cryptochoursome inhibitor and REV-ERB antagonist and then examined changes in gene expression of a limited number of core clock and clock-regulated genes. mRNA levels of both the DNA repair factor XPA and cell cycle checkpoint kinase WEE1 were found to be significantly increased by treatment. This pilot study suggests that clock-controlled gene expression can be altered pharmacologically to possibly alter skin responses to UV radiation.
UV radiation (UVR) leads to the formation of potentially lethal and chromosome-destabilizing double-strand breaks (DSBs) in DNA. However, most studies on UVR-induced DSB formation and repair have used cells that are actively progressing throughout the cell cycle. To explore how nonreplicating, quiescent cells deal with UVR-induced DSBs, we used small-molecule inhibitors of various DSB repair pathways and unexpectedly observed a major role for the recombination protein RAD51 in promoting quiescent HaCaT keratinocyte survival. We further observed that both DSB formation and RAD51 function occur independently of nucleotide excision repair, which generates potentially unstable single-stranded DNA gaps. However, RAD51 inhibition also sensitizes quiescent cells to agents that are known to inhibit transcription, thus suggesting a role for transcription in UVR-induced DSB formation. Interestingly, siRNA-mediated knockdown of RAD51 did not sensitize cells to UVR to the same extent as pharmacological inhibition did. In contrast, knockdown of several Rad51 paralogs negatively impacted cell viability after UVR exposure, similar to pharmacological inhibition, suggesting that pharmacological inhibitors of RAD51 may also target one or more RAD51 paralogs. In summary, these findings highlight the important roles of RAD51 and its paralogs in promoting quiescent cell survival in response to UVR.
BACKGROUND:Since 2000, rates of suicide and opioid overdose have sharply increased. Approximately one-third of individuals with major depressive disorder (MDD) experience treatment-resistant depression (TRD), highlighting the urgent need for novel therapeutic approaches. OBJECTIVE:This review synthesizes pivotal preclinical and clinical findings on low-dose ketamine's rapid antidepressant effects and examines proposed mechanisms underlying its therapeutic action. METHODS:This is a narrative review of key contributions in the literature addressing ketamine's fast-acting antidepressant properties. RESULTS:Low-dose ketamine rapidly alleviates depressive symptoms, including in refractory depression. Despite multiple hypotheses supported by preliminary data, there is no consensus regarding its definitive mechanism of action. Proposed mechanisms include modulation of dopamine signaling via epigenetic neuroadaptation, interactions with D1/D2 receptor systems, optogenetic activation of D1 pathways, and alterations in D2/D3 receptor availability. CONCLUSIONS:Elucidating ketamine's mechanism of action may inform the development of next-generation psychoplastogens that promote neural plasticity in TRD and unipolar MDD. However, ketamine's psychoactive properties and abuse potential, along with concerns regarding misuse and diversion, underscore the need for enhanced clinical oversight and regulatory frameworks.
Background:The 2018 Movement Disorder Society criteria introduced stricter diagnostic requirements for essential tremor (ET) compared with the 1998 consensus; however, how electronic health record (EHR)-based ET diagnostic coding aligns with chart-adjudicated criteria in routine practice remains unclear. We evaluated the diagnostic performance of EHR-based ET coding relative to chart-adjudicated criteria in a US neurology practice. Methods:We conducted a retrospective study within the Geisinger Health System in Pennsylvania. Patients with neurologist-assigned ET diagnoses were identified and stratified as ET-only or ET with differential diagnostic coding. A stratified random sample underwent manual chart review. Clinical features were mapped to both criteria after one and two visits. Accuracy metrics-sensitivity, specificity, sample-based positive predictive value (PPV), and sample-based negative predictive value (NPV)-were calculated with 95% confidence intervals. Results:The reviewed sample included 447 ET-only cases and 137 with differential. With one visit, the 1998 criteria yielded sensitivity of 96% (94-98%), specificity of 60% (53-67%), PPV of 82% (78-86%), and NPV of 88% (82-94%). The 2018 criteria demonstrated similar sensitivity (96%, 94-98%) but lower specificity (38%, 32-44%) and PPV of 53% (48-58%), with NPV of 93% (88-98%). With ≥2 visits, specificity increased to 71% (61-81%) and PPV to 85% (80-90%) for the 1998 criteria, and to 51% (43-59%) and 65% (57-71%) for the 2018 criteria. Conclusion:In this cohort, ET diagnostic coding showed consistently high sensitivity and NPV across frameworks. Specificity and PPV differed by criterion and improved with multiple clinical encounters.
