Spontaneous urinary bladder regeneration after subtotal cystectomy increases YAP/WWTR1 signaling and downstream BDNF expression: Implications for smooth muscle injury responses.

Rodents have the capacity for spontaneous bladder regeneration and bladder smooth muscle cell (BSMC) migration following a subtotal cystectomy (STC). YAP/WWTR1 and BDNF (Brain-derived neurotrophic factor) play crucial roles in development and regeneration. During partial bladder outlet obstruction (PBO), excessive YAP/WWTR1 signaling and BDNF expression increases BSMC hypertrophy and dysfunction. YAP/WWTR1 and expression of BDNF and CYR61 were examined in models of regeneration and wound repair. Live cell microscopy was utilized in an ex vivo model of STC to visualize cell movement and division. In Sprague-Dawley female rats, STC was performed by resection of the bladder dome sparing the trigone, followed by closure of the bladder. Smooth muscle migration and downstream effects on signaling and expression were also examined after scratch wound of BSMC with inhibitors of YAP and BDNF signaling. Sham, PBO and incision (cystotomy) were comparators for the STC model. Scratch wound in vitro increased SMC migration and expression of BDNF, CTGF and CYR61 in a YAP/WWTR1-dependent manner. Inhibition of YAP/WWTR1 and BDNF signaling reduced scratch-induced migration. BDNF and CYR61 expression was elevated during STC and PBO. STC induces discrete genes associated with endogenous de novo cell regeneration downstream of YAP/WWTR1 activation.

Impact of the COVID-19 Pandemic on the Diagnosis of Oral and Maxillofacial Malignancies: A Retrospective Study.

OBJECTIVES: The aims of this study were to characterize the type and frequency of oral and maxillofacial malignancies in an outpatient oral pathology service and to examine the impact of COVID-19 on the diagnosis of such malignancies by dentists in Ontario, Canada. STUDY DESIGN: Our study included 775 malignancies submitted to an outpatient oral pathology service. Demographic and diagnostic data, including age, sex, submitting clinician type, anatomic site and diagnosis, were collected and analyzed for 2 periods, 2015-2019 and 2020. RESULTS: Malignancies represented 2% of total submissions to our biopsy service. Oral surface epithelial malignancies were the most common, followed by hematologic and salivary gland malignancies. During the period in which dental offices were restricted (April-May 2020), 59% fewer malignancies were submitted compared with the preceding 5 years. Despite this reduction, total malignant submissions for 2020 and post-lockdown (July-September 2020) were significantly elevated compared with previous years (p = 0.0006 and p = 0.0008, respectively). CONCLUSIONS: Our study reaffirms the important role that dentists play in the diagnosis of oral and maxillofacial malignancies. Our assessment of 2020 data highlights the impact of dental office closures on the diagnosis of oral and maxillofacial malignancies during the COVID-19 pandemic.

DNA Methylation Reduces the Yes-Associated Protein 1/WW Domain Containing Transcription Regulator 1 Pathway and Prevents Pathologic Remodeling during Bladder Obstruction by Limiting Expression of BDNF.

Chronic bladder obstruction and bladder smooth muscle cell (SMC) stretch provide fibrotic and mechanical environments that can lead to epigenetic change. Therefore, we examined the role of DNA methylation in bladder pathology and transcriptional control. Sprague-Dawley female rats underwent partial bladder obstruction by ligation of a silk suture around the proximal urethra next to a 0.9-mm steel rod. Sham operation comprised passing the suture around the urethra. After 2 weeks, rats were randomized to normal saline or DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (DAC) at 1 mg/kg, three times/week intraperitoneally. After 6 weeks, bladders were weighed and divided for histology and RNA analysis by high-throughput real-time quantitative PCR arrays. DAC treatment during obstruction in vivo profoundly augmented brain-derived neurotrophic factor (BDNF) expression compared with the obstruction with vehicle group, which was statistically correlated with pathophysiologic parameters. BDNF, cysteine rich angiogenic inducer 61 (CYR61), and connective tissue growth factor (CTGF) expression clustered tightly together using Pearson's correlation analysis. Their promoters were associated with the TEA domain family member 1 (TEAD1) and Yes-associated protein 1/WW domain containing transcription regulator 1 pathways. Interestingly, DAC treatment increased BDNF expression in bladder SMCs (P < 0.0002). Stretch-induced BDNF was inhibited by the YAP/WWTR1 inhibitor verteporfin. Verteporfin improved the SMC phenotype (proliferative markers and SMC marker expression), in part by reducing BDNF. Expression of BDNF is limited by DNA methylation and associated with pathophysiologic changes during partial bladder outlet obstruction and SMC phenotypic change in vitro.

Intrinsic oscillations in spike trains indicate non-renewal statistics due to convergence of inputs in dorsal cochlear nucleus neurons.

The occurrence of intrinsic oscillations (IOs) in a unit's discharge is reflected by a prominent peak in the power spectrum (i.e., Fourier transform of the autocorrelation function) of spike trains obtained from single-unit discharge, at a frequency independent of stimulus spectral characteristics. IOs have been reported by researchers in the dorsal cochlear nucleus (DCN) of both the cat and the Mongolian gerbil. It has been hypothesized that IOs are related to inter-spike interval (ISI) regularity (e.g., [Hear. Res. 58 (1992) 153]). This hypothesis is tested in this paper. Responses to multiple presentations of 50-300 ms duration tone bursts, at and near the unit's best frequency (BF) at 20-60 dB re threshold were recorded from DCN units of barbiturate-anesthetized (30 units), as well as decerebrate (53 units) Mongolian gerbils. IOs in the recordings were then compared with the IOs in simulations of spiking-neuron models. The models were selected because: (1) their ISI regularity characteristics follow those of experimental data and (2) their IO properties are completely determined by their ISI regularity. Such comparison reveals that Ghoshal's hypothesis fails for a fraction of the units. These results suggest a re-evaluation of the purported relationship between IOs, ISI regularity, and SAM response. Alternate hypotheses are proposed here using computational models that are based on convergence of multiple neural inputs onto the unit under study. These models produce non-renewal statistics that resemble those of the experimental data, as is evident from IO-based analysis.