On the relative conservativeness of Bayesian logistic regression method in oncology dose-finding studies.

The Bayesian logistic regression method (BLRM) is a widely adopted and flexible design for finding the maximum tolerated dose in oncology phase I studies. However, the BLRM design has been criticized in the literature for being overly conservative due to the use of the overdose control rule. Recently, a discussion paper titled "Improving the performance of Bayesian logistic regression model with overall control in oncology dose-finding studies" in Statistics in Medicine has proposed an overall control rule to address the "excessive conservativeness" of the standard BLRM design. In this short communication, we discuss the relative conservativeness of the standard BLRM design and also suggest a dose-switching rule to further enhance its performance.

Dose-effect relationship between dose-volume parameters of residual gross tumor volume and clinical prognosis in MRI-guided adaptive brachytherapy for locally advanced cervical cancer: a single-center retrospective study.

PURPOSE: To investigate the dose-effect relationship between the dose-volume parameters of residual gross tumor volume (GTVres) and clinical prognosis in MRI image-guided adaptive brachytherapy (IGABT) of patients with locally advanced cervical cancer in our center. MATERIALS AND METHOD: The clinical data of 93 patients with locally advanced cervical squamous cell cancer who received external beam radiotherapy (EBRT) combined with IGABT ± chemotherapy in our center were retrospectively analyzed. The disease stage, overall treatment time (OTT), chemotherapy, and the dose-volume parameters D90, D98, and D100 of GTVres, the intermediate-risk clinical target volume (CTVIR), and the high-risk clinical target volume (CTVHR) of the patients were statistically analyzed. Kaplan-Meier and uni- and multivariable Cox regression analyses were used to analyze 2­year overall survival (OS), progression-free survival (PFS), and local control rate (LC). A probit model was employed to assess the dose-effect relationship between the volume and dose-volume parameters of GTVres and 2­year OS, PFS, and LC. RESULTS: The median follow-up time was 19.6 months and 2­year OS, PFS, and LC were 79.6%, 68.8%, and 94.6%, respectively. CTVHR D90 was an independent influencing factor for 2­year PFS (P = 0.041); GTVresBT1 volume was an independent factor for 2­year OS, PFS, and LC (P < 0.001). The probit model showed that at GTVresBT1 volume < 32.86 cm3, the expected 2­year LC was > 90%; at GTVres D98 > 129.12 GyEQD2, the expected 2­year OS was > 90%. CONCLUSION: Both the volume and dose-volume parameters of GTVres are promising predictors in assessment of IGABT prognosis of cervical cancer.

The association of telomere maintenance and TERT expression with susceptibility to human papillomavirus infection in cervical epithelium.

The role of telomerase reverse transcriptase (TERT) induction and telomere maintenance in carcinogenesis including cervical cancer (CC) pathogenesis has been well established. However, it remains unclear whether they affect infection of high-risk human papillomavirus (hrHPV), an initiating event for CC development. Similarly, genetic variants at the TERT locus are shown to be associated with susceptibility to CC, but it is unclear whether these SNPs modify the risk for cervical HPV infection. Here we show that in CC-derived HeLa cells, TERT overexpression inhibits, while its depletion upregulates expression of Syndecan-1 (SDC-1), a key component for HPV entry receptors. The TCGA cohort of CC analyses reveals an inverse correlation between TERT and SDC-1 expression (R = -0.23, P = 0.001). We further recruited 1330 females (520 non-HPV and 810 hrHPV-infected) without CC or high-grade cervical intraepithelial neoplasia to analyze telomeres in cervical epithelial cells and SNPs at rs2736098, rs2736100 and rs2736108, previously identified TERT SNPs for CC risk. Non-infected females exhibited age-related telomere shortening in cervical epithelial cells and their telomeres were significantly longer than those in hrHPV-infected group (1.31 ± 0.62 vs 1.19 ± 0.48, P < 0.001). There were no differences in rs2736098 and rs2736100 genotypes, but non-infected individuals had significantly a higher C-allele frequency (associated with higher TERT expression) while lower T-allele levels at rs2736108 compared with those in the hrHPV group (P = 0.020). Collectively, appropriate telomere maintenance and TERT expression in normal cervical cells may prevent CC by modulating hrHPV infection predisposition, although they are required for CC development and progression.

Application of three-dimensional multi-imaging combination in brachytherapy of cervical cancer.

BACKGROUND: Three-dimensional (3D) imaging has an important role in brachytherapy and the treatment of cervical cancer. The main imaging methods used in the cervical cancer brachytherapy include magnetic resonance imaging (MRI), computer tomography (CT), ultrasound (US), and positron emission tomography (PET). However, single-imaging methods have certain limitations compared to multi-imaging. The application of multi-imaging can make up for the shortcomings and provide a more suitable imaging selection for brachytherapy. PURPOSE: This review details the situation and scope of existing multi-imaging combination methods in cervical cancer brachytherapy and provides a reference for medical institutions. MATERIALS AND METHODS: Searched the literature related to application of three-dimensional multi-imaging combination in brachytherapy of cervical cancer in PubMed/Medline and Web of Science electronic databases. Summarized the existing combined imaging methods and the application of each method in cervical cancer brachytherapy. CONCLUSION: The current imaging combination methods mainly include MRI/CT, US/CT, MRI/US, and MRI/PET. The combination of two imaging tools can be used for applicator implantation guidance, applicator reconstruction, target and organs at risk (OAR) contouring, dose optimization, prognosis evaluation, etc., which provides a more suitable imaging choice for brachytherapy.

Hexagonal Network of Photocurrent Enhancement in Few-Layer Graphene/InGaN Quantum Dot Junctions.

Strain in two-dimensional (2D) materials has attracted particular attention because of the remarkable modification of electronic and optical properties. However, emergent electromechanical phenomena and hidden mechanisms, such as strain-superlattice-induced topological states or flexoelectricity under strain gradient, remain under debate. Here, using scanning photocurrent microscopy, we observe significant photocurrent enhancement in hybrid vertical junction devices made of strained few-layer graphene and InGaN quantum dots. Optoelectronic response and photoluminescence measurements demonstrate a possible mechanism closely tied to the flexoelectric effect in few-layer graphene, where the strain can induce a lateral built-in electric field and assist the separation of electron-hole pairs. Photocurrent mapping reveals an unprecedentedly ordered hexagonal network, suggesting the potential to create a superlattice by strain engineering. Our work provides insights into optoelectronic phenomena in the presence of strain and paves the way for practical applications associated with strained 2D materials.

Circulating exosomal hsa_circRNA_0039480 is highly expressed in gestational diabetes mellitus and may be served as a biomarker for early diagnosis of GDM.

BACKGROUND: Gestational diabetes mellitus (GDM) seriously affects the health of mothers and babies, and there are still no effective early diagnostic markers. Therefore, it is necessary to find diagnostic biomarkers for screening GDM in early pregnancy. Circular RNA (circRNA) is more stable than linear RNA, and can be encapsulated in exosomes and participate in the pathological process of various diseases, which makes it a better candidate biomarker for various diseases. In this study, we attempted to identify the exosomal circRNA biomarkers for detecting early GDM. METHODS: We performed microarray analysis to compare the plasma exosomal circRNA expression profiles of three GDM patients 48 h before and 48 h after delivery. The repeatability of the expression of circRNAs were randomly validated by RT-PCR analysis. Pearson correlation analysis was applied to evaluate the correlation between circRNAs and OGTT level. ROC curve was established to assess the diagnostic value of circRNAs for GDM at different stages. RESULTS: Plasma exosomal hsa_circRNA_0039480 and hsa_circRNA_0026497 were highly expressed in GDM patients before delivery (P < 0.05). The hsa_circRNA_0039480 expression was higher for GDM group than NGT group at different stages, and was also positively correlated with OGTT during the second trimester (P < 0.05). The expression of hsa_circRNA_0026497 was higher for GDM group during the third, and second trimesters. And there was a strong correlation between two circRNAs in GDM patients during the first-trimester (r = 0.496, P = 0.014). Hsa_circRNA_0039480 showed significant diagnostic value in the first, second, and third trimesters of pregnancy (AUC = 0.704, P = 0.005; AUC = 0.898, P < 0.001 and AUC = 0.698, P = 0.001, respectively). Notably, the combination of hsa_circRNA_0039480 and hsa_circRNA_0026497 exhibited promising discriminative effect on GDM in the first trimesters (AUC = 0.754, P < 0.001). CONCLUSION: Plasma exosomal hsa_cirRNA_0039480 is highly expressed in GDM patients at different stages and may be served as a candidate biomarker for early detection of GDM.

Observation of Diffusion and Drift of the Negative Trions in Monolayer WS2.

Monolayer transition metal dichalcogenides (ML-TMDCs) are a versatile platform to explore the transport dynamics of the tightly bound excitonic states. The diffusion of neutral excitons in various ML-TMDCs has been observed. However, the transport of charged excitons (trions), which can be driven by an in-plane electric field and facilitate the formation of an excitonic current, has yet been well investigated. Here, we report the direct observation of diffusion and drift of the trions in ML-WS2 through spatially and time-resolved photoluminescence. An effective diffusion coefficient of 0.47 cm2/s was extracted from the broadening of spatial profiles of the trion emission. When an in-plane electric field is applied, the spatial shift of the trion emission profiles indicated a drift velocity of 7400 cm/s. Both the diffusion caused broadening and the drift caused shift of the emission profiles saturate because of the Coulomb interactions between trions and the background charges.

CMTM7 as a novel molecule of ATG14L-Beclin1-VPS34 complex enhances autophagy by Rab5 to regulate tumorigenicity.

BACKGROUND: CMTM7 is a tumor suppressor that positively regulates EGFR degradation by promoting Rab5 activation, and plays a vital role in tumor progression. Rab5 forms complexes with Beclin1 and VPS34, and acts in the early stage of autophagy. However, the affects of CMTM7 on autophagy and its mechanism are still unclear. METHODS: The effect of CMTM7 on autophagy induction was confirmed by western blotting, confocal microscopy and transmission electron microscopy. Co-immunoprecipitation was used to analyse the interaction of CMTM7 with autophagy initiation complex and Rab5. The xenograft model in nude mice was used to elucidate the function of CMTM7 in tumorigenicity and autophagy in vivo. RESULTS: In this study, we first demonstrated that CMTM7 facilitated the initiation of autophagosome formation, which consequently promoted the subsequent multistage process of autophagic flux, i.e. from autophagosome assembly till autolysosome formation and degradation. Confocal and co-immunoprecipitation showed that CMTM7 interacted with Rab5, VPS34, Beclin1, and ATG14L, but not with ULK1, UVRAG and LC3B. CMTM7 also increased the activity of ATG14L-linked VPS34 complex and its association with Rab5. Both in vitro and in vivo experiments demonstrated that knockdown of CMTM7 enhanced tumor growth by impairing autophagy. CONCLUSION: These findings highlighted the role of CMTM7 in the regulation of autophagy and tumorigenicity, revealing it as a novel molecule that is associated with the interaction of Rab5 and ATG14L-Beclin1-VPS34 complex. Video Abstract.

A Multi-Institutional Retrospective Analysis of Oncologic Outcomes for Patients With Locally Advanced Cervical Cancer Undergoing Platinum-Based Adjuvant Chemotherapy After Concurrent Chemoradiotherapy.

OBJECTIVE: To evaluated the oncologic outcomes associated with platinum-based adjuvant chemotherapy following concurrent chemoradiotherapy (CCRT) in the management of patients with locally advanced cervical cancer (LACC). METHODS: A total of 695 patients with FIGO stage IB2, IIA2, IIB-IVA LACC treated at 6 medical facilities were enrolled and divided into 2 groups: 478 were assigned to CCRT alone (CCRT group) and 217 to adjuvant chemotherapy after CCRT (CCRT-ACT group). The treatment outcomes were retrospectively compared and reported after the propensity score matching (PSM) analysis. RESULTS: With a median follow-up of 56.4 months, no statistically significant differences were found in overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and distance metastasis-free survival (DMFS) between 2 groups. In CCRT-ACT group, patients with lymph nodes involvement or squamous cell carcinoma (SCC) had significantly longer DMFS, but no significant benefit in survival outcomes were observed with more than 2 cycles of adjuvant chemotherapy. Moreover, patients with a high level of CA125 (>20.5U/mL) or SCC-Ag (>22.8µg/L) had a relatively better DFS or PFS, and grade 3-4 acute hematological toxicity, late urinary and lower gastrointestinal complications and diarrhea symptom were more frequent in CCRT-ACT group. CONCLUSIONS: Adjuvant chemotherapy after CCRT has a potential role in further improving disease control for LACC patients with lymph nodal-metastasis or SCC with a high level of CA125 or SCC-Ag. Due to increased treatment-related complications and diarrhea symptom affecting the quality of life, post-CCRT adjuvant chemotherapy with excessive cycles was not be considered as the most appropriate choice in general.

Enhanced logical chaotic resonance.

It was demonstrated recently that logical chaotic resonance (LCR) can be observed in a bistable system. In other words, the system can operate robustly as a specific logic gate in an optimal window of chaotic signal intensity. Here, we report that the size of the optimal window of chaotic signal intensity can be remarkably extended by exploiting the constructive interaction of chaotic signal and periodic force, as well as coupling, in a coupled bistable system. In addition, medium-frequency periodic force and an increasing system size can also lead to an improvement in the response speed of logic devices. The results are corroborated by circuit experiments. Taken together, a reliable and rapid-response logic operation can be realized based on periodic force- and array-enhanced LCR.

Effect of time delay in a bistable synthetic gene network.

The essence of logical stochastic resonance is the dynamic manipulation of potential wells. The effect of time delay on the depth of potential wells and the width of a bistable region can be inferred by logic operations in the bistable system with time delay. In a time-delayed synthetic gene network, time delay in the synthesis process can increase the depth of the potential wells, while that in the degradation process, it can reduce the depth of the potential wells, which will result in a decrease in the width of the bistable region (the reason for time delay to induce logic operations without external driving force) and the instability of the system (oscillation). These two opposite effects imply stretching and folding, leading to complex dynamical behaviors of the system, including period, chaos, bubble, chaotic bubble, forward and reverse period doubling bifurcation, intermittency, and coexisting attractors.

The telomerase gene polymorphisms, but not telomere length, increase susceptibility to primary glomerulonephritis/end stage renal diseases in females.

BACKGROUND: Primary glomerulonephritis (GN) is the leading cause of chronic kidney disease (CKD) and frequently progresses into end stage renal diseases (ESRDs). Shorter leukocyte telomere length (LTL) has been implicated in the CKD susceptibility and diminished kidney function, however, it is unclear whether the variants in telomerase genes contribute to risk to GN/CKD/ESRD. Here we address this issue by determining their association with the genetic variants of rs12696304 at the telomerase RNA component (TERC) and rs2736100 at the telomerase reverse transcriptase (TERT) loci. METHODS: The study includes 769 patients (243 primary GN-derived CKD and 526 ESRD cases) and sex-/age-matched healthy controls. Genomic DNA was extracted from peripheral blood of both controls and patients. Genotyping of rs12696304 and rs2736100 variants was carried out using PCR-based assays. Leukocyte telomere length (LTL) was determined using quantitative PCR (qPCR). RESULTS: A significantly higher frequency of TERC rs12696304 G allele was observed in patients and associated with increased disease risk (C vs G: OR = 1.334, 95% CI 1.112-1.586, P = 0.001; CC + GC vs GG: OR = 1.334, 95% CI 1.122-1.586, P = 0.001). Further analyses showed that such significant differences were only present between female controls and patients (C vs G: OR = 1.483, 95% CI 1.140-1.929, P = 0.003; CC + GC vs CC: OR = 1.692, 95% CI 1.202-2.383, P = 0.003), but not males. There were no differences in rs2736100 variants between controls and patients, but female ESRD patients carried significantly higher C allele frequencies than did female controls (A vs C: OR = 1.306, 95% CI 1.005-1.698, P = 0.046; AA vs CC: OR = 1.781, 95% CI 1.033-3.070, P = 0.037). There was no difference in LTL between controls and patients. CONCLUSIONS: Our results reveal that the TERC rs12696304 and TERT rs2736100 polymorphisms, but not LTL per se, contribute to GN/CDK/ESRD risk.

Shorter Leukocyte Telomere Length coupled with lower expression of Telomerase Genes in patients with Essential Hypertension.

Background: The essential hypertension (EH) pathophysiology remains poorly understood. Many studies indicate that reduced leukocyte telomere length (LTL) is involved in the EH pathogenesis, however, the direct analysis of arterial telomere length (ATL) from EH patients and normotensive individuals did not show a difference. To address these discrepant observations between LTL and ATL, we performed comprehensive analyses of LTL, telomerase gene expression and their genetic variants in healthy normotensive controls and EH patients. Methods: Sex-matched 206 EH patients and equal numbers of healthy controls were recruited. LTL, and the expression of two key telomerase components, telomerase reverse transcriptase (TERT) and internal RNA template (TERC) were determined using qPCR. Genetic variants of rs2736100 at the TERT and rs12696304 at the TERC loci were determined using TaqMan genotyping kits. Results: LTL was significantly shorter in EH patients than in their normotensive controls (0.96 ± 0.52 vs 1.19 ± 0.58, P = 0.001). Moreover, TERT and TERC expression in patients' leukocytes were substantially lower compare to that in healthy controls (TERT, 0.98 ± 0.98 vs 1.76 ± 1.75, P = 0.003; TERC, 1.26 ± 1.62 vs 4.69 ± 3.61, P < 0.001). However, there were no differences in the genetic variants of rs2736100 and rs12696304 between patient and control groups. Conclusions: EH patients have significantly shorter LTL, which may result from defective TERT and TERC expression in leukocytes. Collectively, lower telomerase expression contributes to shorter LTL observed in EH patients, and telomerase activators may be considered for EH therapy.

Actin­like protein 8 executes a promoting function in the malignant progression of endometrial cancer: identification of a promising biomarker.

Endometrial cancer (EC) is generally considered as a disease that affects older women. We attempt to explore the role of actin­like protein 8 (ACTL8) in EC and how it achieves its function. Based on the data from The Cancer Genome Atlas (TCGA), we found that ACTL8 expression was up-regulated in EC tissues and correlated with shorter overall survival of EC patients. ACTL8 expression was significantly associated with age, clinical-stage, or grade. Cox proportional hazards model analysis revealed that ACTL8 expression, grade, and clinical-stage were promising independent prognostic factors of EC. Knockdown of ACTL8 repressed the proliferative, migrating and invading capabilities of human EC cell lines KLE and Ishikawa. Silencing ACTL8 up-regulated the negative cell cycle regulator p21 and epithelial marker E-cadherin, and down-regulated the positive cell cycle regulator Cyclin A, mesenchymal markers MMP-9 and N-cadherin in KLE cells. Collectively, these outcomes illustrated that ACTL8 might act as a tumor facilitator during EC progression.

Clinical Application of Ultrasound Guidance for Parametrial Treatment of Advanced Cervical Cancer.

OBJECTIVES: To evaluate the accuracy of ultrasound (US) in determining the positions of parametrial implants by comparing US with magnetic resonance imaging (MRI) for advanced cervical cancer. METHODS: Patients undergoing brachytherapy with parametrial implantation for cervical cancer from February 2017 to February 2019 were involved in the study. The transverse section of the cervix (surface S1 ) and the transverse section 1 cm above the external cervix (surface S2 ) were selected from MRI and US images as the observation planes. In the MRI observation plane, the distances between the uterine titanium needles and the uterine tube/implanter were set as M1 to M4 ; in the US observation plane, the distances between the uterine titanium needles and the uterine tube/implanter were set as D1 to D4 . The differences and consistency in M and D of each group were then compared. RESULTS: There were no significant differences between M and D in each group (P = .058; P = .821; P = .870; and P = .936, respectively). The intraclass correlation coefficients of M and D in each group were 0.970, 0.968, 0.952, and 0.956. A regression analysis showed that the relationships between M and D in each group were as follows: M1 = 0.9449D1 + 0.1812; M2 = 0.9463D2 + 0.0965; M3 = 0.9176D3 + 0.1233; and M4 = 0.9253D4 + 0.1224. CONCLUSIONS: In parametrial brachytherapy for cervical cancer, US can accurately determine the positions of parametrial implantation needles, which is already applicable on MRI, and can provide assistance in parametrial brachytherapy for advanced cervical cancer.

Periodic and aperiodic force-induced logical stochastic resonance in a bistable system.

It was demonstrated recently that there are optimal windows of noise intensity or frequency and amplitude of the periodic driving force, which let a bistable system operate reliably as logic gates. These phenomena are called logical stochastic resonance (LSR). Given that the driving force is not always perfect regular, there may be phase disturbance in driving force; therefore, the Wiener process is used here to model phase disturbance of driving force, and then the effects of phase disturbance on reliability and agility of logic gates are explored in detail. Comparing with the periodic force, the aperiodic force with appropriate intensity phase disturbance can drive a bistable system to yield phenomena similar to LSR in a wider reliable region and can reduce mean switching time to obtain a faster response of logic devices to the input signal. On the other hand, depending on the amplitude and average angular frequency, moderate-intensity phase disturbance may also reduce success probability and increase mean switching time and thus lead to the instability and the slower response of logic devices.

Set-reset latch logic operation in a bistable system under suprathreshold and subthreshold signals.

A set-reset latch is a basic building block of computers and can be used to store state information. Here, by testing the influence of the two logical input signals on the reliable set-reset latch logic operation in the bistable system, we found that there are two types of input signals, namely, suprathreshold and subthreshold signals. For the suprathreshold signals, reliable set-reset logic operation can be achieved without any driving forces and exhibits certain anti-interference ability; for the subthreshold signals, a single harmonic could induce correct set-reset latch logic operation but with a narrow optimal parameter region. The introduction of biharmonic-induced set-reset latch logic operation (logical vibrational resonance) could greatly expand the parameter region. Explanations for the above results were provided by taking the logical inputs as the dynamic bias to analyze the dynamic changes in the system. Finally, the results were further verified by circuit simulation and actual hardware circuit.

TEST FOR HIGH DIMENSIONAL CORRELATION MATRICES.

Testing correlation structures has attracted extensive attention in the literature due to both its importance in real applications and several major theoretical challenges. The aim of this paper is to develop a general framework of testing correlation structures for the one-, two-, and multiple sample testing problems under a high-dimensional setting when both the sample size and data dimension go to infinity. Our test statistics are designed to deal with both the dense and sparse alternatives. We systematically investigate the asymptotic null distribution, power function, and unbiasedness of each test statistic. Theoretically, we make great efforts to deal with the non-independency of all random matrices of the sample correlation matrices. We use simulation studies and real data analysis to illustrate the versatility and practicability of our test statistics.

Interfacially Bound Exciton State in a Hybrid Structure of Monolayer WS2 and InGaN Quantum Dots.

van der Waals heterostructures that are usually formed using atomically thin transition-metal dichalcogenides (TMDCs) with a direct band gap in the near-infrared to the visible range are promising candidates for low-dimension optoelectronic applications. The interlayer interaction or coupling between two-dimensional (2D) layer and the substrate or between adjacent 2D layers plays an important role in modifying the properties of the individual 2D material or device performances through Coulomb interaction or forming interlayer excitons. Here, we report the realization of quasi-zero-dimensional (0D) photon emission of WS2 in a coupled hybrid structure of monolayer WS2 and InGaN quantum dots (QDs). An interfacially bound exciton, i.e., the coupling between the excitons in WS2 and the electrons in QDs, has been identified. The emission of this interfacially bound exciton inherits the 0D confinement of QDs as well as the spin-valley physics of excitons in monolayer WS2. The effective coupling between 2D materials and conventional semiconductors observed in this work provides an effective way to realize the 0D emission of 2D materials and opens the potential of compact on-chip integration of valleytronics and conventional electronics and optoelectronics.

Reduced bladder responses to capsaicin and GSK-1016790A in retired-breeder female rats with diminished volume sensitivity.

Literature documents an age-related reduction of bladder sensory function. Transient receptor potential vanilloid (TRPV)1 or TRPV4 channels have been implicated in bladder mechanotransduction. To investigate contributions of TRPV1 or TRPV4 to the age-related reduction of bladder sensory function, bladder responses to capsaicin (CAP; TRPV1 agonist) and GSK-1016790A (GSK; TRPV4 agonist) in retired breeder (RB; 12-15 mo) and young adult (2-3 mo) female rats were compared using multiple methods. Metabolic cage and continuous infusion cystometry [cystometrogram (CMG)] recordings revealed that RB rats exhibit larger bladder capacity and lower voiding frequency. RB rats also have a greater intravesical pressure threshold for micturition; however, the voiding contraction strength was equivalent to that in young rats. CAP (1 µM) or GSK (20 nM) administered intravesically evoked smaller changes in all CMG parameters in RB rats. In vitro, CAP (1 µM) or GSK (20 nM) evoked smaller enhancement of bladder strip contractions, while the muscarinic receptor agonist carbachol (at 100, 300, and 1,000 nM) elicited greater amplitude contractions in RB rats. Patch-clamp recording revealed smaller CAP (100 nM) induced inward currents in bladder primary sensory neurons, and Ca2+ imaging revealed smaller GSK (20 nM) evoked increases in intracellular Ca2+ concentration in urothelial cells in RB rats. These results suggest that RB rats have a decreased bladder sensory function commonly observed in elderly women, and could be used as an animal model to study the underling mechanisms. Reduced functional expression of TRPV1 in bladder afferents or reduced functional expression of urothelial TRPV4 may be associated with the diminished sensory function.