Influence of hydrometeorological risk factors on child diarrhea and enteropathogens in rural Bangladesh.

BACKGROUND: A number of studies have detected relationships between weather and diarrhea. Few have investigated associations with specific enteric pathogens. Understanding pathogen-specific relationships with weather is crucial to inform public health in low-resource settings that are especially vulnerable to climate change. OBJECTIVES: Our objectives were to identify weather and environmental risk factors associated with diarrhea and enteropathogen prevalence in young children in rural Bangladesh, a population with high diarrheal disease burden and vulnerability to weather shifts under climate change. METHODS: We matched temperature, precipitation, surface water, and humidity data to observational longitudinal data from a cluster-randomized trial that measured diarrhea and enteropathogen prevalence in children 6 months-5.5 years from 2012-2016. We fit generalized additive mixed models with cubic regression splines and restricted maximum likelihood estimation for smoothing parameters. RESULTS: Comparing weeks with 30°C versus 15°C average temperature, prevalence was 3.5% higher for diarrhea, 7.3% higher for Shiga toxin-producing Escherichia coli (STEC), 17.3% higher for enterotoxigenic E. coli (ETEC), and 8.0% higher for Cryptosporidium. Above-median weekly precipitation (median: 13mm; range: 0-396mm) was associated with 29% higher diarrhea (adjusted prevalence ratio 1.29, 95% CI 1.07, 1.55); higher Cryptosporidium, ETEC, STEC, Shigella, Campylobacter, Aeromonas, and adenovirus 40/41; and lower Giardia, sapovirus, and norovirus prevalence. Other associations were weak or null. DISCUSSION: Higher temperatures and precipitation were associated with higher prevalence of diarrhea and multiple enteropathogens; higher precipitation was associated with lower prevalence of some enteric viruses. Our findings emphasize the heterogeneity of the relationships between hydrometeorological variables and specific enteropathogens, which can be masked when looking at composite measures like all-cause diarrhea. Our results suggest that preventive interventions targeted to reduce enteropathogens just before and during the rainy season may more effectively reduce child diarrhea and enteric pathogen carriage in rural Bangladesh and in settings with similar meteorological characteristics, infrastructure, and enteropathogen transmission.

Computational fluid dynamics analysis on endoscopy of main left coronary artery: An application of applied mathematics.

The endoscopy of a coronary arterial segment having a symmetric emergence of plaque at its innermost region is numerically modeled via computational fluid dynamics toolbox Open-FOAM. The considered left coronary artery for this model has a radius of 2 mm and span of 10 mm. The formation of plaque inside the artery that is a stenosis has length 2 mm and height 0.82 mm. The catheter used for this analysis has a diameter of 1 mm with a balloon over it with a height of 0.53 mm. The blood flow rate considered for this analysis has a range 2.00 ml/s to 2.50 ml/s. The fluid under consideration for this endoscopy review is the non-Newtonian Casson model. The mesh illustrations are arranged for the proposed model with numerical simulations of velocity, pressure profile and streamlines. The narrow channel formed due to assembly of stenosis and balloon over catheter inside this arterial segment has developed some swirling flow profile with turbulence effects just after the flow leaves the stenosis plus balloon region. Although this disturbance caused due to narrowing of channel has made the flow slightly turbulent, the flow eventually leaves the arterial segment again as a laminar flow. To cure coronary artery disease, catheterization, and balloon dilation of stenosed arteries is performed to locate the position and shape of stenosis. A catheter is inserted inside the body through a minor cut and then it is moved inside arteries to place it exactly at the stenosis location. A balloon is placed at front of that catheter and the stenosed region can be opened wide by using balloon dilation.

Protoporphyrin IX-induced phototoxicity: Mechanisms and therapeutics.

Protoporphyrin IX (PPIX) is an intermediate in the heme biosynthesis pathway. Abnormal accumulation of PPIX due to certain pathological conditions such as erythropoietic protoporphyria and X-linked protoporphyria causes painful phototoxic reactions of the skin, which can significantly impact daily life. Endothelial cells in the skin have been proposed as the primary target for PPIX-induced phototoxicity through light-triggered generation of reactive oxygen species. Current approaches for the management of PPIX-induced phototoxicity include opaque clothing, sunscreens, phototherapy, blood therapy, antioxidants, bone marrow transplantation, and drugs that increase skin pigmentation. In this review, we discuss the present understanding of PPIX-induced phototoxicity including PPIX production and disposition, conditions that lead to PPIX accumulation, symptoms and individual differences, mechanisms, and therapeutics.

PLAAT1 deficiency alleviates high-fat diet-induced hepatic lipid accumulation in mice.

The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipid-metabolizing enzymes exhibiting phospholipase A1 /A2 and acyltransferase activities. Plaat3-deficient (Plaat3-/- ) mice were previously reported to show lean phenotype and remarkable hepatic fat accumulation under high-fat diet (HFD) feeding, while Plaat1-/- mice have not been analyzed. In the present study, we generated Plaat1-/- mice and investigated the effects of PLAAT1 deficiency on HFD-induced obesity, hepatic lipid accumulation, and insulin resistance. After HFD treatment, PLAAT1 deficiency caused a lower body weight gain compared to wild-type mice. Plaat1-/- mice also showed reduced liver weight with negligible hepatic lipid accumulation. In accordance with these findings, PLAAT1 deficiency improved HFD-induced hepatic dysfunction and lipid metabolism disorders. Lipidomics analysis in the liver revealed that in Plaat1-/- mice, the levels of various glycerophospholipids tended to increase, while all classes of lysophospholipids examined tended to decrease, suggesting that PLAAT1 functions as phospholipase A1 /A2 in the liver. Interestingly, the HFD treatment of wild-type mice significantly increased the mRNA level of PLAAT1 in the liver. Furthermore, the deficiency did not appear to elevate the risk of insulin resistance in contrast to PLAAT3 deficiency. These results suggested that the suppression of PLAAT1 improves HFD-induced overweight and concomitant hepatic lipid accumulation.

CFD analysis on blood flow inside a symmetric stenosed artery: Physiology of a coronary artery disease.

This research article interprets the computational fluid dynamics analysis on blood flow inside a symmetric stenosed artery. The current problem models the blood flow inside the left coronary artery as having a symmetric stenosis in the central region. A comprehensive physiological examination of coronary artery disease is numerically evaluated by using the computational fluid dynamics toolbox Open-Field Operation And Manipulation. There are no assumptions of mild stenosis taken into account since the considered stenosis has an exactly measured length, height and position, etc. The blood flow problem is modeled for the non-Newtonian Casson fluid with unsteady, laminar, and incompressible flow assumptions. The underlying problem is solved numerically in its dimensional form. A thorough graphical analysis is provided on the blood flow simulations, pressure profile, velocity line graphs, pressure line graphs, and streamlines for the left coronary artery having a symmetric stenosis formation. The considered artery is divided into three sections, i.e. pre-stenosis, post-stenosis, and stenosis region, and the velocity and pressure line graphs are plotted for these considered regions. The graphical illustrations provide a detailed analysis of how the blood flow is affected inside the left coronary artery due to coronary artery disease. These pre- and post-stenosis velocity line graphs reveal two intriguing results: In the pre-stenosis zone, the velocity increases with increasing axial coordinate length, whereas in the post-stenosis region, the velocity decreases with rising axial coordinate length. It is evident that as the flow moves toward the stenosis region, the flow profile rises; yet, after passing through the stenosis zone, the flow profile begins to fall as the flow moves away from the stenosis region.

Blood Pressure Correlates with Serum Leptin and Body Mass Index in Overweight Male Saudi Students.

The precise association of serum leptin (Lep) with the body mass index (BMI) and blood pressure (BP) is not well known for understanding their involvement in health and disease. Hence, the present study was conducted to investigate the association of BP, BMI and serum Lep levels in young normal-weight (NW) and overweight (OW) male Saudi students. The NW (n: 198) and OW (n: 192) male subjects in the age range of 18-20 years were consulted. The BP was measured with a mercury sphygmomanometer. Leptin Human ELISA Kits were employed for the determination of the serum Lep levels. The mean ± SD values of BMI (kg/m2), Lep (ng/mL), systolic BP (SBP; mmHg), and diastolic BP (DBP; mmHg) all showed significant differences for young OW vs. NW subjects as: 27.52 ± 1.42 vs. 21.49 ± 2.03; 10.70 ± 4.67 vs. 4.68 ± 1.91; 121.37 ± 2.59 vs. 118.51 ± 1.54 and 81.44 ± 1.97 vs. 78.79 ± 1.44, respectively. All associations (among BMI, Lep, SBP and DBP) showed a positive linear and significant correlation, except the nonsignificant correlation of BMI and SBP for the NW group. Other variables showing significant variation for NW vs. OW subjects were: interleukin-6, high sensitivity C-reactive protein, apelin (APLN) and resistin. Serum APLN correlated significantly with Lep, BMI, SBP and DBP in lower and higher levels of BMI, with considerable progressive patterns in both the NW and OW groups and subgroups. The present study in young Saudi male students presents significant variations for BP and serum leptin levels, and a significant positive linear association among serum leptin, BMI and BP.

Identification of PXR Activators from Uncaria Rhynchophylla (Gou Teng) and Uncaria Tomentosa (Cat's Claw).

Uncaria rhynchophylla (Gou Teng) and Uncaria tomentosa (cat's claw) are frequently used herbal supplements in Asia and America, respectively. Despite their common usage, information is limited regarding potential herb-drug interactions associated with Gou Teng and cat's claw. The pregnane X receptor (PXR) is a ligand-dependent transcription factor that regulates cytochrome P450 3A4 (CYP3A4) expression and contributes to some known herb-drug interactions. A recent study found that Gou Teng induces CYP3A4 expression, but its mechanism is unknown. Cat's claw has been determined as a PXR-activating herb, but the PXR activators in cat's claw have not been identified. Using a genetically engineered PXR cell line, we found that the extracts of Gou Teng and cat's claw can dose-dependently activate PXR and induce CYP3A4 expression. We next used a metabolomic approach to profile the chemical components in the extracts of Gou Teng and cat's claw followed by screening for PXR activators. Four compounds, isocorynoxeine, rhynchophylline, isorhynchophylline, and corynoxeine, were identified as PXR activators from both Gou Teng and cat's claw extracts. In addition, three more PXR activators were identified from the extracts of cat's claw, including isopteropodine, pteropodine, and mitraphylline. All seven of these compounds showed the half-maximal effective concentration <10 µM for PXR activation. In summary, our work determined Gou Teng as a PXR-activating herb and discovered novel PXR activators from Gou Teng as well as cat's claw. SIGNIFICANCE STATEMENT: This study's data can be used to guide the safe use of Gou Teng and cat's claw by avoiding PXR-mediated herb-drug interactions.

Deep Learning for Robust Adaptive Inverse Control of Nonlinear Dynamic Systems: Improved Settling Time with an Autoencoder.

An adaptive deep neural network is used in an inverse system identification setting to approximate the inverse of a nonlinear plant with the aim of constituting the plant controller by copying to the latter the weights and architecture of the converging deep neural network. This deep learning (DL) approach to the adaptive inverse control (AIC) problem is shown to outperform the adaptive filtering techniques and algorithms normally used in adaptive control, especially when in nonlinear plants. The deeper the controller, the better the inverse function approximation, provided that the nonlinear plant has an inverse and that this inverse can be approximated. Simulation results prove the feasibility of this DL-based adaptive inverse control scheme. The DL-based AIC system is robust to nonlinear plant parameter changes in that the plant output reassumes the value of the reference signal considerably faster than with the adaptive filter counterpart of the deep neural network. The settling and rise times of the step response are shown to improve in the DL-based AIC system.

Formation of N-acyl-phosphatidylethanolamines by cytosolic phospholipase A2ε in an ex vivo murine model of brain ischemia.

N-Acyl-phosphatidylethanolamines (NAPEs), a minor class of membrane glycerophospholipids, accumulate along with their bioactive metabolites, N-acylethanolamines (NAEs) during ischemia. NAPEs can be formed through N-acylation of phosphatidylethanolamine by cytosolic phospholipase A2ε (cPLA2ε, also known as PLA2G4E) or members of the phospholipase A and acyltransferase (PLAAT) family. However, the enzyme responsible for the NAPE production in brain ischemia has not yet been clarified. Here, we investigated a possible role of cPLA2ε using cPLA2ε-deficient (Pla2g4e-/-) mice. As analyzed with brain homogenates of wild-type mice, the age dependency of Ca2+-dependent NAPE-forming activity showed a bell-shape pattern being the highest at the first week of postnatal life, and the activity was completely abolished in Pla2g4e-/- mice. However, liquid chromatography-tandem mass spectrometry revealed that the NAPE levels of normal brain were similar between wild-type and Pla2g4e-/- mice. In contrast, post-mortal accumulations of NAPEs and most species of NAEs were only observed in decapitated brains of wild-type mice. These results suggested that cPLA2ε is responsible for Ca2+-dependent formation of NAPEs in the brain as well as the accumulation of NAPEs and NAEs during ischemia, while other enzyme(s) appeared to be involved in the maintenance of basal NAPE levels.

Beneficial Effects of Black Cardamom (Amomum subulatum) on Hemodynamic Parameters in Normotensive and Spontaneously Hypertensive Rats.

<b>Background and Objectives:</b> <i>Amomum subulatum</i> (AS) is used to improve cardiac health in traditional medicine practice. The present study evaluates the pharmacological effect of AS aqueous extract on blood pressure in Normotensive (NR) and Spontaneously Hypertensive Rats (SHR). <b>Materials and Methods:</b> Blood pressure, Heart Rate (HR) and Heart Rate Variability (HRV), was recorded in catheterized Sprague-Dawley rats before and after AS intravenous administration by using Mikro-Tip Pressure-Volume System (MPVS), PowerLab. The receptor activity was assessed by using the drugs Acetylcholine (ACh) and Atropine (Atr). <b>Results:</b> Preliminary phytochemistry of AS suggests that it contains tannins, flavonoids and saponins. Mean Arterial Pressure (MAP) was found to decrease significantly in NR and SHR as compared with the control. The lowest dose (1 mg kg¹) produced the least (16%) while 30 mg kg¹ caused the maximum reduction (40%) in MAP. Electrocardiograph analysis revealed a significant increase in RR interval (decreased heart rate), time-domain Standard Deviation of Interbeat Interval (SDNN) and the Root Mean Square of the Successive Differences (RMSSD) and High-frequency Domain (HF%) parameters and a decrease in the Low-Frequency (LF) range, suggesting the activation and involvement of the parasympathetic limb. It was also observed that the cardiovascular effects of AS were comparable to Acetylcholine (ACh) and both were completely blocked by Atropine (1 µg kg¹). <b>Conclusion:</b> The obtained results suggest that AS has a hypotensive effect, with an impact on the HRV of NR and SHR. <i>Amomum subulatum</i> might cause an augmented effect on the cholinergic limb of the Autonomic Nervous System (ANS) and decrease the blood pressure and heart rate significantly.

Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity.

Methimazole (MMI) is a widely used antithyroid drug, but it can cause hepatotoxicity by unknown mechanisms. Previous studies showed that the hepatic metabolism of MMI produces N-methylthiourea, leading to liver damage. However, the specific enzyme responsible for the production of the toxic metabolite N-methylthiourea is still unclear. In this study, we screened cytochromes P450 (CYPs) in N-methylthiourea production from MMI. CYP2A6 was identified as the key enzyme in catalyzing MMI metabolism to produce N-methylthiourea. When mice were pretreated with a CYP2A6 inhibitor, formation of N-methylthiourea from MMI was remarkably reduced. Consistently, the CYP2A6 inhibitor prevented MMI-induced hepatotoxicity. These results demonstrated that CYP2A6 is essential in MMI bioactivation and hepatotoxicity.

Involvement of the γ Isoform of cPLA2 in the Biosynthesis of Bioactive N-Acylethanolamines.

Arachidonylethanolamide (anandamide) acts as an endogenous ligand of cannabinoid receptors, while other N-acylethanolamines (NAEs), such as palmitylethanolamide and oleylethanolamide, show analgesic, anti-inflammatory, and appetite-suppressing effects through other receptors. In mammalian tissues, NAEs, including anandamide, are produced from glycerophospholipid via N-acyl-phosphatidylethanolamine (NAPE). The ɛ isoform of cytosolic phospholipase A2 (cPLA2) functions as an N-acyltransferase to form NAPE. Since the cPLA2 family consists of six isoforms (α, ß, γ, δ, ɛ, and ζ), the present study investigated a possible involvement of isoforms other than ɛ in the NAE biosynthesis. Firstly, when the cells overexpressing one of the cPLA2 isoforms were labeled with [14C]ethanolamine, the increase in the production of [14C]NAPE was observed only with the ɛ-expressing cells. Secondly, when the cells co-expressing ɛ and one of the other isoforms were analyzed, the increase in [14C]N-acyl-lysophosphatidylethanolamine (lysoNAPE) and [14C]NAE was seen with the combination of ɛ and γ isoforms. Furthermore, the purified cPLA2γ hydrolyzed not only NAPE to lysoNAPE, but also lysoNAPE to glycerophospho-N-acylethanolamine (GP-NAE). Thus, the produced GP-NAE was further hydrolyzed to NAE by glycerophosphodiesterase 1. These results suggested that cPLA2γ is involved in the biosynthesis of NAE by its phospholipase A1/A2 and lysophospholipase activities.

Roles of Endocannabinoids and Endocannabinoid-Like Molecules in Energy Homeostasis and Metabolic Regulation: A Nutritional Perspective.

The endocannabinoid system is involved in signal transduction in mammals. It comprises principally G protein-coupled cannabinoid receptors and their endogenous agonists, called endocannabinoids, as well as the enzymes and transporters responsible for the metabolism of endocannabinoids. Two arachidonic acid-containing lipid molecules, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, function as endocannabinoids. N-acylethanolamines and monoacylglycerols, in which the arachidonic acid chain is replaced with a saturated or monounsaturated fatty acid, are not directly involved in the endocannabinoid system but exhibit agonistic activities for other receptors. These endocannabinoid-like moleculesinclude palmitoylethanolamide, oleoylethanolamide (OEA), and 2-oleoylglycerol. Endocannabinoids stimulate feeding behavior and the anabolism of lipids and glucose, while OEA suppresses appetite. Both central and peripheral systems are included in these nutritional and metabolic contexts. Therefore, they have potential in the treatment and prevention of obesity. We outline the structure, metabolism, and biological activities of endocannabinoids and related molecules, and focus on their involvement in energy homeostasis and metabolic regulation.

Metabolism and Hepatotoxicity of Pyrazinamide, an Antituberculosis Drug.

Pyrazinamide (PZA) is an important component of a standard combination therapy against tuberculosis. However, PZA is hepatotoxic, and the underlying mechanisms are poorly understood. Biotransformation of PZA in the liver was primarily suggested behind its hepatoxicity. This review summarizes the knowledge of the key enzymes involved in PZA metabolism and discusses their contributions to PZA hepatotoxicity. SIGNIFICANCE STATEMENT: This review outlines the current understanding of PZA metabolism and hepatotoxicity. This work also highlights the gaps in this field, which can be used to guide the future studies on PZA-induced liver injury.

Deep Learning versus Spectral Techniques for Frequency Estimation of Single Tones: Reduced Complexity for Software-Defined Radio and IoT Sensor Communications.

Despite the increasing role of machine learning in various fields, very few works considered artificial intelligence for frequency estimation (FE). This work presents comprehensive analysis of a deep-learning (DL) approach for frequency estimation of single tones. A DL network with two layers having a few nodes can estimate frequency more accurately than well-known classical techniques can. While filling the gap in the existing literature, the study is comprehensive, analyzing errors under different signal-to-noise ratios (SNRs), numbers of nodes, and numbers of input samples under missing SNR information. DL-based FE is not significantly affected by SNR bias or number of nodes. A DL-based approach can properly work using a minimal number of input nodes N at which classical methods fail. DL could use as few as two layers while having two or three nodes for each, with the complexity of O{N} compared with discrete Fourier transform (DFT)-based FE with O{Nlog2 (N)} complexity. Furthermore, less N is required for DL. Therefore, DL can significantly reduce FE complexity, memory cost, and power consumption, which is attractive for resource-limited systems such as some Internet of Things (IoT) sensor applications. Reduced complexity also opens the door for hardware-efficient implementation using short-word-length (SWL) or time-efficient software-defined radio (SDR) communications.

The impact of operative duration and intraoperative fluid dynamics on postoperative hypocalcemia after total thyroidectomy: a prospective non-randomized study.

BACKGROUND: Postoperative hypocalcemia after total thyroidectomy (TT) still remains common. This prospective observation study examined the role of intraoperative time period (IOP) and intravenous fluids (IVF) in transient and permanent (> 6 months) hypocalcemia post-TT. SUBJECTS AND METHOD: Consecutive patients (n = 328; age = median (IQR); 34 (15) years; M:F = 65:263) with benign or malignant thyroid disease undergoing TT were evaluated for IOP, intraoperative IVF, serum corrected calcium, intact parathormone (iPTH), and 25-hydroxyvitamin D (25OHD) levels at baseline, 48 h, and 6 months post-TT. RESULTS: The incidence of symptomatic transient and permanent hypocalcemia post-TT was 33.5% and 7.9% respectively. In multivariate logistic regression analysis, the independent risk factors for transient hypocalcemia were IOP (odds ratio: 11.6), 48-h iPTH (4.8), IVF (2.9), hyperthyroidism (2.8), and percent calcium decline (1.07), while 25OHD deficiency increased the risk by 10.5 odds in subset with preoperative hypocalcemia. In receiver operating characteristic analysis, IOP, and IVF strongly predicted transient hypocalcemia with a threshold of 123 min and 1085 mL. Area under the curve, sensitivity, and specificity were 0.883 (95% CI: 0.838-0.928), 88.1%, and 74.4% and 0.883 (0.840-0.926; each P = 0.001), 84.4%, and 74.4% respectively. Serum 48-h calcium < 7.8 mg/dL was the only reliable predictor of permanent hypocalcemia. CONCLUSION: Operative duration > 123 min and IVF > 1085 mL increased the risk of transient hypocalcemia post-TT manyfold but not permanent hypocalcemia. Routine intraoperative identification, preservation of viable in situ parathyroid glands, and laryngeal nerves increased IOP and rates of transient hypocalcemia but improved long-term outcome.

Potassium losing, aldosterone producing adrenocortical carcinoma: a rare presentation.

Adrenocortical carcinomas (ACCs) are rare malignancies with an incidence of one to two per million per year. Aldosterone-producing ACCs (APACs) are extremely rare with an incidence less than 1%. We describe a rare case of APAC, presenting with episodic lower-limb weakness and hypertension. Our patient was found to have serum aldosterone levels of 20.8 ng/dL (2.5-15.2) with persistent hypokalaemia and a 9.7×8.3×7.7 cm right adrenal mass, which was suspicious of malignancy on evaluation. He underwent a complete surgical resection which confirmed the diagnosis of ACC and normalised his aldosterone and potassium levels. He was then subjected to postoperative chemotherapy. Postoperative adjuvant chemotherapy with mitotane has a role in preventing recurrence.

Effect of water, sanitation, handwashing and nutrition interventions on enteropathogens in children 14 months old: a cluster-randomized controlled trial in rural Bangladesh.

BACKGROUND: We evaluated the impact of low-cost water, sanitation, handwashing (WSH) and child nutrition interventions on enteropathogen carriage in the WASH Benefits cluster-randomized controlled trial in rural Bangladesh. METHODS: We analyzed 1411 routine fecal samples from children 14±2 months old in the WSH (n = 369), nutrition counseling plus lipid-based nutrient supplement (n = 353), nutrition plus WSH (n = 360), and control (n = 329) arms for 34 enteropathogens using quantitative PCR. Outcomes included the number of co-occurring pathogens; cumulative quantity of four stunting-associated pathogens; and prevalence and quantity of individual pathogens. Masked analysis was by intention-to-treat. RESULTS: 326 (99.1%) control children had one or more enteropathogens detected (mean 3.8±1.8). Children receiving WSH interventions had lower prevalence and quantity of individual viruses than controls (prevalence difference for norovirus: -11% [95% confidence interval [CI], -5 to -17%]; sapovirus: -9% [95%CI, -3 to -15%]; and adenovirus 40/41: -9% [95%CI, -2 to - 15%]). There was no difference in bacteria, parasites, or cumulative quantity of stunting-associated pathogens between controls and any intervention arm. CONCLUSIONS: WSH interventions were associated with fewer enteric viruses in children aged 14 months. Different strategies are needed to reduce enteric bacteria and parasites at this critical young age.

TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors.

Testosterone regulates dimorphic sexual behaviors in all vertebrates. However, the molecular mechanism underlying these behaviors remains unclear. Here, we report that a newly identified rapid testosterone signaling receptor, Transient Receptor Potential Melastatin 8 (TRPM8), regulates dimorphic sexual and social behaviors in mice. We found that, along with higher steroid levels in the circulation, TRPM8-/- male mice exhibit increased mounting frequency indiscriminate of sex, delayed sexual satiety, and increased aggression compared to wild-type controls, while TRPM8-/- females display an increased olfaction-exploratory behavior. Furthermore, neuronal responses to acute testosterone application onto the amygdala were attenuated in TRPM8-/- males but remained unchanged in females. Moreover, activation of dopaminergic neurons in the ventral tegmental area following mating was impaired in TRPM8-/- males. Together, these results demonstrate that TRPM8 regulates dimorphic sexual and social behaviors, and potentially constitutes a signalosome for mediation of sex-reward mechanism in males. Thus, deficiency of TRPM8 might lead to a delayed sexual satiety phenomenon.