Serotonin exerts a direct modulatory role on bladder afferent firing in mice.

KEY POINTS: Functional disorders (i.e. interstitial cystitis/painful bladder syndrome and irritable bowel syndrome) are associated with hyperexcitability of afferent nerves innervating the urinary tract and the bowel, respectively. Various non-5-HT3 receptor mRNA transcripts are expressed in mouse urothelium and exert functional responses to 5-HT. Whilst 5-HT3 receptors were not detected in mouse urothelium, 5-HT3 receptors expressed on bladder sensory neurons plays a role in bladder afferent excitability both under normal conditions and in a mouse model of chronic visceral hypersensitivity. These data suggest that the role 5-HT3 receptors play in bladder afferent signalling warrants further study as a potential therapeutic target for functional bladder disorders. ABSTRACT: Serotonin (5-HT) is an excitatory mediator that in the gastrointestinal (GI) tract plays a physiological role in gut-brain signalling and is dysregulated in functional GI disorders such as irritable bowel syndrome (IBS). Patients suffering from IBS frequently suffer from urological symptoms characteristic of interstitial cystitis/painful bladder syndrome, which manifests due to cross-sensitization of shared innervation pathways between the bladder and colon. However, a direct modulatory role of 5-HT in bladder afferent signalling and its role in colon-bladder neuronal crosstalk remain elusive. The aim of this study was to investigate the action of 5-HT on bladder afferent signalling in normal mice and mice with chronic visceral hypersensitivity (CVH) following trinitrobenzenesulfonic acid-induced colitis. Bladder afferent activity was recorded directly using ex vivo afferent nerve recordings. Expression of 14 5-HT receptor subtypes, the serotonin transporter (SERT) and 5-HT-producing enzymes was determined in the urothelium using RT-PCR. Retrograde labelling of bladder-projecting dorsal root ganglion neurons was used to investigate expression of 5-HT3 receptors using single cell RT-PCR, while sensory neuronal and urothelial responses to 5-HT were determined by live cell calcium imaging. 5-HT elicited bladder afferent firing predominantly via 5-HT3 receptors expressed on afferent terminals. CVH animals showed a downregulation of SERT mRNA expression in urothelium, suggesting increased 5-HT bioavailability. Granisetron, a 5-HT3 antagonist, reversed bladder afferent hypersensitivity in CVH mice. These data suggest 5-HT exerts a direct effect on bladder afferents to enhance signalling. 5-HT3 antagonists could therefore be a potential therapeutic target to treat functional bladder and bowel disorders.

Precision Analysis of the

We present a precision analysis of the ^{136}Xe two-neutrino ßß electron spectrum above 0.8 MeV, based on high-statistics data obtained with the KamLAND-Zen experiment. An improved formalism for the two-neutrino ßß rate allows us to measure the ratio of the leading and subleading 2νßß nuclear matrix elements (NMEs), ξ_{31}^{2ν}=-0.26_{-0.25}^{+0.31}. Theoretical predictions from the nuclear shell model and the majority of the quasiparticle random-phase approximation (QRPA) calculations are consistent with the experimental limit. However, part of the ξ_{31}^{2ν} range allowed by the QRPA is excluded by the present measurement at the 90% confidence level. Our analysis reveals that predicted ξ_{31}^{2ν} values are sensitive to the quenching of NMEs and the competing contributions from low- and high-energy states in the intermediate nucleus. Because these aspects are also at play in neutrinoless ßß decay, ξ_{31}^{2ν} provides new insights toward reliable neutrinoless ßß NMEs.

Leveraging a Landscape-Level Monitoring and Assessment Program for Developing Resilient Shorelines throughout the Laurentian Great Lakes.

Traditionally, ecosystem monitoring, conservation, and restoration have been conducted in a piecemeal manner at the local scale without regional landscape context. However, scientifically driven conservation and restoration decisions benefit greatly when they are based on regionally determined benchmarks and goals. Unfortunately, required data sets rarely exist for regionally important ecosystems. Because of early recognition of the extreme ecological importance of Laurentian Great Lakes coastal wetlands, and the extensive degradation that had already occurred, significant investments in coastal wetland research, protection, and restoration have been made in recent decades and continue today. Continued and refined assessment of wetland condition and trends, and the evaluation of restoration practices are all essential to ensuring the success of these investments. To provide wetland managers and decision makers throughout the Laurentian Great Lakes basin with the optimal tools and data needed to make scientifically-based decisions, our regional team of Great Lakes wetland scientists developed standardized methods and indicators used for assessing wetland condition. From a landscape perspective, at the Laurentian Great Lakes ecosystem scale, we established a stratified random-site-selection process to monitor birds, anurans, fish, macroinvertebrates, vegetation, and physicochemical conditions of coastal wetlands in the US and Canada. Monitoring of approximately 200 wetlands per year began in 2011 as the Great Lakes Coastal Wetland Monitoring Program. In this paper, we describe the development, delivery, and expected results of this ongoing international, multi-disciplinary, multi-stakeholder, landscape-scale monitoring program as a case example of successful application of landscape conservation design.

Publisher's Note: Search for Majorana Neutrinos Near the Inverted Mass Hierarchy Region with KamLAND-Zen [Phys. Rev. Lett. 117, 082503 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.117.082503.

Search for Majorana Neutrinos Near the Inverted Mass Hierarchy Region with KamLAND-Zen.

We present an improved search for neutrinoless double-beta (0νßß) decay of ^{136}Xe in the KamLAND-Zen experiment. Owing to purification of the xenon-loaded liquid scintillator, we achieved a significant reduction of the ^{110m}Ag contaminant identified in previous searches. Combining the results from the first and second phase, we obtain a lower limit for the 0νßß decay half-life of T_{1/2}^{0ν}>1.07×10^{26} yr at 90% C.L., an almost sixfold improvement over previous limits. Using commonly adopted nuclear matrix element calculations, the corresponding upper limits on the effective Majorana neutrino mass are in the range 61-165 meV. For the most optimistic nuclear matrix elements, this limit reaches the bottom of the quasidegenerate neutrino mass region.

Fragment-Based Analysis of Ligand Dockings Improves Classification of Actives.

We describe ADChemCast, a method for using results from virtual screening to create a richer representation of a target binding site, which may be used to improve ranking of compounds and characterize the determinants of ligand-receptor specificity. ADChemCast clusters docked conformations of ligands based on shared pairwise receptor-ligand interactions within chemically similar structural fragments, building a set of attributes characteristic of binders and nonbinders. Machine learning is then used to build rules from the most informational attributes for use in reranking of compounds. In this report, we use ADChemCast to improve the ranking of compounds in 11 diverse proteins from the Database of Useful Decoys-Enhanced (DUD-E) and demonstrate the utility of the method for characterizing relevant binding attributes in HIV reverse transcriptase.

Long-term monitoring of captive red drum Sciaenops ocellatus reveals that calling incidence and structure correlate with egg deposition.

In the present study, quantitative data were collected to clarify the relationship between calling, call structure and eggs produced in a captive population of red drum Sciaenops ocellatus. Sciaenops ocellatus were held in four tanks equipped with long-term acoustic loggers to record underwater sound throughout a simulated reproductive season. Maximal sound production of captive S. ocellatus occurred when the photoperiod shifted from 13·0 to 12·5 h of light, and the water temperature decreased to c. 25° C. These captive settings are similar to the amount of daylight and water temperatures observed during the autumn, which is the primary spawning period for S. ocellatus. Sciaenops ocellatus exhibited daily patterns of calling with peak sound production occurring in the evenings between 0·50 h before dark and 1·08 h after dark. Spawning occurred only on evenings in which S. ocellatus were calling, and spawning was more productive when S. ocellatus produced more calls with longer durations and more pulses. This study provides ample evidence that sound production equates to spawning in captive S. ocellatus when calls are longer than 0·8 s and contain more than seven pulses. The fact that more calling, longer calls and higher sound pressure levels are associated with spawns that are more productive indicates that acoustic metrics can provide quantitative information on spawning in the wild.

Altered gastric vagal mechanosensitivity in diet-induced obesity persists on return to normal chow and is accompanied by increased food intake.

BACKGROUND AND AIMS: Gastric vagal afferents convey satiety signals in response to mechanical stimuli. The sensitivity of these afferents is decreased in diet-induced obesity. Leptin, secreted from gastric epithelial cells, potentiates the response of vagal afferents to mechanical stimuli in lean mice, but has an inhibitory effect in high-fat diet (HFD)-induced obese mice. We sought to determine whether changes in vagal afferent function and response to leptin in obesity were reversible by returning obese mice consuming a HFD to standard laboratory chow diet (SLD). METHODS: Eight-week-old female C57BL/6 mice were either fed a SLD (N=20) or HFD (N=20) for 24 weeks. A third group was fed a HFD for 12 weeks and then a SLD for a further 12 weeks (RFD, N=18). An in vitro gastro-oesophageal vagal afferent preparation was used to determine the mechanosensitivity of gastric vagal afferents and the modulatory effect of leptin (0.1-10 nM) was examined. Retrograde tracing and quantitative RT-PCR were used to determine the expression of leptin receptor (LepR) messenger RNA (mRNA) in whole nodose and specific cell bodies traced from the stomach. RESULTS: After 24 weeks, both the HFD and RFD mice had increased body weight, gonadal fat mass, plasma leptin, plasma insulin and daily energy consumption compared with the SLD mice. The HFD and RFD mice had reduced tension receptor mechanosensitivity and leptin further inhibited responses to tension in HFD, RFD but not SLD mice. Mucosal receptors from both the SLD and RFD mice were potentiated by leptin, an effect not seen in HFD mice. LepR expression was unchanged in the whole nodose, but was reduced in the mucosal afferents of the HFD and RFD mice. CONCLUSION: Disruption of gastric vagal afferent function by HFD-induced obesity is only partially reversible by dietary change, which provides a potential mechanism preventing maintenance of weight loss.

Genetic population structure of spotted seatrout Cynoscion nebulosus along the south-eastern U.S.A.

Analyses of the genetic population structure of spotted seatrout Cynoscion nebulosus along the south-eastern U.S. coast using 13 microsatellites suggest significant population differentiation between fish in North Carolina (NC) compared with South Carolina (SC) and Georgia (GA), with New River, NC, serving as an area of integration between northern and southern C. nebulosus. Although there is a significant break in gene flow between these areas, the overall pattern throughout the sampling range represents a gradient in genetic diversification with the degree of geographic separation. Latitudinal distance and estuarine density appear to be main drivers in the genetic differentiation of C. nebulosus along the south-eastern U.S. coast. The isolation-by-distance gene-flow pattern creates fine-scale differences in the genetic composition of proximal estuaries and dictates that stocking must be confined to within 100 km of the location of broodstock collection in order to maintain the natural gradient of genetic variation along the south-eastern U.S. coast.

Limit on neutrinoless ßß decay of 136Xe from the first phase of KamLAND-Zen and comparison with the positive claim in 76Ge.

We present results from the first phase of the KamLAND-Zen double-beta decay experiment, corresponding to an exposure of 89.5 kg yr of (136)Xe. We obtain a lower limit for the neutrinoless double-beta decay half-life of T(1/2)(0ν)>1.9×10(25) yr at 90% C.L. The combined results from KamLAND-Zen and EXO-200 give T(1/2)(0ν)>3.4×10(25) yr at 90% C.L., which corresponds to a Majorana neutrino mass limit of <(120-250) meV based on a representative range of available matrix element calculations. Using those calculations, this result excludes the Majorana neutrino mass range expected from the neutrinoless double-beta decay detection claim in (76)Ge, reported by a part of the Heidelberg-Moscow Collaboration, at more than 97.5% C.L.

Assessing watershed transport of atrazine and nitrate to evaluate conservation practice effects and advise future monitoring strategies.

Continued public support for U.S. taxpayer funded programs aimed at reducing agricultural pollutants depends on clear demonstrations of water quality improvements. The objective of this research was to determine if implementation of agricultural best management practices (BMPs) in the Goodwater Creek Experimental Watershed (GCEW) resulted in changes to atrazine and nitrate (NO(3)-N) loads during storm events. An additional objective was to estimate future monitoring periods necessary to detect a 5, 10, 20, and 25% reduction in atrazine and NO(3)-N event load. The GCEW is a 73 km(2) watershed located in northcentral Missouri, USA. Linear regressions and Akaike Information Criteria were used to determine if reductions in atrazine and NO(3)-N event loads occurred as BMPs were implemented. No effects due to any BMP type were indicated for the period of record. Further investigation of event sampling from the long-term GCEW monitoring program indicated errors in atrazine load calculations may be possible due to pre-existing minimum threshold levels used to trigger autosampling and sample compositing. Variation of event loads was better explained by linear regressions for NO(3)-N than for atrazine. Decommissioning of upstream monitoring stations during the study period represented a missed opportunity to further explain variation of event loads at the watershed outlet. Atrazine requires approximately twice the monitoring period relative to NO(3)-N to detect future reductions in event load. Appropriate matching of pollutant transport mechanisms with autosampling protocols remains a critical information need when setting up or adapting watershed monitoring networks aimed at detecting watershed-scale BMP effects.

Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice.

The atheroprotective effects of estrogen in women are well recognized, but the underlying mechanisms responsible are not well understood. Blood vessel cells express the classic estrogen receptor, ER alpha (ref. 2-6), and are directly affected by estrogen, which inhibits the development of atherosclerotic and injury-induced vascular lesions. We have generated mice in which the ER alpha gene is disrupted and have used a mouse model of carotid arterial injury to compare the effects of estrogen on wild-type and estrogen receptor-deficient mice. Increases in vascular medial area and smooth muscle cell proliferation were quantified following vascular injury in ovariectomized mice treated with vehicle or with physiologic levels of 17 beta-estradiol. Surprisingly, in both wild-type and estrogen receptor-deficient mice, 17 beta-estradiol markedly inhibited to the same degree all measures of vascular injury. These data demonstrate that estrogen inhibits vascular by a novel mechanism that is independent of the classic estrogen receptor, ER alpha.

Experimental investigation of geologically produced antineutrinos with KamLAND.

The detection of electron antineutrinos produced by natural radioactivity in the Earth could yield important geophysical information. The Kamioka liquid scintillator antineutrino detector (KamLAND) has the sensitivity to detect electron antineutrinos produced by the decay of 238U and 232Th within the Earth. Earth composition models suggest that the radiogenic power from these isotope decays is 16 TW, approximately half of the total measured heat dissipation rate from the Earth. Here we present results from a search for geoneutrinos with KamLAND. Assuming a Th/U mass concentration ratio of 3.9, the 90 per cent confidence interval for the total number of geoneutrinos detected is 4.5 to 54.2. This result is consistent with the central value of 19 predicted by geophysical models. Although our present data have limited statistical power, they nevertheless provide by direct means an upper limit (60 TW) for the radiogenic power of U and Th in the Earth, a quantity that is currently poorly constrained.

Partial Articular Resurfacing Secondary to Pediatric Hip Chondroblastoma Curettage with a 5-YearFollow-Up: A Case Report.

CASE: This report describes a case of pediatric femoral head chondroblastoma, which was initially treated by minimally invasive curettage. At the 18-month follow-up, a subsequent osteochondral defect occurred, which was treated with a partial articular resurfacing system. At 5.5 years follow-up, he was symptom-free with minor degenerative x-ray changes. CONCLUSION: We describe a technique of focal anatomic hip resurfacing using the HemiCAP system in a pediatric chondroblastoma patient who presented with an osteochondral defect after primary curettage. This approach yielded good short-term to midterm results and is a potential alternative to total hip arthroplasty in young patients.

Impact on postoperative complications of changes in skeletal muscle mass during neoadjuvant chemotherapy for gastro-oesophageal cancer.

BACKGROUND: Risk assessment is relevant to predict postoperative outcomes in patients with gastro-oesophageal cancer. This cohort study aimed to assess body composition changes during neoadjuvant chemotherapy and investigate their association with postoperative complications. METHODS: Consecutive patients with gastro-oesophageal cancer undergoing neoadjuvant chemotherapy and surgery with curative intent between 2016 and 2019 were identified from a specific database and included in the study. CT images before and after neoadjuvant chemotherapy were used to assess the skeletal muscle index, sarcopenia, and subcutaneous and visceral fat index. RESULTS: In a cohort of 199 patients, the mean skeletal muscle index decreased during neoadjuvant therapy (from 51·187 to 49·19 cm2 /m2 ; P < 0·001) and the rate of sarcopenia increased (from 42·2 to 54·3 per cent; P < 0·001). A skeletal muscle index decrease greater than 5 per cent was not associated with an increased risk of total postoperative complications (odds ratio 0·91, 95 per cent c.i. 0·52 to 1·59; P = 0·736) or severe complications (odds ratio 0·66, 0·29 to 1·53; P = 0·329). CONCLUSION: Skeletal muscle index decreased during neoadjuvant therapy but was not associated with postoperative complications.

ANTECEDENTES: La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea. RESULTADOS: En una cohorte de 199 pacientes, el índice de masa muscular esquelética disminuyó durante el tratamiento neoadyuvante (de 51,87 cm2 /m2 a 49,19 cm2 /m2 , P < 0,001) y las tasas de sarcopenia aumentaron (de 42,2% a 54,2%, P < 0,001). Una disminución del índice de masa muscular esquelética > 5% no se asoció con un mayor riesgo de complicaciones postoperatorias globales (razón de oportunidades, odds ratio: 0,908; ic. del 95%: 0,520-1,587, P = 0,736) ni de complicaciones graves (odds ratio: 0,661; i.c. del 95%: 0,286-1,525, P = 0,329). CONCLUSIÓN: El índice de masa muscular esquelética disminuyó durante el tratamiento neoadyuvante, pero no se asoció con complicaciones postoperatorias.

Estrogen inhibits the response-to-injury in a mouse carotid artery model.

The atheroprotective effects of estrogen are well documented, but the mechanisms responsible for these effects are not well understood. To study the role of physiologic (nanomolar) estrogen levels on the arterial response-to-injury, we applied a mouse carotid artery injury model to ovariectomized C57BL/6J mice. Mice were treated with vehicle (-E2, n = 10) or 17 beta-estradiol (+E2, n = 10) for 7 d, subjected to unilateral carotid injury, and 14 d later contralateral (normal = NL) and injured carotids from -E2 and +E2 animals were pressure fixed, harvested, and analyzed by quantitative morphometry. E2 levels in +E2 mice were consistently in the nanomolar range (2.1-2.5 nM) at days 0, 7, and 14. At 14 d, measures of both intimal and medial area were markedly increased in the -E2 group: (-E2 vs NL, P < 0.05 for both), but were unchanged from normal levels in the +E2 group (+E2 vs NL, P = NS and +E2 vs -E2, P < 0.05 for both). Cellular proliferation, as assessed by bromodeoxyuridine (BrdU) labeling, was significantly increased over NL in the -E2 mice, but this increase was markedly attenuated in the estrogen replacement group (total BrdU positive cells/section: NL = 6.4 +/- 4.5; -E2 = 113 +/- 26, +E2 = 40 +/- 3.7; -E2 vs NL, P < 0.05; +E2 vs NL, P = NS; -E2 vs +E2, P < 0.05). These data (a) demonstrate significant suppression of the mouse carotid response-to-injury by physiologic levels of estrogen replacement; (b) support the utility of this model in the study of the biologic effects of estrogen on the vascular-injury response; and (c) suggest a direct effect of estrogen on vascular smooth muscle cell proliferation in injured vessels.

chemalot and chemalot_knime: Command line programs as workflow tools for drug discovery.

BACKGROUND: Analyzing files containing chemical information is at the core of cheminformatics. Each analysis may require a unique workflow. This paper describes the chemalot and chemalot_knime open source packages. Chemalot is a set of command line programs with a wide range of functionalities for cheminformatics. The chemalot_knime package allows command line programs that read and write SD files from stdin and to stdout to be wrapped into KNIME nodes. The combination of chemalot and chemalot_knime not only facilitates the compilation and maintenance of sequences of command line programs but also allows KNIME workflows to take advantage of the compute power of a LINUX cluster. RESULTS: Use of the command line programs is demonstrated in three different workflow examples: (1) A workflow to create a data file with project-relevant data for structure-activity or property analysis and other type of investigations, (2) The creation of a quantitative structure-property-relationship model using the command line programs via KNIME nodes, and (3) The analysis of strain energy in small molecule ligand conformations from the Protein Data Bank database. CONCLUSIONS: The chemalot and chemalot_knime packages provide lightweight and powerful tools for many tasks in cheminformatics. They are easily integrated with other open source and commercial command line tools and can be combined to build new and even more powerful tools. The chemalot_knime package facilitates the generation and maintenance of user-defined command line workflows, taking advantage of the graphical design capabilities in KNIME. Graphical abstract Example KNIME workflow with chemalot nodes and the corresponding command line pipe.

A randomized controlled trial to assess the central hemodynamic response to exercise in patients with transient ischaemic attack and minor stroke.

Early exercise engagement elicits meaningful changes in peripheral blood pressure in patients diagnosed with transient ischaemic attack (TIA) or minor stroke. However, central hemodynamic markers may provide clinicians with important diagnostic and prognostic information beyond that provided by peripheral blood pressure readings. The purpose of this single-centre, randomized, parallel-group clinical trial was to determine the effect of a 12-week aerobic exercise intervention on central and peripheral hemodynamic variables in patients with TIA or minor stroke. In this study, 47 participants (66±10 years) completed a baseline assessment, which involved the measurement of central and peripheral hemodynamic parameters, undertaken in the morning, in a fasted state. Participants were randomized to either a 12-week exercise or control group on completion of the baseline assessment. An identical follow-up assessment was completed post intervention. Central hemodynamic variables were assessed using an oscillometric device at both assessments. Analysis of covariance demonstrated a significant interaction for central and peripheral blood pressure and augmentation index (all P<0.05; ηp2.09-.11), with the exercise group presenting lower values than the control group post intervention (118±17 vs 132±28 mm Hg for central blood pressure; 125±19 vs 138±28 mm Hg for peripheral blood pressure; 104±49 vs 115±67% for augmentation index). The present study demonstrates that participation in an exercise program soon after stroke/TIA diagnosis may elicit significant beneficial changes to a patient's central systolic blood pressure and augmentation index. This may positively impact upon the treatment strategies implemented by clinicians in the care of patients with TIA and minor stroke.

Inhibition of mechanosensitivity in visceral primary afferents by GABAB receptors involves calcium and potassium channels.

GABA(B) receptors inhibit mechanosensitivity of visceral afferents. This is associated with reduced triggering of events that lead to gastro-esophageal reflux, with important therapeutic consequences. In other neuronal systems, GABA(B) receptor activation may be linked via G-proteins to reduced N-type Ca(2+) channel opening, increased inward rectifier K(+) channel opening, plus effects on a number of intracellular messengers. Here we aimed to determine the role of Ca(2+) and K(+) channels in the inhibition of vagal afferent mechanoreceptor function by the GABA(B) receptor agonist baclofen. The responses of three types of ferret gastro-esophageal vagal afferents (mucosal, tension and tension mucosal receptors) to graded mechanical stimuli were investigated in vitro. The effects of baclofen (200 microM) alone on these responses were quantified, and the effects of baclofen in the presence of the G-protein-coupled inward rectifier potassium channel blocker Rb(+) (4.7 mM) and/or the N-type calcium channel blocker omega-conotoxin GVIA (0.1 microM). Baclofen inhibition of mucosal receptor mechanosensitivity was abolished by both blockers. Its inhibitory effect on tension mucosal receptors was partly reduced by both. The inhibitory effect of baclofen on tension receptors was unaffected. The data indicate that the inhibitory action of GABA(B) receptors is mediated via different pathways in mucosal, tension and tension mucosal receptors via mechanisms involving both N-type Ca(2+) channels and inwardly rectifying K(+) channels and others.