Search

Summary: Neurodegeneration in central nervous system disorders is linked to dysregulated neuronal calcium. Direct inhibition of glutamate-induced neuronal calcium influx, particularly via N-methyl-D-aspartate receptors (NMDAR), has led to adverse effects and clinical trial failures. A more feasible approach is to modulate NMDAR activity or calcium signaling indirectly. In this respect, the calcium-activated non-selective cation channel transient receptor potential melastatin 4 (TRPM4) has been identified as a promising target. However, high affinity and specific antagonists are lacking. Here, we conducted high-throughput screening of a compound library to identify high affinity TRPM4 antagonists. This yielded five lead compound series with nanomolar half-maximal inhibitory concentration values. Through medicinal chemistry optimization of two series, we established detailed structure-activity relationships and inhibition of excitotoxicity in neurons. Moreover, we identified their potential binding site supported by electrophysiological measurements. These potent TRPM4 antagonists are promising drugs for treating neurodegenerative disorders and TRPM4-related pathologies, potentially overcoming previous therapeutic challenges.

Freshwater salinization is a growing global concern impacting human and ecosystem needs with impacts to water availability for human and ecological uses. In the Upper Colorado River Basin (UCRB), dissolved solids in streams compound ongoing water supply challenges to further limit water availability and cause economic damages. Much effort has been dedicated to understanding dissolved solid sources, transport, and management in the region, yet temporal variability in loading from key sources such as irrigated lands and the influence of climate on dissolved solids loading remains unknown. Quantifying the contributions and temporal variability of dissolved solids loads from irrigated lands may benefit salinity management efforts. This study applies a time-varying (dynamic) modeling approach to predict annual dissolved solids loads across the UCRB from 1986 through 2017. Between 66% and 82% of the total accumulated dissolved solids load in the basin is from groundwater (storage and baseflow). Our findings link climate, irrigation, and groundwater, and confirm large storage contributions that have declined slightly with time. Dissolved solids loads increase during wet periods and decrease during dry periods, although the relative contributions of different sources vary little with time. Irrigation enhances loading efficiency relative to unirrigated areas through runoff and groundwater, and can locally be a major source of dissolved solids where irrigation occurs. Results indicate that loads from irrigated areas increase when irrigated area and/or water available for runoff increase. Increased regional aridification over the study period may have contributed to decreasing stream salinity through both quicker surface runoff and lagged groundwater storage processes. Study results may be relevant to salinity management in arid environments where water availability is limited and where irrigation influences salinity loading to streams.

Abstract ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

The severity of climatic effects of a regional nuclear conflict between India and Pakistan, involving the use of a hundred Hiroshima-scale nuclear weapons, is contested between two groups; Mills et al. from the National Center for Atmospheric Research (NCAR), University of Colorado, and Rutgers University conclude that a global Nuclear Winter would occur; Reisner et al. from Los Alamos National Laboratory (LANL) conclude that No Nuclear Winter would occur. This paper discusses the different assumptions that lead to the two different conclusions. Specifically, it highlights the use of different fuel loading and different input methods for the amount and initial location of black carbon (BC) into the climate models, and discusses some underlying reasons for these different choices, including the question of what kind of fire will occur in the aftermath of a nuclear weapon being dropped on a densely populated city. The paper also briefly discusses some physical phenomena that have not been considered by either group and lays out some questions for research before any definitive conclusion about the climatic effects of a limited nuclear war can be reached. However, until these problems are resolved, from a disarmament point of view, the precautionary principle is, in situations of such high stakes involving millions of deaths, there is an obligation to assume a worst-case scenario. Such a scenario would include the possibility that a limited nuclear conflict could cause a Nuclear Winter by leading to a broader nuclear conflict.

Abstract This study aimed to evaluate the effects of the dietary supplementation Curcuma longa hydrolate on Nile tilapia (Oreochromis niloticus) reared in a recirculation system. Hemato-immunological parameters, growth performance, nitrogen and phosphorus retention, as well as body composition and its interaction with the intestinal microbiota, were studied. Nile tilapia fingerlings (120) were distributed randomly in 8 polyethylene tanks (40 L). The experimental units were divided into two treatments, in quadruplicate: commercial diet supplemented with 2.5% of C. longa hydrolate and commercial diet without supplementation (control). After 45 days, the treatment supplemented hydrolate showed higher survival than the control group, 95.25% and 82.22%, receptively. In the blood profile, fish supplemented with hydrolate had a higher count of total leukocytes and neutrophils, as well as mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, than control group. The hydrolate group showed a substantial increase in the relative abundance of Cetobacterium and Romboutsia, as well as lower diversity in gut microbiota. The dietary addition of C. longa hydrolate for Nile tilapia seems to have a beneficial effect on gut microbiota, in addition to a likely positive effect on the physiological performance of Nile tilapia by maintaining intestinal homeostasis and promoting survival in reared conditions.

In recent years, the thienopyrazole moiety has emerged as a pharmacologically active scaffold with antitumoral and kinase inhibitory activity. In this study, high-throughput screening of 2000 small molecules obtained from the ChemBridge DIVERset library revealed a unique thieno[2,3-c]pyrazole derivative (Tpz-1) with potent and selective cytotoxic effects on cancer cells. Compound Tpz-1 consistently induced cell death at low micromolar concentrations (0.19 μM to 2.99 μM) against a panel of 17 human cancer cell lines after 24 h, 48 h, or 72 h of exposure. Furthermore, an in vitro investigation of Tpz-1’s mechanism of action revealed that Tpz-1 interfered with cell cycle progression, reduced phosphorylation of p38, CREB, Akt, and STAT3 kinases, induced hyperphosphorylation of Fgr, Hck, and ERK 1/2 kinases, and disrupted microtubules and mitotic spindle formation. These findings support the continued exploration of Tpz-1 and other thieno[2,3-c]pyrazole-based compounds as potential small-molecule anticancer agents.

In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC50) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability.

Background. Health professionals and new graduates alike are expected to be efficient in applying evidence-based practice. Research and evidencebasedpractice skills are taught in the research modules at university, but it is not clear whether students translate those skills into clinical practice.Objective. To determine the self-assessment literature-searching behaviour, self-perceived knowledge of critical appraisal skills and evidence-basedpractice beliefs of final-year undergraduate physiotherapy students at a university in South Africa.Methods. This study used a quantitative approach, with a small qualitative component. A convenience sample of the final-year undergraduate physiotherapy students (N=36) registered for the 2012 academic year was approached to participate in the study. Data were collected using an existing questionnaire.Results. The study yielded a 75% response rate. With regard to literature-searching skills, 30% searched for literature more than once a week, 52%searched only for specific information and most had access to literature. Students received their information from journal articles (85%), the internetand databases. They were slightly confident when it came to literature appraisal and believed that evidence-based practice was essential to their practice(96%), but expressed a need for more training (59%). Their understanding of the evidence-based practice concept was limited because they based theirtreatment choices on content and other role-models, and related their choices to their previous patient experiences.Conclusion. Students believed that evidence-based practice was vital, yet their understanding of the concept was restricted when compared with theliterature and they expressed a need for further training.

Non-profit organizations and leaders may benefit from the utilization of behaviors attributed to emotional intelligence. The consideration of emotional intelligence skills becomes a strategy for the development of the non-profit organizational leader’s ability to assess the impact and consequences of decisions, while simultaneously improving the quality and effectiveness of the decision-making process. The purpose of this paper is to identify how emotional intelligence skills can be applied to enhance the leadership decision-making processes within the non-profit organization. Goleman’s (2001) and Boyatzis’ et al. (2000) four essential elements of emotional intelligence and their associated 20 behavioral competencies are utilized to develop a methodology for the practical application of emotional intelligence skills to leadership decision-making within the non-profit organization. A checklist of questions and observations is provided to assist non-profit leaders in the improvement of emotional intelligence awareness, as well as the application of emotional intelligence skills to decisions and decision-making processes.

We report a case of long-term (9 years) response to 4th-line endocrine treatment with fulvestrant given for advanced breast cancer after no or poor response to prior endocrine therapies. Complete remission was achieved with full dose and maintained even after dose reduction due to unanticipated intensity of mucosal toxicity. Complete remission was temporarily lost after fulvestrant was tentatively withdrawn (63 months after treatment start), but was re-achieved after renewal of half-dose treatment and last reconfirmed 90 months after treatment start. The pharmacokinetic profile provides evidence to hypothesize a unique sensitivity to fulvestrant in this patient which might explain both: toxicity and extraordinary efficacy.

Los efectos de cinco suplementos con diferente relación proteína cruda:energía metabólica (PC:EM) sobre los niveles de nitrógeno amoniacal en rumen (AR) y nitrógeno ureico en sangre (NUS) y leche (NUL), fueron evaluados en vacas doble propósito en el trópico bajo del Piedemonte llanero colombiano, mediante un diseño cuadrado latino 5x5. En el tratamiento 1, los animales recibieron a voluntad forraje de pasto Brachiaria decumbens y 900 g de harina de arroz; en el tratamiento 2 recibieron adicionalmente 39 g de úrea; en el tratamiento 3 recibieron 84 g de úrea; el tratamiento 4 fue similar al tratamiento 2 más 1200 g de azúcar de caña; y el tratamiento 5 fue igual al tratamiento 3 más 950 g de azúcar. La relación PC:EM fue de 26, 66, 103, 27 y 50 g de PC por megacaloría de energía metabólica, respectivamente. Los niveles más altos de AR, NUS y NUL los presentaron el tratamiento 3 (pOs efeitos de cinco diferentes relações com suplementos de proteína bruta: energia metabólica (PC : MS) sobre os níveis de nitrogênio no rúmen (RA) e da BUN (NUS) e leite (NUL), foram avaliadas em vacas dupla finalidade nos trópicos sob o piedemonte llanero colombiano, através de um quadrado latino 5 x 5. No tratamento 1, os animais receberam em gramíneas forrageiras irá Brachiaria decumbens e 900 gramas de farinha de arroz; no tratamento 2, recebido mais 39 gramas de uréia; para o tratamento 3, recebido 84 gramas de uréia; no tratamento 4 foi semelhante ao tratamento 2 mais 1200 g de cana-de-açúcar; eo tratamento 5 era igual a 3 tratamento mais 950 g de açúcar. O PC : MS foi de 26, 66, 103, 27 e 50 g PC megacaloría energia metabólica, respectivamente. Os níveis mais elevados de AR, NUS e NUL apresentou o tratamento 3 (p The effects of five diets with different protein to energy ratios (CP:ME) on rumen ammonia (RA) and blood (BUN) and milk úrea nitrogen (MUN) in dual-purpose cows were evaluated in the piedemonte of Colombia. Five rumen fistulated cows were assigned to five treatments using a 5 x 5 Latin Square design. All animals received a basal diet consisting of Brachiaria decumbens forage ad libitum and 900 g of ground rice (treatment 1); treatment 2 was identical to treatment 1 plus 39 g of urea; treatment 3 was identical to treatment 1 plus 84 g urea; treatment 4 was identical to treatment 2 plus 1200 g of sugar; and treatment 5 was identical to treatment 3 plus 934 g of sugar. The ratio between crude protein and metabolizable energy (CP:ME) was 26, 66, 103, 27 and 50 g /Mcal for treatment 1 to treatment 5, respectively. The highest concentrations of RA, BUN and MUN were observed in treatment 3 (p

Profiling of putative lead compounds against a representative panel of relevant enzymes, receptors, ion channels and transporters is a pragmatic approach to establish a preliminary view of potential issues that might later hamper development. An early idea of which off-target activities must be minimized can save valuable time and money during the preclinical lead optimization phase if pivotal questions are asked beyond the usual profiling at hERG. The best data for critical evaluation of activity at ion channels is obtained using functional assays, since binding assays cannot detect all interactions and do not provide information on whether the interaction is that of an agonist, antagonist, or allosteric modulator. For ion channels present in human cardiac muscle, depending on the required throughput, manual- or automated- patch-clamp methodologies can be easily used to evaluate compounds individually to accurately reveal any potential liabilities. The issue of expanding screening capacity against a cardiac panel has recently been addressed by developing a series of robust, high-throughput, cell-based counter-screening assays employing fluorescence-based readouts. Similar assay development approaches can be used to configure panels of efficacy assays that can be used to assess selectivity within a family of related ion channels, such as Nav1.X channels. This overview discusses the benefits of in vitro assays, specific decision points where profiling can be of immediate benefit, and highlights the development and validation of patch-clamp and fluorescence-based profiling assays for ion channels.