Functional identification and characterizationof the diuretic hormone 31 (DH31) signaling system in the Green shore crab, Carcinus maenas

<p>The functional characterization of crustacean neuropeptides and their cognate receptors has not kept pace with the recent advances in sequence determination and, therefore, our understanding of the physiological roles of neuropeptides in this important arthropod sub-phylum is rather limited. We identified a candidate receptor-ligand pairing for diuretic hormone 31 (DH31) in a neural transcriptome of the crab, Carcinus maenas. In insects, DH31 plays species -specific but central roles in many facets of physiology, including fluid secretion, myoactivity, and gut peristalsis but little is known concerning its functions in crustaceans. The C. maenas DH31 transcript codes for a 147 amino acid prepropeptide, and a single receptor transcript translates to a secretin-like (Class B1) G protein-coupled receptor (GPCR). We used an in vitro aequorin luminescence Ca²⁺ mobilization assay to demonstrate that this candidate DH31R is activated byCarcinus and insect DH31s in a dose-dependent manner (EC₅₀ 15–30 nM). Whole mount immunohistochemical and in situ hybridization localization revealed extensive DH31 expressing neurons throughout the central nervous system, most notably in the abdominal ganglion where large, unpaired cells give rise to medial nerves, which terminate in extensive DH31 immunopositive dendritic fields intimately associated with oesophageal musculature. This system constitutes a large and hitherto undescribed neurohemal area adjacent to key muscle groups associated with the gastric system. DH31 expressing neurons were also seen in the cardiac, commissural, oesophageal, and stomatogastric ganglia and intense labeling was seen in dendrites innervating fore- and hindgut musculature but not with limb muscles. These labeling patterns, together with measurement of DH31R mRNA in the heart and hindgut, prompted us test the effects of DH31 on semi-isolated heart preparations. Cardiac superfusion with peptide evoked increased heart rates (10–100 nM). The neuroanatomical distribution of DH31 and its receptor transcripts, particularly that associated with gastric and cardiac musculature, coupled with the cardio- acceleratory effects of the peptide implicate this peptide in key myoactive roles, likely related to rhythmic coordination.</p

Road Development in Asia: Assessing the Range-Wide Risks to Tigers

Roads are proliferating worldwide at an unprecedented rate, with potentially severe impacts on wildlife. We calculated the extent and potential impacts of road networks across the 1,160,000-km2, 13-country range of the globally endangered tiger (Panthera tigris)—a conservation umbrella species. We found that roads were pervasive, totaling 134,000 km across tiger conservation landscapes (TCLs), even in tiger priority sites and protected areas. Approximately 43% of the area where tiger breeding occurs and 57% of the area in TCLs fell within the road-effect zone. Consequently, current road networks may be decreasing tiger and prey abundances by more than 20%. Nearly 24,000 km of new roads will be built in TCLs by 2050, stimulated through major investment projects such as China’s Belt and Road Initiative. Given that roads will be a pervasive challenge to tiger recovery in the future, we urge decision-makers to make sustainable road development a top priority

Dye Tracing Studies of the Fountain, Minnesota Sewage System

Posted with permission of the National Ground Water Association. Copyright 1986.Fountain, a small community in southeastern Minnesota, is located on a sinkhole plain developed in the Ordovician Galena Formation. Many of the approximately 100 houses in the town have sewer systems that empty directly into sinkholes. Qualitative dye traces using Fluorescein and a quantitative dye trace using Rhodamine WT indicate that effluent from the community's individual disposal systems resurges at a group of springs about a mile northwest of the community. These springs are located in the Galena aquifer which comprises the upper karst above the Decorah Shale aquitard. The travel time of the underground flow here is about one day. The citizens of Fountain are considering the construction of a community drainfield to alleviate the sewage disposal problem. The effluent from individual septic tanks would be collected and piped to a drainfield about two miles south of town. The proposed drainfield site is stratigraphically below the Decorah Shale in a valley underlain by limestones and dolomites of the Praire du Chien Group. Watson Creek, which flows through the valley, is a karst stream which loses water into the ground in the vicinity of the proposed site. The quantitative dye trace from the proposed site indicates that the water beneath it is moving southeast at a velocity of about 1.3 miles/year. Water in the lower karst aquifer (in the Prairie du Chien) is moving two to three orders of magnitude more slowly than in the upper karst aquifer (in the Galena). [Carbon-14] analyses of the water in the Prairie du Chien aquifer are consistent with the dye trace results and indicate residence times of less than 25 years. Flow in the upper karst aquifer is about 300 times faster than in the lower aquifer, and in the opposite direction.This work was supported in part under grant C271047-02 to Fountain from the U.S. EPA via McGhie and Betts, Inc., Rochester, Minn. and in part under a grant from the Legislative Commission on Minnesota Resources (LCMR)

Pigment Dispersing Factors and Their Cognate Receptors in a Crustacean Model, With New Insights Into Distinct Neurons and Their Functions

Pigment dispersing factors (PDFs, or PDHs in crustaceans) form a structurally related group of neuropeptides found throughout the Ecdysozoa and were first discovered as pigmentary effector hormones in crustaceans. In insects PDFs fulfill crucial neuromodulatory roles, most notably as output regulators of the circadian system, underscoring their central position in physiological and behavioral organization of arthropods. Intriguingly, decapod crustaceans express multiple isoforms of PDH originating from separate genes, yet their differential functions are still to be determined. Here, we functionally define two PDH receptors in the crab Carcinus maenas and show them to be selectively activated by four PDH isoforms: PDHR 43673 was activated by PDH-1 and PDH-2 at low nanomolar doses whilst PDHR 41189 was activated by PDH-3 and an extended 20 residue e-PDH. Detailed examination of the anatomical distribution of all four peptides and their cognate receptors indicate that they likely perform different functions as secreted hormones and/or neuromodulators, with PDH-1 and its receptor 43,673 implicated in an authentic hormonal axis. PDH-2, PDH-3, and e-PDH were limited to non-neurohemal interneuronal sites in the CNS; PDHR 41189 was largely restricted to the nervous system suggesting a neuromodulatory function. Notably PDH-3 and e-PDH were without chromatophore dispersing activity. This is the first report which functionally defines a PDHR in an endocrine system in a crustacean and to indicate this and other putative roles of this physiologically pivotal peptide group in these organisms. Thus, our findings present opportunities to further examine the endocrine and circadian machinery in this important arthropod phylum

Predicting Individual Treatment Response to rTMS for Motor Recovery After Stroke: A Review and the CanStim Perspective

BackgroundRehabilitation is critical for reducing stroke-related disability and improving quality-of-life post-stroke. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique used as stand-alone or adjunct treatment to physiotherapy, may be of benefit for motor recovery in subgroups of stroke patients. The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) seeks to advance the use of these techniques to improve post-stroke recovery through clinical trials and pre-clinical studies using standardized research protocols. Here, we review existing clinical trials for demographic, clinical, and neurobiological factors which may predict treatment response to identify knowledge gaps which need to be addressed before implementing these parameters for patient stratification in clinical trial protocols.ObjectiveTo provide a review of clinical rTMS trials of stroke recovery identifying factors associated with rTMS response in stroke patients with motor deficits and develop research perspectives for pre-clinical and clinical studies.MethodsA literature search was performed in PubMed, using the Boolean search terms stroke AND repetitive transcranial magnetic stimulation OR rTMS AND motor for studies investigating the use of rTMS for motor recovery in stroke patients at any recovery phase. A total of 1,676 articles were screened by two blinded raters, with 26 papers identified for inclusion in this review.ResultsMultiple possible factors associated with rTMS response were identified, including stroke location, cortical thickness, brain-derived neurotrophic factor (BDNF) genotype, initial stroke severity, and several imaging and clinical factors associated with a relatively preserved functional motor network of the ipsilesional hemisphere. Age, sex, and time post-stroke were generally not related to rTMS response. Factors associated with greater response were identified in studies of both excitatory ipsilesional and inhibitory contralesional rTMS. Heterogeneous study designs and contradictory data exemplify the need for greater protocol standardization and high-quality controlled trials.ConclusionClinical, brain structural and neurobiological factors have been identified as potential predictors for rTMS response in stroke patients with motor impairment. These factors can inform the design of future clinical trials, before being considered for optimization of individual rehabilitation therapy for stroke patients. Pre-clinical models for stroke recovery, specifically developed in a clinical context, may accelerate this process

Therapeutic utilization of meditation resources by people with multiple sclerosis : Insights from an online patient discussion forum

We aimed to describe website traffic and qualitatively analyze an e-health community discussion forum. Participants in this study were people affected by multiple sclerosis visiting the Overcoming Multiple Sclerosis (OMS) website. This mixed methods study combined descriptive analysis of website traffic over 7 years and 1 month, and qualitative analysis of 1 week of posts in the meditation topic, coded into theme groups using qualitative thematic analysis. There were 166 meditation topics posted with 21,530 initial views of primary post and 785 sub-post responses. Meditation posts and sub-posts received 368,713 replies. Number of views increased from 4,684 in 2011 to over 80,000 in 2017, a considerably greater rate of increase than overall traffic. Qualitative analysis of posts on the meditation forum identified themes of barriers and enablers to utilization of meditation resources. Enablement themes dominated, observed across six of the seven theme groups with various forms of positive social and emotional support to learn and practice meditation. One theme, negative emotion, was identified as a barrier. The OMS peer-to-peer patient online discussion forum serves important functions in encouraging, educating and enabling its growing online community. Our analysis may help improve and innovate online support for lifestyle management in many chronic diseases

Cancer Stem Cell Chemotherapeutics Assay for Prospective Treatment of Recurrent Glioblastoma and Progressive Anaplastic Glioma: A Single-Institution Case Series

© 2020 BACKGROUND: Chemotherapy-resistant cancer stem cells (CSC) may lead to tumor recurrence in glioblastoma (GBM). The poor prognosis of this disease emphasizes the critical need for developing a treatment stratification system to improve outcomes through personalized medicine. METHODS: We present a case series of 12 GBM and 2 progressive anaplastic glioma cases from a single Institution prospectively treated utilizing a CSC chemotherapeutics assay (ChemoID) guided report. All patients were eligible to receive a stereotactic biopsy and thus undergo ChemoID testing. We selected one of the most effective treatments based on the ChemoID assay report from a panel of FDA approved chemotherapy as monotherapy or their combinations for our patients. Patients were evaluated by MRI scans and response was assessed according to RANO 1.1 criteria. RESULTS: Of the 14 cases reviewed, the median age of our patient cohort was 49 years (21–63). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Patients treated with ChemoID assay-directed therapy, in combination with other modality of treatment (RT, LITT), had a longer median overall survival (OS) of 13.3 months (5.4-NA), compared to the historical median OS of 9.0 months (8.0–10.8 months) previously reported. Notably, patients with recurrent GBM or progressive high-grade glioma treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival observed in previous studies. CONCLUSIONS: The results presented here suggest that the ChemoID Assay has the potential to stratify individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient survival. Importance of the Study: Glioblastoma (GBM) and progressive anaplastic glioma are the most aggressive brain tumor in adults and their prognosis is very poor even if treated with the standard of care chemoradiation Stupp\u27s protocol. Recent knowledge pointed out that current treatments often fail to successfully target cancer stem cells (CSCs) that are responsible for therapy resistance and recurrence of these malignant tumors. ChemoID is the first and only CLIA (clinical laboratory improvements amendment) -certified and CAP (College of American Pathologists) -accredited chemotherapeutic assay currently available in oncology clinics that examines patient\u27s derived CSCs susceptibility to conventional FDA (Food and Drugs Administration) -approved drugs. In this study we observed that although the majority of our patients (71.5%) presented with unfavorable prognostic predictors (wild type IDH-1/2 and unmethylated MGMT promoter), patients treated with ChemoID assay-directed therapy had an overall response rate of 86% and increased median OS of 13.3 months compared to the historical median OS of 9.1 months (8.1–10.1 months) previously reported [1] suggesting that the ChemoID assay may be beneficial in personalizing treatment strategies

Validation of the brain health index in the European Prevention of Alzheimer's Dementia cohort

Background Brain Health Index (BHI) assimilates various MRI sequences, giving a quantitative measure of brain health. To date, BHI validation has been cross-sectional and limited to selected populations. Further large-scale validation and assessment of temporal change is required to understand its clinical utility. Aim Assess 1) relationships between variables associated with cognitive decline and BHI 2) associations between BHI and measures of cognition and 3) longitudinal changes in BHI and relationship with cognitive function. Methods BHI computation involved Gaussian mixture-model cluster analysis of T1, T2, T2*, and T2 FLAIR MRI data from participants within the European Prevention of Alzheimer's Dementia (EPAD) cohort. Group differences (gender- and health-based) were evaluated using independent samples Welch's t-tests. Relationships between BHI, age and cognitive tests used linear regression. Longitudinal analysis (12/24 months) utilised mixed linear regression models to examine BHI changes, and paired BHI/cognition associations. Results Data from N = 1496 predominantly Caucasian participants (50–88 years old, 43.32% male) were used. BHI scores were lower in those with diabetes (p &lt; 0.001, d = 0.419), hypertension (p &lt; 0.001, d = 0.375), hypercholesterolemia (p &lt; 0.001, d = 0.193) and stroke (p &lt; 0.05, d = 0.512). APOE was not significantly related to BHI scores. After correction for age, cross-sectional BHI scores were significantly associated with all measures of cognitive function in males, but only the Four Mountains Test (4MT) in females. Longitudinal change in BHI and cognition were not consistently related. Conclusions BHI is a valid marker of cognitive decline and relatively stable over 1-2 year follow-up periods. Further work should assess temporal changes over a longer duration and determine relationships between BHI and cognition in more diverse populations

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years