Geertsenburks7222

High-performance numerical codes are an indispensable tool for hydrogeologists when modeling subsurface flow and transport systems. But as they are written in compiled languages, like C/C++ or Fortran, established software packages are rarely user-friendly, limiting a wider adoption of such tools. OpenGeoSys (OGS), an open-source, finite-element solver for thermo-hydro-mechanical-chemical processes in porous and fractured media, is no exception. Graphical user interfaces may increase usability, but do so at a dramatic reduction of flexibility and are difficult or impossible to integrate into a larger workflow. Python offers an optimal trade-off between these goals by providing a highly flexible, yet comparatively user-friendly environment for software applications. Hence, we introduce ogs5py, a Python-API for the OpenGeoSys 5 scientific modeling package. It provides a fully Python-based representation of an OGS project, a large array of convenience functions for users to interact with OGS and connects OGS to the scientific and computational environment of Python.Background and purpose NALCN is a Na+ leak, GPCR-activated channel that regulates the resting membrane potential and neuronal excitability. Despite numerous possible roles for NALCN in both normal physiology and disease processes, lack of specific blockers hampers further investigation. Experimental approach The effect of N-benzhydryl quinuclidine compounds on NALCN channels was demonstrated using whole-cell patch-clamp recordings in HEK293T cells overexpressing NALCN and acutely isolated nigral dopaminergic neurons that express NALCN endogenously. Src kinase activity was measured using a Src kinase assay kit, and voltage and current-clamp recordings from nigral dopaminergic neurons were used to measure NALCN currents and membrane potentials. Key results N-benzhydryl quinuclidine compounds inhibited NALCN channels without affecting TRPC channels, another important route for Na+ leak. In HEK293T cells overexpressing NALCN, N-benzhydryl quinuclidine compounds potently suppressed muscarinic M3 receptor-activated NALCN currents. Structure-function relationship studies suggest that the quinuclidine ring with a benzhydryl group imparts the ability to inhibit NALCN currents regardless of Src family kinases. Moreover, N-benzhydryl quinuclidine compounds inhibited not only GPCR-activated NALCN currents but also background Na+ leak currents and hyperpolarized the membrane potential in native midbrain dopaminergic neurons that express NALCN endogenously. Conclusion and implications These findings suggest that N-benzhydryl quinuclidine compounds have a pharmacological potential to directly inhibit NALCN channels and could be a useful tool to investigate functions of NALCN channels.Introduction Sleeve resection is an established oncological operative treatment for centrally located tumors with reduced complications compared to pneumonectomy. In cases of neoadjuvant chemoradiotherapy, the optimal timing of surgery for bronchial anastomotic healing has not been adequately explored. Materials and methods Between 2006 and 2017, 584 tracheobronchial sleeve resections were retrospectively analyzed. We selected all patients (n = 88) after sleeve lobectomy or sleeve bilobectomy for lung cancer with fully completed neoadjuvant chemoradiotherapy. Bronchial healing was assessed by bronchoscopy on the 7th postoperative day using our earlier published classification from grades 1 to 5. Results The median interval to surgery was 50 days (interquartile range 46-53, mean 50.03 ± 3.72). Mean anastomotic grade was 2.05 ± 1.03 and in 29.5% of the patients a critical anastomosis (grade ≥3) was documented. Anastomotic healing showed optimal results (bronchoscopic grade mean value 1.5 ± 0.70) between the 6th and 8th postchemoradiotherapy week (P = .001). All patients operated before (bronchoscopic grade mean value 2.3 ± 1.02) or after the above period (bronchoscopic grade mean value 2.5 ± 1.15) had an increased ratio of anastomotic healing complications. Conclusion It is safer to perform sleeve-resections for non-small cell lung cancer after neoadjuvant trimodal treatment between the 6th and 8th week of completion of chemoradiotherapy.Hereditary spherocytosis (HS) is a common inherited haemolytic anaemia attributed to disturbances in five different red cell membrane proteins. We performed a retrospective study of 166 children with HS and describe the clinical phenotype according to the genotype. In 160/166 (97%) children with HS a disease-causing mutation was identified. Pathogenic variants in ANK1, SPTB, SLC4A1 and SPTA1 were found in 49%, 33%, 13% and 5% of patients. Children with SLC4A1-HS had the mildest phenotype, showing the highest haemoglobin (P less then 0·001), lowest reticulocyte counts (P less then 0·001) and lowest unconjugated bilirubin levels (P = 0·006), and none required splenectomy in childhood (P less then 0·001). Conversely, children with autosomal recessive SPTA1-HS had the most severe clinical phenotype, with almost all patients undergoing splenectomy in early childhood. Patients with ANK1 and SPTB variants showed a similar clinical phenotype. Within each gene, variant type or location did not predict disease severity or likelihood of splenectomy. Among patients with a genetic diagnosis, 47 (29%) underwent splenectomy (23 partial; 24 total) while 57 (36%) underwent cholecystectomy. Total splenectomy led to greater improvements in haemoglobin (P = 0·02). Select use of genetic testing (especially in patients without a family history) may help predict clinical phenotype in childhood and guide family counselling.Background and purpose Despite a growing awareness, the annual losses of honeybee colonies worldwide continue to reach threatening levels for food safety and global biodiversity. Among the biotic and abiotic stresses that may be responsible for these losses, pesticides, including those targeting GABA receptors, are one of the major drivers. PIKfyve inhibitor Most insect genome include a GABA receptor subunit gene, Rdl, and two GABA-like receptor subunit genes, Lcch3 and Grd. Most studies have focused on Rdl which forms homomeric GABA-gated chloride channels, and a complete analysis of all the putative molecular combinations of GABA receptors is still lacking. Experimental approach In this study, we have cloned the Rdl, Grd and Lcch3 genes of Apis mellifera and undertaken a systematic characterization of the resulting GABA receptors in the Xenopus oocyte system. Key results We have shown that these subunits are able to interact with each other thus forming GABA-gated heteromeric channels with peculiar properties. Strikingly, these heteromers are always more sensitive than AmRDL homomer to all the pharmacological agents tested.