Copper(II)- and gold(III)-mediated cyclization of a thiourea to a substituted 2-aminobenzothiazole

Benzothiazole derivatives are a class of privileged molecules due to their biological activity and pharmaceutical applications. One route to these molecules is via intramolecular cyclization of thioureas to form substituted 2-aminobenzothiazoles, but this often requires harsh conditions or employs expensive metal catalysts. Herein, the copper(II)- and gold(III)-mediated cyclizations of thioureas to substituted 2-aminobenzothiazoles are reported. The single-crystal X-ray structures of the thiourea N-(3-methoxyphenyl)-N\u27- (pyridin-2-yl)thiourea, C13H13N3OS, and the intermediate metal complexes aquabis[5-methoxy-N-(pyridin-2-yl-κN)-1,3-benzothiazol-2-amine-κN3]copper(II) dinitrate, [Cu(C13H11N3OS)2(H2O)](NO3)2, and bis{2-[(5-methoxy-1,3-benzothiazol- 2-yl)amino]pyridin-1-ium} dichloridogold(I) chloride monohydrate, (C13H12N3OS)2[AuCl2]Cl⋅H2O, are reported. The copper complex exhibits a distorted trigonal–bipyramidal geometry, with direct metal-to-benzothiazoleligand coordination, while the gold complex is a salt containing the protonated uncoordinated benzothiazole, and offers evidence that metal reduction (in this case, AuIII to AuI) is required for the cyclization to proceed. As such, this study provides further mechanistic insight into the role of the metal cations in these transformations

The association of maternal prenatal psychosocial stress with vascular function in the child at age 10-11 years: findings from the Avon longitudinal study of parents and children

Objective To investigate whether (1) maternal psychosocial stress (depression/anxiety) during pregnancy is associated with offspring vascular function and (2) whether any association differs depending on the gestational timing of exposure to stress. We also investigated whether any association is likely to be due to intrauterine mechanisms by (3) comparing with the association of paternal stress with offspring vascular function and (4) examining whether any prenatal association is explained by maternal postnatal stress. Methods and results Associations were examined in a UK birth cohort, with offspring outcomes (systolic and diastolic blood pressure, SBP and DBP, endothelial function assessed by brachial artery flow-mediated dilatation (FMD); arterial stiffness assessed by carotid to radial pulse wave velocity (PWV), brachial artery distensibility (DC), and brachial artery diameter (BD) assessed at age 10–11 years (n = 4318). Maternal depressive symptoms and anxiety were assessed at 18 and 32 weeks gestation and 8 months postnatally. Paternal symptoms were assessed at week 19. With the exception of DBP and BD, there were no associations of maternal depressive symptoms with any of the vascular outcomes. Maternal depressive and anxiety symptoms were associated with lower offspring DBP and wider BD, though the latter attenuated to the null with adjustment for confounding factors. Paternal symptoms were not associated with offspring outcomes. Maternal postnatal depressive symptoms were associated with lower offspring SBP. Conclusions We found no evidence to support the hypothesis that maternal stress during pregnancy adversely affects offspring vascular function at age 10–12 years via intrauterine mechanisms

"Twiddler" In A Canine Model And A Modified Implant Technique To Prevent It

This report explains the Twiddler's syndrome, a well known human entity, in a canine model. We also describe a modified technique to implant internal cardioverter defibrillators (ICD) in dogs to prevent Twiddler's syndrome. Our original study was to identify the factors influencing the DFT measurement and a canine model was selected as it is the best proven electrophysiological model. During the course of the study, one of the dogs was evaluated for device failure at three weeks following implantation. While under general anesthesia, interrogation of the dog's ICD showed that the right ventricular (RV) pacing threshold was high and ventricular capture was intermittent. When examined under fluoroscopy, it was noted that the defibrillator lead was dislodged from the right ventricular apex. A surgical revision of the device pocket showed that the leads were twisted in an almost braided fashion - as if "twiddled" into position around the device [Figure1 (arrow)]. We suspect that this "twiddling" resulted in shortening and pulling of the lead from the ventricular myocardium causing intermittent capture and device failure

Bioinformatic analysis of ciliary transition zone proteins reveals insights into the evolution of ciliopathy networks

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Cilia are critical for diverse functions, from motility to signal transduction, and ciliary dysfunction causes inherited diseases termed ciliopathies. Several ciliopathy proteins influence developmental signalling and aberrant signalling explains many ciliopathy phenotypes. Ciliary compartmentalisation is essential for function, and the transition zone (TZ), found at the proximal end of the cilium, has recently emerged as a key player in regulating this process. Ciliary compartmentalisation is linked to two protein complexes, the MKS and NPHP complexes, at the TZ that consist largely of ciliopathy proteins, leading to the hypothesis that ciliopathy proteins affect signalling by regulating ciliary content. However, there is no consensus on complex composition, formation, or the contribution of each component. RESULTS: Using bioinformatics, we examined the evolutionary patterns of TZ complex proteins across the extant eukaryotic supergroups, in both ciliated and non-ciliated organisms. We show that TZ complex proteins are restricted to the proteomes of ciliated organisms and identify a core conserved group (TMEM67, CC2D2A, B9D1, B9D2, AHI1 and a single TCTN, plus perhaps MKS1) which are present in >50% of all ciliate/flagellate organisms analysed in each supergroup. The smaller NPHP complex apparently evolved later than the larger MKS complex; this result may explain why RPGRIP1L, which forms the linker between the two complexes, is not one of the core conserved proteins. We also uncovered a striking correlation between lack of TZ proteins in non-seed land plants and loss of TZ-specific ciliary Y-links that link microtubule doublets to the membrane, consistent with the interpretation that these proteins are structural components of Y-links, or regulators of their formation. CONCLUSIONS: This bioinformatic analysis represents the first systematic analysis of the cohort of TZ complex proteins across eukaryotic evolution. Given the near-ubiquity of only 6 proteins across ciliated eukaryotes, we propose that the MKS complex represents a dynamic complex built around these 6 proteins and implicated in Y-link formation and ciliary permeability.We would like to thank Jordan Raff and Teunis J.P. van Dam for helpful discussions. This work was supported by the Medical Research Council (grant number #G1001644 to HRD, support for AB)

Evolutionary and Structural Perspectives of Plant Cyclic Nucleotide-Gated Cation Channels

Ligand-gated cation channels are a frequent component of signaling cascades in eukaryotes. Eukaryotes contain numerous diverse gene families encoding ion channels, some of which are shared and some of which are unique to particular kingdoms. Among the many different types are cyclic nucleotide-gated channels (CNGCs). CNGCs are cation channels with varying degrees of ion conduction selectivity. They are implicated in numerous signaling pathways and permit diffusion of divalent and monovalent cations, including Ca2+ and K+. CNGCs are present in both plant and animal cells, typically in the plasma membrane; recent studies have also documented their presence in prokaryotes. All eukaryote CNGC polypeptides have a cyclic nucleotide-binding domain and a calmodulin binding domain as well as a six transmembrane/one pore tertiary structure. This review summarizes existing knowledge about the functional domains present in these cation-conducting channels, and considers the evidence indicating that plant and animal CNGCs evolved separately. Additionally, an amino acid motif that is only found in the phosphate binding cassette and hinge regions of plant CNGCs, and is present in all experimentally confirmed CNGCs but no other channels was identified. This CNGC-specific amino acid motif provides an additional diagnostic tool to identify plant CNGCs, and can increase confidence in the annotation of open reading frames in newly sequenced genomes as putative CNGCs. Conversely, the absence of the motif in some plant sequences currently identified as probable CNGCs may suggest that they are misannotated or protein fragments

Narrowband ultraviolet B treatment for psoriasis is highly economical and causes significant savings in cost for topical treatments

Background: Narrowband ultraviolet B (NB-UVB) treatment for psoriasis is considered expensive. However, existing data are based on estimates and do not consider indirect cost savings. Objectives: To define the actual costs of NB-UVB incurred by the service provider, as well as treatment-associated cost savings. Methods: We performed data linkage of (i) comprehensive treatment records and (ii) prescribing data for all NB-UVB treatment episodes spanning 6 years in a population of 420 000. We minimized data fluctuation by compiling data from four independent treatment sites, and using drug prescriptions unrelated to psoriasis as a negative control. Results: National Health Service Tayside spent an average of £257 per NB-UVB treatment course (mean 257 ± 63, range 150–286, across four independent treatment sites), contrasting sharply with the estimate of £1882 used by the U.K. National Institute for Health and Care Excellence. The cost of topical treatments averaged £128 per patient in the 12 months prior to NB-UVB, accounting for 42% of the overall drug costs incurred by these patients. This was reduced by 40% to £53 per patient over the 12-month period following NB-UVB treatment, while psoriasis-unrelated drug prescription remained unchanged, suggesting disease-specific effects of NB-UVB. The data were not due to site-specific factors, as confirmed by highly similar results observed between treatment sites operated by distinct staff. Finally, we detail all staff hours directly and indirectly involved in treatment, allowing direct translation of cost into other healthcare systems. Conclusions: NB-UVB is a low-cost treatment; cost figures currently used in health technology appraisals are an overestimate based on the data presented here. Creating or extending access to NB-UVB is likely to offer additional savings by delaying or avoiding costly third-line treatments for many patients.PostprintPeer reviewe

Predicting posttraumatic stress disorder after childbirth

Objective: around 50% of women report symptoms that indicate some aspect of their childbirth experience was 'traumatic', and at least 3.1% meet diagnosis for PTSD six months post partum. Here we aimed to conduct a prospective longitudinal study and examine predictors of birth-related trauma - predictors that included a range of pre-event factors - as a first step in the creation of a screening questionnaire. Method: of the 933 women who completed an assessment in their third trimester, 866 were followed-up at four to six week post partum. Two canonical discriminant function analyses were conducted to ascertain factors associated with experiencing birth as traumatic and, of the women who found the birth traumatic, which factors were associated with those who developed PTSD. Findings: a mix of 16 pre-birth predictor variables and event-specific predictor variables distinguished women who reported symptoms consistent with trauma from those who did not. Fourteen predictor variables distinguished women who went on to develop PTSD from those who did not. Conclusions: anxiety sensitivity to possible birthing problems, breached birthing expectations, and severity of any actual birth problem, predicted those who found the birth traumatic. Prior trauma was the single most important predictive factor of PTSD. Evaluating the utility of brief, cost-effective, and accurate screening for women at risk of developing birth-related PTSD is suggested

Could psoralen plus ultraviolet A1 (“PUVA1”) work? Depth penetration achieved by phototherapy lamps

Funding: PhD Studentship UK EPRSC EP/N509759/1.Psoralen and ultraviolet A (PUVA) is useful in treating various hand and foot skin diseases.1 Most cases of psoriasis respond well to phototherapy or PUVA. However, for some diseases, such as palmoplantar pustular psoriasis, PUVA is not always sufficient to produce therapeutic effect. If PUVA fails, it is sometimes necessary to progress to other treatments such as Grenz ray therapy (where available),2 systemic retinoid or systemic immunosuppression. Could “PUVA1” (psoralen combined with ultraviolet A1 long wavelength ultraviolet A [UVA]) work in cases where conventional PUVA (psoralen plus broadband UVA) has been inadequate?PostprintPeer reviewe