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Purpose: Physical activity can improve health outcomes for cancer patients; however, only 30% of patients are physically active. This review explored barriers to and facilitators of physical activity promotion and participation in patients living with and beyond cancer. Secondary aims were to (1) explore similarities and differences in barriers and facilitators experienced in head and neck cancer versus other cancers, and (2) identify how many studies considered the influence of socioeconomic characteristics on physical activity behaviour. Methods: CINAHL Plus, MEDLINE, PsycINFO, Scopus and Cochrane (CDSR) were searched for qualitative and mixed methods evidence. Quality assessment was conducted using the Mixed Methods Appraisal Tool and a Critical Appraisal Skills Programme Tool. Thematic synthesis and frequency of reporting were conducted, and results were structured using the Capability-Opportunity-Motivation-Behaviour model and Theoretical Domains Framework. Results: Thirty qualitative and six mixed methods studies were included. Socioeconomic characteristics were not frequently assessed across the included studies. Barriers included side effects and comorbidities (physical capability; skills) and lack of knowledge (psychological capability; knowledge). Having a dry mouth or throat and choking concerns were reported in head and neck cancer, but not across other cancers. Facilitators included improving education (psychological capability; knowledge) on the benefits and safety of physical activity. Conclusion: Educating patients and healthcare professionals on the benefits and safety of physical activity may facilitate promotion, uptakeand adherence. Head and neck cancer patients experienced barriers not cited across other cancers, and research exploring physical activity promotion in this patient group is required to improve physical activity engagement. [ABSTRACT FROM AUTHOR]

Theneoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptoragonist, making it an attractive scaffold for development into a treatmentfor substance abuse. Although several successful semisynthetic studieshave been performed to elucidate structure–activity relationships,the lack of analogues with substitutions to the furan ring of salvinorinA has prevented a thorough understanding of its role in binding tothe κ-opioid receptor. Herein we report the synthesis of severalsalvinorin A derivatives with modified furan rings. Evaluation ofthese compounds in a functional assay indicated that sterically lessdemanding substitutions are preferred, suggesting the furan ring isbound in a congested portion of the binding pocket. The most potentof the analogues successfully reduced drug-seeking behavior in ananimal model of drug-relapse without producing the sedation observedwith other κ-opioid agonists. [ABSTRACT FROM AUTHOR]

Background Multiple treatments exist for fecal incontinence. However, the relative and additive influence of commonly used behavioral approaches remains unclear. Objective We conducted a systematic review of randomized controlled trials to synthesize the effects of behavioral treatment of fecal incontinence with constipation in children aged 4–18 years. Mixed treatment comparisons (MTCs) and random effects models were used to analyze outcomes. Risk of bias and quality of evidence were rated. Results Although 10 studies were identified for MTCs, results did not yield reliable or valid estimates. Four studies were retained for random effects pooled outcome analysis. Results indicated that behavioral intervention was more effective than control conditions for author-defined success and soiling frequency. Conclusion Although evidence supports behavioral treatments for fecal incontinence with constipation in children, available evidence is limited. More and higher-quality trials are needed to better understand the relative effects of different treatments, including behavioral strategies. [ABSTRACT FROM AUTHOR]

IP3R (IP3 [inositol 1,4,5-trisphosphate] receptors) and ryanodine receptors are the most widely expressed intracellular Ca2+ channels and both are regulated by thiol reagents. In DT40 cells stably expressing single subtypes of mammalian IP3R, low concentrations of thimerosal (also known as thiomersal), which oxidizes thiols to form a thiomercurylethyl complex, increased the sensitivity of IP3-evoked Ca2+ release via IP3R1 and IP3R2, but inhibited IP3R3. Activation of IP3R is initiated by IP3 binding to the IBC (IP3-binding core; residues 224-604) and proceeds via re-arrangement of an interface between the IBC and SD (suppressor domain; residues 1-223). Thimerosal (100 μM) stimulated IP3 binding to the isolated NT (N-terminal; residues 1-604) of IP3R1 and IP3R2, but not to that of IP3R3. Binding of a competitive antagonist (heparin) or partial agonist (dimeric-IP3) to NT1 was unaffected by thiomersal, suggesting that the effect of thimerosal is specifically related to IP3R activation. IP3 binding to NT1 in which all cysteine residues were replaced by alanine was insensitive to thimerosal, so too were NT1 in which cysteine residues were replaced in either the SD or IBC. This demonstrates that thimerosal interacts directly with cysteine in both the SD and IBC. Chimaeric proteins in which the SD of the IP3R was replaced by the structurally related A domain of a ryanodine receptor were functional, but thimerosal inhibited both IP3 binding to the chimaeric NT and IP3-evoked Ca2+ release from the chimaeric IP3R. This is the first systematic analysis of the effects of a thiol reagent on each IP3R subtype. We conclude that thimerosal selectively sensitizes IP3R1 and IP3R2 to IP3 by modifying cysteine residues within both the SD and IBC and thereby stabilizing an active conformation of the receptor. [ABSTRACT FROM AUTHOR]

Inositol 1,4,5-trisphosphate receptors (IP3R) are intracellular Ca2+ channels. Most animal cells express mixtures of the three IP3R subtypes encoded by vertebrate genomes. Adenophostin A (AdA) is the most potent naturally occurring agonist of IP3R and it shares with IP3 the essential features of all IP3R agonists, namely structures equivalent to the 4,5-bisphosphate and 6-hydroxyl of IP3. The two essential phosphate groups contribute to closure of the clam-like IP3-binding core (IBC), and thereby IP3R activation, by binding to each of its sides (the α- and β-domains). Regulation of the three subtypes of IP3R by AdA and its analogues has not been examined in cells expressing defined homogenous populations of IP3R. We measured Ca2+ release evoked by synthetic adenophostin A (AdA) and its analogues in permeabilized DT40 cells devoid of native IP3R and stably expressing single subtypes of mammalian IP3R. The determinants of high-affinity binding of AdA and its analogues were indistinguishable for each IP3R subtype. The results are consistent with a cation-π interaction between the adenine of AdA and a conserved arginine within the IBC α-domain contributing to closure of the IBC. The two complementary contacts between AdA and the α-domain (cation-π interaction and 3″-phosphate) allow activation of IP3R by an analogue of AdA (3″-dephospho-AdA) that lacks a phosphate group equivalent to the essential 5-phosphate of IP3. These data provide the first structure-activity analyses of key AdA analogues using homogenous populations of all mammalian IP3R subtypes. They demonstrate that differences in the Ca2+ signals evoked by AdA analogues are unlikely to be due to selective regulation of IP3R subtypes. [ABSTRACT FROM AUTHOR]

Most animal cells express mixtures of the three subtypes of inositol 1,4,5-trisphosphate receptor (IP3R) encoded by vertebrate genomes. Activation of each subtype by different agonists has not hitherto been examined in cells expressing defined homogenous populations of IP3R. Here we measure Ca2+ release evoked by synthetic analogues of IP3 using a Ca2+ indicator within the lumen of the endoplasmic reticulum of permeabilized DT40 cells stably expressing single subtypes of mammalian IP3R. Phosphorylation of (1,4,5)IP3 to (1,3,4,5)IP4 reduced potency by ~100-fold. Relative to (1,4,5)IP3, the potencies of IP3 analogues modified at the 1-position (malachite green (1,4,5)IP3), 2-position (2-deoxy(1,4,5)IP3) or 3-position (3-deoxy(1,4,5)IP3, (1,3,4,5)IP4) were similar for each IP3R subtype. The potency of an analogue, (1,4,6)IP3, in which the orientations of the 2- and 3-hydroxyl groups were inverted, was also reduced similarly for all three IP3R subtypes. Most analogues of IP3 interact similarly with the three IP3R subtypes, but the decrease in potency accompanying removal of the 1-phosphate from (1,4,5)IP3 was least for IP3R3. Addition of a large chromophore (malachite green) to the 1-phosphate of (1,4,5)IP3 only modestly reduced potency suggesting that similar analogues could be used to measure (1,4,5)IP3 binding optically. These data provide the first structure-activity analyses of key IP3 analogues using homogenous populations of each mammalian IP3R subtype. They demonstrate broadly similar structure-activity relationships for all mammalian IP3R subtypes and establish the potential utility of (1,4,5)IP3 analogues with chromophores attached to the 1-position. [ABSTRACT FROM AUTHOR]

The Waste Vitrification Plant (WVP), operated by Sellafield Ltd, converts highly active liquor (HAL) from the reprocessing of spent nuclear fuel into vitrified high level waste (HLW) product for safe interim storage, and ultimate disposal in a deep geological repository. One of the important aspects to understand in relation to disposal of HLW glass is its behaviour over long timescales under aqueous conditions. To this end, a series of laboratory based leach tests on the expected range of WVP glass compositions has been initiated; some of the preliminary results are described. The aqueous dissolution behaviour of a range of simulated UK vitrified HLW glasses has been investigated using static leach tests at different surface area to volume ratios for durations up to 16 weeks. Both 'Magnox' and 'Blend' glass compositions have been investigated at a range of waste oxide incorporations. The experiments demonstrated the complex dissolution behaviour of UK HLW glass with the results depending on the waste incorporation being studied and the test conditions used. However, a number of general observations can be made, such as the improvement in dissolution behaviour with increased waste loading and as the proportion of Oxide waste in 'Blend' HLW glass is increased. [ABSTRACT FROM AUTHOR]

Although adenophostin A (AdA), the most potent agonistof d-myo-inositol 1,4,5-trisphosphate receptors(IP3R), is thought to mimic IP3, the relativerolesof the different phosphate groups and the adenosine motif have notbeen established. We synthesized all three possible bisphosphate analoguesof AdA and glucose 3,4-bisphosphate (7, AdA lacking the2′-AMP). 2′-Dephospho-AdA (6) was preparedvia a novel regioselective dephosphorylation strategy. Assessmentof the abilities of these bisphosphates to stimulate intracellularCa2귩幪 using recombinant rat type 1 IP3R (IP3R1) revealed that 6, a mimic of Ins(4,5)P2, is only 4-fold less potent than IP3, while 7is some 400-fold weaker and even 3″-dephospho-AdA(5) is measurably active, despite missing one of thevicinal bisphosphate groups normally thought to be crucial for IP3-like activity. Compound 6is the most potentbisphosphate yet discovered with activity at IP3R. Thus,adenosine has a direct role independent of the 2′-phosphategroup in contributing toward the potency of adenophostins, the vicinalbisphosphate motif is not essential for activity at the IP3R, as always thought, and it is possible to design potent agonistswith just two of the three phosphates. A model with a possible adenine–R504interaction supports the activity of 5and 6and also allows a reappraisal of the unexpected activity previouslyreported for the AdA regioisomer 2″-phospho-3″-dephospho-AdA 40. [ABSTRACT FROM AUTHOR]

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are ubiquitous intracellular Ca2+ channels. IP3 binding to the IP3-binding core (IBC) near the N terminus initiates conformational changes that lead to opening of a pore. The mechanisms underlying this process are unresolved. We synthesized 2-O–modified IP3 analogs that are partial agonists of IP3R. These are similar to IP3 in their interactions with the IBC, but they are less effective than IP3 in rearranging the relationship between the IBC and the N-terminal suppressor domain (SD), and they open the channel at slower rates. IP3R with a mutation in the SD occupying a position similar to the 2-O substituent of the partial agonists has a reduced open probability that is similar for full and partial agonists. Bulky or charged substituents from either the ligand or the SD therefore block obligatory coupling of the IBC and the SD. Analysis of ΔG for ligand binding shows that IP3 is recognized by the IBC and conformational changes then propagate entirely via the SD to the pore. [ABSTRACT FROM AUTHOR]

The article provides an overview of the study which examines the impact of the increased waste loading on the quality and durability of vitrified high level radioactive waste (HLW) glass. It had found out test work on Vitrification Test Rig (VTR) has showed that good quality glass can be made at 32, 35 and 38-watt (wt)% using Magnox waste. It also determined an operational envelope, which provide an opportunity for waste vitrification plant (WWP) to adopt high glass production.

Surfactant templating is a method that has successfully been used to produce nanoporous inorganic structures from a wide range of oxide-based material. Co-assembly of inorganic precursor molecules with amphiphilic organic molecules is followed first by inorganic condensation to produce rigid amorphous frameworks and then, by template removal, to produce mesoporous solids. A range of periodic surfactant/semiconductor and surfactant/metal composites have also been produced by similar methods, but for virtually all the non-oxide semiconducting phases, the surfactant unfortunately cannot be removed to generate porous materials. Here we show that it is possible to use surfactant-driven self-organization of soluble Zintl clusters to produce periodic, nanoporous versions of classic semiconductors such as amorphous Ge or Ge/Si alloys. Specifically, we use derivatives of the anionic Ge94- cluster, a compound whose use in the synthesis of nanoscale materials is established. Moreover, because of the small size, high surface area, and flexible chemistry of these materials, we can tune optical properties in these nanoporous semiconductors through quantum confinement, by adsorption of surface species, or by altering the elemental composition of the inorganic framework. Because the semiconductor surface is exposed and accessible in these materials, they have the potential to interact with a range of species in ways that could eventually lead to new types of sensors or other novel nanostructured devices. [ABSTRACT FROM AUTHOR]

Abstract: Ins(1,4,5,6)P4, a biologically active cell constituent, was recently advocated as a substrate of human Ins(3,4,5,6)P4 1-kinase (hITPK1), because stereochemical factors were believed relatively unimportant to specificity [Miller, G.J., Wilson, M.P., Majerus, P.W. and Hurley, J.H. (2005) Specificity determinants in inositol polyphosphate synthesis: crystal structure of inositol 1,3,4-triphosphate 5/6-kinase. Mol. Cell. 18, 201–212]. Contrarily, we provide three examples of hITPK1 stereospecificity. hITPK1 phosphorylates only the 1-hydroxyl of both Ins(3,5,6)P3 and the meso-compound, Ins(4,5,6)P3. Moreover, hITPK1 has >13,000-fold preference for Ins(3,4,5,6)P4 over its enantiomer, Ins(1,4,5,6)P4. The biological significance of hITPK1 being stereospecific, and not physiologically phosphorylating Ins(1,4,5,6)P4, is reinforced by our demonstrating that Ins(1,4,5,6)P4 is phosphorylated (K m =0.18μM) by inositolphosphate-multikinase. [Copyright &y& Elsevier]

2-O-(2-Aminoethyl)-Ins(1,4,5)P3 (5), a novel derivative of the Ca2+-mobilising second messenger d-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], was synthesised from myo-inositol. 5 was found to be a potent mobiliser of intracellular Ca2+, and an Ins(1,4,5)P3 affinity matrix synthesised from 5 was effective at selectively binding N-terminal fragments of the Ins(1,4,5)P3 receptor containing the intact Ins(1,4,5)P3 binding site. The microprotonation scheme for 5 was resolved and the related constants were determined in comparison with Ins(1,4,5)P3 and another reactive Ins(1,4,5)P3 analogue 1-O-(2-aminoethyl-1-phospho)-Ins(4,5)P2 (2a) by potentiometric and NMR titration methods. The 31P and 1H NMR titration curves for compound 5 and Ins(1,4,5)P3 are remarkably close, indicating analogous acid–base properties and intramolecular interactions for the two compounds. The 1-phosphate-modified Ins(1,4,5)P3 derivative 2a, on the contrary, behaves as a bisphosphorylated rather than a trisphosphorylated inositol. Thus, 5 is a new reactive Ins(1,4,5)P3 analogue of considerable potential for investigation of the chemical biology of Ins(1,4,5)P3-mediated cellular signalling. [Copyright &y& Elsevier]

Investigates the function of inositol 1,3,4,5-tetrakisphosphate (InsP[sub4]) in calcium[sup2+] influx in the mast cell line RBL-2H3. Role of InsP[sub4] in the inhibition of inositol 1,4,5-triphosphate (insP[sub3]) metabolism through InsP[sub3] 5-phophatase, thereby facilitating the activation of the store-operated calcium[sup2+] current I[subCRAC]; Role of InsP[sub4] as a bi-modal regulator of cellular sensitivity to InsP[sub3] in relation to calcium signalling.

Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) are intracellular Ca2+ channels that link extracellular stimuli to Ca2+ signals. Ca2+ release from intracellular stores is "quantal": low IP 3 concentrations rapidly release a fraction of the stores. Ca2+ release then slows or terminates without compromising responses to further IP 3 additions. The mechanisms are unresolved. Here, we synthesize a high-affinity partial agonist of IP 3 Rs and use it to demonstrate that quantal responses do not require heterogenous Ca2+ stores. IP 3 Rs respond incrementally to IP 3 and close after the initial response to low IP 3 concentrations. Comparing functional responses with IP 3 binding shows that only a tiny fraction of a cell's IP 3 Rs mediate incremental Ca2+ release; inactivation does not therefore affect most IP 3 Rs. We conclude, and test by simulations, that Ca2+ signals evoked by IP 3 pulses arise from rapid activation and then inactivation of very few IP 3 Rs. This allows IP 3 Rs to behave as increment detectors mediating graded Ca2+ release. [Display omitted] • IP 3 evokes quantal Ca2+ release from the endoplasmic reticulum • IP 3 receptors rapidly activate and then inactivate • Submaximal responses to IP 3 require activation of very few IP 3 receptors • Rapid activation and inactivation of very few IP 3 Rs allow incremental responses to IP 3 Rossi et al. define mechanisms for IP 3 -evoked quantal Ca2+ release that reconcile response termination with undiminished sensitivity to further IP 3 additions. They show that responses require very few IP 3 receptors that rapidly open and then inactivate, allowing graded responses despite the ability of IP 3 receptors to propagate regenerative Ca2+ signals. [ABSTRACT FROM AUTHOR]

Although a large cohort of potential biomarkers for thyroid cancer aggressiveness have been tested in various formats in recent years, to the best of our knowledge, thyroglobulin and calcitonin remain the only two established biomarkers associated with thyroid cancer management. Our group has recently validated a novel means of maintaining live, human ex vivo thyroid tissue within a tissue-on-chip format. The present pilot study aimed to interrogate the tissue effluent, containing all the soluble markers released by the tissue samples maintained within the devices' tissue chamber, for the presence of markers potentially associated with thyroid cancer aggressiveness. Culture effluent from tissue samples harvested from 19 individual patients who had undergone thyroidectomy for the treatment of suspected thyroid cancer was assessed, first using a proteome profiler™ angiogenesis array kit. Patients were subcategorised as 'aggressive' if they possessed a minimum of N1b level metastases, whilst 'non-aggressive' samples were T3 or lower without evidence of multifocality; and contralateral healthy thyroid tissue was harvested for comparative studies. Levels of Serpin-F1, vascular endothelial growth factor, Thrombospondin-1 and chemokine (C-C motif) ligand were significantly altered and, thus, were further investigated using ELISA to allow for quantitative analysis. The concentration of serpin-F1 was significantly increased in the effluent of aggressive thyroid cancer tissue when compared with levels released by both non-aggressive and benign samples. The present study demonstrated the usability of microfluidic technology for the analysis of the ex vivo tissue secretome in order to identify novel biomarkers. [ABSTRACT FROM AUTHOR]

[Display omitted] Modifications of RNA molecules have a significant effect on their structure and function. One of the most common modifications is the isomerization from uridine to pseudouridine. Despite its prevalence in natural RNA sequences, organic synthesis of pseudouridine has been challenging because of the stereochemistry requirement and the sensitivity of reaction steps to moisture. Herein, a semi-enzymatic synthetic route is developed for the synthesis of pseudouridine using adenosine 5′-monophosphate and uracil as the starting materials and a reverse reaction catalyzed by the pseudouridine monophosphate glycosidase. This synthetic route has only three steps and the overall yield of β-pseudouridine production was 68.4%. [ABSTRACT FROM AUTHOR]

Introduction: Cannabis use in the United States is increasingly accepted and legal. Rise in use among childbearing aged adults is potentially concerning, as the impacts of parental cannabis use on children are largely unknown, especially for young children. This study examined whether cannabis use is associated with increased risk for negative parenting and child emotional and behavioral problems among the parents of young children. Methods: We conducted a cross-sectional survey of parents and child behavior, recruited through five primary care practices in three states. Parents of children aged 1.5–5 years reported on family demographics, last 6-months cannabis use, negative parenting, parent mental health, parents' adverse childhood experiences (ACEs), and child emotional/behavioral problems. We conducted hierarchical regressions to determine if parental cannabis use predicts negative parenting and/or child emotional/behavioral problems when controlling for other risk factors. Results: Of 266 responding parents, 34 (13%) reported cannabis use in the last 6 months. Parents who endorsed cannabis use reported significantly more negative parenting, ACEs, anxiety, depression, and child emotional/behavioral problems. Adjusting for the effects of other risk factors, cannabis use significantly predicted more negative parenting, but was not uniquely and significantly associated with child emotional/behavioral problems. Conclusion: Parental cannabis predicted negative parenting, which in turn predicted early childhood emotional/behavioral problems; however, parental cannabis use did not predict child emotional/behavioral problems when other risk factors were considered. Further research is needed to elucidate the nature and direction of relationships between parent cannabis use, negative parenting, child psychological outcomes, and other risk factors. [ABSTRACT FROM AUTHOR]