A light‐mediated Truce–Smiles arylative rearrangement is described that proceeds in the absence of any photocatalyst. The protocol creates two C−C bonds from simple starting materials, with the ...installation of an aryl ring and a difluoroacetate moiety across unactivated alkenes. The reaction proceeds via a radical mechanism, utilizing a light‐mediated reduction of ethyl bromodifluoroacetate by N,N,N′,N′‐tetramethylethylenediamine (TMEDA) to set up intermolecular addition to an unactivated alkene, followed by Truce–Smiles rearrangement.
Light up a Smile. A visible light‐mediated Truce–Smiles arylative rearrangement is described that proceeds in the absence of any photocatalyst. The protocol creates two C−C bonds from simple starting materials, adding an aryl ring and a difluoroacetate moiety across an unactivated alkene.
The ring‐opening of 3‐aminocyclobutanone oximes enables easy generation of primary alkyl radicals, capable of undergoing an unprecedented strain‐release, desulfonylative radical Truce–Smiles ...rearrangement, providing divergent access to valuable 1,3 diamines and unnatural β‐amino acids. Characterized by mild conditions and wide scope of migrating species, this protocol allows the modular assembly of sp3‐aryls under transition metal‐free, room‐temperature conditions.
The Truce–Smiles rearrangement has proven to be a powerful tool for the synthesis of new sp3‐aryls via ipso substitution. The reaction has been applied to the strain‐release ring‐opening of 3‐aminocyclobutanone oximes, giving cyanide‐free access to β‐amino nitriles under metal‐free, room temperature conditions. The reaction displays a wide scope of migrating arenes.
Rationale
Lysergic acid diethylamide (LSD) has a history of use as a psychotherapeutic aid in the treatment of mood disorders and addiction, and it was also explored as an enhancer of mind control.
...Objectives
The present study sought to test the effect of LSD on suggestibility in a modern research study.
Methods
Ten healthy volunteers were administered with intravenous (i.v.) LSD (40–80 μg) in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale (CIS) and a mental imagery test (MIT). CIS and MIT items were split into two versions (A and B), balanced for ‘efficacy’ (i.e. A≈B) and counterbalanced across conditions (i.e. 50 % completed version ‘A’ under LSD). The MIT and CIS were issued 110 and 140 min, respectively, post-infusion, corresponding with the peak drug effects.
Results
Volunteers gave significantly higher ratings for the CIS (
p
= 0.018), but not the MIT (
p
= 0.11), after LSD than placebo. The magnitude of suggestibility enhancement under LSD was positively correlated with trait conscientiousness measured at baseline (
p
= 0.0005).
Conclusions
These results imply that the influence of suggestion is enhanced by LSD. Enhanced suggestibility under LSD may have implications for its use as an adjunct to psychotherapy, where suggestibility plays a major role. That cued imagery was unaffected by LSD implies that suggestions must be of a sufficient duration and level of detail to be enhanced by the drug. The results also imply that individuals with high trait conscientiousness are especially sensitive to the suggestibility-enhancing effects of LSD.
Proglucagon is cleaved to glucagon by prohormone convertase 2 (PC2) in pancreatic α-cells, but is cleaved to glucagon-like peptide-1 (GLP-1) by PC1 in intestinal L-cells. The aim of this study was to ...identify mechanisms which switch processing of proglucagon to generate GLP-1 in the pancreas, given that GLP-1 can increase insulin secretion and β-cell mass. The α-cell line, αTC1-6, expressed PC1 at low levels and GLP-1 was detected in cells and in culture media. GLP-1 was also found in isolated human islets and in rat islets cultured for 7 days. High glucose concentrations increased Pc1 gene expression and PC1 protein in rat islets. High glucose (25 mM) also increased GLP-1 but decreased glucagon secretion from αTC1-6 cells suggesting a switch in processing to favour GLP-1. Three G protein-coupled receptors, GPR120, TGR5 and GPR119, implicated in the release of GLP-1 from L-cells are expressed in αTC1-6 cells. Incubation of these cells with an agonist of TGR5 increased PC1 promoter activity and GLP-1 secretion suggesting that this is a mechanism for switching processing to GLP-1 in the pancreas. Treatment of isolated rat islets with streptozotocin caused β-cell toxicity as evidenced by decreased glucose-stimulated insulin secretion. This increased GLP-1 but not glucagon in the islets. In summary, proglucagon can be processed to GLP-1 in pancreatic cells. This process is upregulated by elevated glucose, activation of TGR5 and β-cell destruction. Understanding this phenomenon may lead to advances in therapies to protect β-cell mass, and thereby slow progression from insulin resistance to type 2 diabetes.
A synthetic lethal relationship exists between disruption of polymerase theta (Polθ), and loss of either 53BP1 or homologous recombination (HR) proteins, including BRCA1; however, the mechanistic ...basis of these observations are unclear. Here we reveal two distinct mechanisms of Polθ synthetic lethality, identifying dual influences of 1) whether Polθ is lost or inhibited, and 2) the underlying susceptible genotype. Firstly, we find that the sensitivity of BRCA1/2- and 53BP1-deficient cells to Polθ loss, and 53BP1-deficient cells to Polθ inhibition (ART558) requires RAD52, and appropriate reduction of RAD52 can ameliorate these phenotypes. We show that in the absence of Polθ, RAD52 accumulations suppress ssDNA gap-filling in G2/M and encourage MRE11 nuclease accumulation. In contrast, the survival of BRCA1-deficient cells treated with Polθ inhibitor are not restored by RAD52 suppression, and ssDNA gap-filling is prevented by the chemically inhibited polymerase itself. These data define an additional role for Polθ, reveal the mechanism underlying synthetic lethality between 53BP1, BRCA1/2 and Polθ loss, and indicate genotype-dependent Polθ inhibitor mechanisms.
Aims To determine the incidence of, and clinically relevant risk factors for, new foot ulceration in a large cohort of diabetic patients in the community healthcare setting.
Methods Diabetic patients ...(n = 9710) underwent foot screening in six districts of North‐west England in various healthcare settings. All were assessed at baseline for demographic information, medical and social history, neuropathy symptom score, neuropathy disability score, cutaneous pressure perception (insensitivity to the 10 g monofilament), foot deformities, and peripheral pulses. Two years later, patients were followed up via postal questionnaire to determine the incidence of new foot ulcers. Cox’s proportional hazards regression analysis was used to determine the independent, relative risk of baseline variables for new foot ulceration.
Results New foot ulcers occurred in 291/6613 patients who completed and returned their 2‐year follow‐up questionnaire (2.2% average annual incidence). The following factors were independently related to new foot ulcer risk: ulcer present at baseline (relative risk (95% confidence interval)) 5.32 (3.71–7.64), past history of ulcer 3.05 (2.16–4.31), abnormal neuropathy disability score (≥ 6/10) 2.32 (1.61–3.35), any previous podiatry attendance 2.19 (1.50–3.20), insensitivity to the 10 g monofilament 1.80 (1.36–2.39), reduced pulses 1.80 (1.40–2.32), foot deformities 1.57 (1.22–2.02), abnormal ankle reflexes 1.55 (1.01–2.36) and age 0.99 (0.98–1.00).
Conclusions More than 2% of community‐based diabetic patients develop new foot ulcers each year. The neuropathy disability score, 10 g monofilament and palpation of foot pulses are recommended as screening tools in general practice.
Posttraumatic stress disorder (PTSD) is reliably associated with reduced brain volume relative to healthy controls, in areas similar to those found in depression. We investigated whether in a PTSD ...sample brain volumes in these areas were related to reporting specific symptoms of PTSD or to overall symptom severity.
Structural MRI scans were obtained from 28 participants diagnosed with PTSD according to DSM-IV-TR. Participants reported the extent of individual PTSD symptoms using the Posttraumatic Diagnostic Scale. Voxel-based morphometry applying the Dartel algorithm implemented within SPM5 was used to identify volumetric changes, related to PTSD total, symptom cluster, and individual symptom scores.
Brain volume was unrelated to overall PTSD severity, but greater reexperiencing scores predicted reduced volumes in the middle temporal and inferior occipital cortices. Increased reports of flashbacks predicted reduced volume in the insula/parietal operculum and in the inferior temporal gyrus.
The data illustrate the value of analyses at the symptom level within a patient population to supplement group comparisons of patients and healthy controls. Areas identified were consistent with a neurobiological account of flashbacks implicating specific abnormalities in the ventral visual stream.
Flashbacks in posttraumatic stress disorder (PTSD) are commonly experienced as visual, auditory, olfactory or tactile re-livings of a previously experienced traumatic event. We present the case ...report of one survivor of the July 7th 2005 London underground bombings who was diagnosed with PTSD and who experienced painful flashbacks. We present retrospective multidimensional measures of his pain using standardised instruments. The case provides further evidence that somatosensory re-experiencing of pain memories is possible. Findings are discussed with regards to memory for pain.
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