Synthesis, structure and unusual reactivity of a stable 3-(oxazolidin-2-ylidene)thiophen-2-one

The authors thank EPSRC (UK) for a DTA studentship (Grant EP/L505079/1) and the EPSRC UK National Mass Spectrometry Facility at Swansea University.Treatment of 2- and 3-thienyloxazolines with butyllithium and bis(trimethylsilyl) peroxide results in ring hydroxylation to give products which exist mainly as the oxazolidinylidenethiophenones. The 3-oxazolidinylidenethiophen-2-one is a rare example of a stable heterocyclic ortho-quinone methide analog which shows a varied pattern of reactivity, including both C- and O-alkylation, Michael addition via C-5 to an acetylenic ester, tetrachlorobenzannulation across positions 4 and 5, and formation of a hexacyclic fused-ring product with N-phenyltriazolinedione. Crystal structures of the products are dominated by inter- and intramolecular NH to CO hydrogen bonding.PostprintPeer reviewe

Vascular endothelial growth factor-A165b restores normal glomerular water permeability in a diphtheria-toxin mouse model of glomerular injury

BACKGROUND/AIMS:Genetic cell ablation using the human diphtheria toxin receptor (hDTR) is a new strategy used for analysing cellular function. Diphtheria toxin (DT) is a cytotoxic protein that leaves mouse cells relatively unaffected, but upon binding to hDTR it ultimately leads to cell death. We used a podocyte-specific hDTR expressing (Pod-DTR) mouse to assess the anti-permeability and cyto-protective effects of the splice isoform vascular endothelial growth factor (VEGF-A165b). METHODS:The Pod-DTR mouse was crossed with a mouse that over-expressed VEGF-A165b specifically in the podocytes (Neph-VEGF-A165b). Wild type (WT), Pod-DTR, Neph-VEGF-A165b and Pod-DTR X Neph-VEGF-A165b mice were treated with several doses of DT (1, 5, 100, and 1,000 ng/g bodyweight). Urine was collected and the glomerular water permeability (LpA/Vi) was measured ex vivo after 14 days. Structural analysis and podocyte marker expression were also assessed. RESULTS: Pod-DTR mice developed an increased glomerular LpA/Vi 14 days after administration of DT (all doses), which was prevented when the mice over-expressed VEGF-A165b. No major structural abnormalities, podocyte ablation or albuminuria was observed in Pod-DTR mice, indicating this to be a mild model of podocyte disease. However, a change in expression and localisation of nephrin within the podocytes was observed, indicating disruption of the slit diaphragm in the Pod-DTR mice. This was prevented in the Pod-DTR X Neph-VEGF-A165b mice. CONCLUSION: Although only a mild model of podocyte injury, over-expression of the anti-permeability VEGF-A165b isoform in the podocytes of Pod-DTR mice had a protective effect. Therefore, this study further highlights the therapeutic potential of VEGF-A165b in glomerular disease

Nutrition and the elite and highly trained junior and young adult tennis player: A scoping review

Objectives The primary objective of this scoping review was to examine existing evidence regarding the dietary intake and nutrition habits of elite and highly trained junior and young adult tennis players. Methods Systematic searches of MEDLINE, EBSCOHost and Scopus were undertaken from the earliest record to December 2021. Reference lists of articles selected were manually searched. A five-stage protocol informed by Arkey and O’Malley's framework with consideration for the Joanna Briggs Institute (JBI) methodology from scoping reviews was followed. Results The initial searches yielded an initial 145 records following the removal of duplicates. Following the screening process 14 articles were accepted for analyses. Three major themes were identified: (1) dietary intake and negative energy balance, (2) sub-optimal nutrient intake/habits, and (3) the use and impact of dietary supplements/ergogenic aids. Conclusion Research indicates sub-optimal nutritional practices amongst elite and highly trained junior and young adult tennis players. Particular concerns have emerged regarding insufficient calorie consumption to support performance, growth, and wellbeing

Base-induced cyclisation of ortho-substituted 2-phenyloxazolines to give 3-aminobenzofurans and related heterocycles

The authors thank EPSRC (UK) for a DTA studentship (Grant No. EP/L505079/1) and the EPSRC UK National Mass Spectrometry Facility at Swansea UniversityTreatment of ortho-benzyloxyphenyloxazolines with butyllithium and potassium t-butoxide results in cyclisation with ring-opening of the oxazoline to give 2-aryl-3-aminobenzofurans. The reaction also occurs with the corresponding benzylthio- and benzylamino-compounds to give benzothiophenes and indoles, respectively. Use of an ortho-allyloxyphenyloxazoline gives the corresponding 2-vinylbenzofuran, while both α-methylbenzyloxy and benzylsulfonyl compounds form stable spirooxazolidine products. The X-ray structure of an aminobenzothiophene product has been determined.PostprintPeer reviewe

Logical Step-Indexed Logical Relations

Appel and McAllester's "step-indexed" logical relations have proven to be a simple and effective technique for reasoning about programs in languages with semantically interesting types, such as general recursive types and general reference types. However, proofs using step-indexed models typically involve tedious, error-prone, and proof-obscuring step-index arithmetic, so it is important to develop clean, high-level, equational proof principles that avoid mention of step indices. In this paper, we show how to reason about binary step-indexed logical relations in an abstract and elegant way. Specifically, we define a logic LSLR, which is inspired by Plotkin and Abadi's logic for parametricity, but also supports recursively defined relations by means of the modal "later" operator from Appel, Melli\`es, Richards, and Vouillon's "very modal model" paper. We encode in LSLR a logical relation for reasoning relationally about programs in call-by-value System F extended with general recursive types. Using this logical relation, we derive a set of useful rules with which we can prove contextual equivalence and approximation results without counting steps

The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway

Amino acids signal to the mTOR complex I (mTORC1) growth pathway through the Rag GTPases. Multiple distinct complexes regulate the Rags, including GATOR1, a GTPase activating protein (GAP), and GATOR2, a positive regulator of unknown molecular function. Arginine stimulation of cells activates mTORC1, but how it is sensed is not well understood. Recently, SLC38A9 was identified as a putative lysosomal arginine sensor required for arginine to activate mTORC1 but how arginine deprivation represses mTORC1 is unknown. Here, we show that CASTOR1, a previously uncharacterized protein, interacts with GATOR2 and is required for arginine deprivation to inhibit mTORC1. CASTOR1 homodimerizes and can also heterodimerize with the related protein, CASTOR2. Arginine disrupts the CASTOR1-GATOR2 complex by binding to CASTOR1 with a dissociation constant of ∼30 μM, and its arginine-binding capacity is required for arginine to activate mTORC1 in cells. Collectively, these results establish CASTOR1 as an arginine sensor for the mTORC1 pathway.United States. National Institutes of Health (R01CA103866)United States. National Institutes of Health (AI47389)United States. Department of Energy (W81XWH-07-0448)United States. National Institutes of Health (F31 CA180271)United States. National Institutes of Health (F31 CA189437

Brain Cells in the Avian ‘Prefrontal Cortex’ Code for Features of Slot-Machine-Like Gambling

Slot machines are the most common and addictive form of gambling. In the current study, we recorded from single neurons in the ‘prefrontal cortex’ of pigeons while they played a slot-machine-like task. We identified four categories of neurons that coded for different aspects of our slot-machine-like task. Reward-Proximity neurons showed a linear increase in activity as the opportunity for a reward drew near. I-Won neurons fired only when the fourth stimulus of a winning (four-of-a-kind) combination was displayed. I-Lost neurons changed their firing rate at the presentation of the first nonidentical stimulus, that is, when it was apparent that no reward was forthcoming. Finally, Near-Miss neurons also changed their activity the moment it was recognized that a reward was no longer available, but more importantly, the activity level was related to whether the trial contained one, two, or three identical stimuli prior to the display of the nonidentical stimulus. These findings not only add to recent neurophysiological research employing simulated gambling paradigms, but also add to research addressing the functional correspondence between the avian NCL and primate PFC

Physical Fatigue, Fitness and Muscle Function in Patients with Anti-neutrophil Cytoplasm Antibody-Associated Vasculitis.

Objective. This study investigated differences in cardiorespiratory fitness, muscular function, perceived exertion, and anxiety/depression between patients and healthy controls (HCs) and assessed which of these variables may account for the fatigue experienced by patients. Methods. Fatigue was measured in 48 antineutrophil cytoplasmic antibody–associated vasculitis patients and 41 healthy controls using the Multidimensional Fatigue Inventory (MFI-20), focusing on the physical component. Quality of life, anxiety/depression, and sleep quality were assessed by validated questionnaires. Muscle mass was measured by dual-energy x-ray absorptiometry scan, strength as the maximal voluntary contraction (MVC) force, and endurance as sustained isometric contraction at 50% MVC of the quadriceps. Voluntary activation was assessed by superimposed electrical stimulation. Cardiorespiratory fitness (_Vo2 max and oxygen pulse [O2 pulse]) and perceived exertion (Borg scale) were measured during progressive submaximal exercise. Results. Patients reported elevated physical fatigue scores compared to HCs (patients MFI-20 physical 13 [interquar-tile range (IQR) 8–16], HCs MFI-20 physical 5.5 [IQR 4–8]; P<0.001). Muscle mass was the same in both groups, but MVC and time to failure in the endurance test were lower due to reduced voluntary activation in patients. Estimated _Vo2max and O2 pulse were the same in both groups. For the same relative workload, patients reported higher ratings of perceived exertion, which correlated with reports of MFI-20 physical fatigue (R 25 0.2). Depression (R 25 0.6), anxiety (R250.3), and sleep disturbance (R 25 0.3) were all correlated with MFI-20 physical fatigue. Conclusion. These observations suggest that fatigue in patients is of a central rather than peripheral origin, supported by associations of fatigue with heightened perception of exertion, depression, anxiety, and sleep disturbance but normal muscle and cardiorespiratory function

Seeing the way: visual sociology and the distance runner's perspective

Employing visual and autoethnographic data from a two‐year research project on distance runners, this article seeks to examine the activity of seeing in relation to the activity of distance running. One of its methodological aims is to develop the linkage between visual and autoethnographic data in combining an observation‐based narrative and sociological analysis with photographs. This combination aims to convey to the reader not only some of the specific subcultural knowledge and particular ways of seeing, but also something of the runner's embodied feelings and experience of momentum en route. Via the combination of narrative and photographs we seek a more effective way of communicating just how distance runners see and experience their training terrain. The importance of subjecting mundane everyday practices to detailed sociological analysis has been highlighted by many sociologists, including those of an ethnomethodological perspective. Indeed, without the competence of social actors in accomplishing these mundane, routine understandings and practices, it is argued, there would in fact be no social order