MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognostic implications. This is partly due to a large proportion of PDACs carrying mutations in TP53, which impart gain-of-function characteristics that promote metastasis. There is evidence that microRNAs (miRNAs) may play a role in both gain-of-function TP53 mutations and metastasis, but this has not been fully explored in PDAC. Here we set out to identify miRNAs which are specifically dysregulated in metastatic PDAC. To achieve this, we utilised established mouse models of PDAC to profile miRNA expression in primary tumours expressing the metastasis-inducing mutant p53R172H and compared these to two control models carrying mutations, which promote tumour progression but do not induce metastasis. We show that a subset of miRNAs are dysregulated in mouse PDAC tumour tissues expressing mutant p53R172H, primary cell lines derived from mice with the same mutations and in TP53 null cells with ectopic expression of the orthologous human mutation, p53R175H. Specifically, miR-142-3p is downregulated in all of these experimental models. We found that DNA methyltransferase 1 (Dnmt1) is upregulated in tumour tissue and cell lines, which express p53R172H. Inhibition or depletion of Dnmt1 restores miR-142-3p expression. Overexpression of miR-142-3p attenuates the invasive capacity of p53R172H-expressing tumour cells. MiR-142-3p dysregulation is known to be associated with cancer progression, metastasis and the miRNA is downregulated in patients with PDAC. Here we link TP53 gain-of-function mutations to Dnmt1 expression and in turn miR-142-3p expression. Additionally, we show a correlation between expression of these genes and patient survival, suggesting that they may have potential to be therapeutic targets

Choosing the lesser of two evils, the better of two goods: Specifying the roles of ventromedial prefrontal cortex and dorsal anterior cingulate in object choice

The ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortices (ACd) are considered important for reward-based decision making. However, work distinguishing their individual functional contributions has only begun. One aspect of decision making that has received little attention is that making the right choice often translates to making the better choice. Thus, response choice often occurs in situations where both options are desirable (e.g., choosing between mousse au chocolat or crème caramel cheesecake from a menu) or, alternatively, in situations where both options are undesirable. Moreover, response choice is easier when the reinforcements associated with the objects are far apart, rather than close together, in value. We used functional magnetic resonance imaging to delineate the functional roles of the vmPFC and ACd by investigating these two aspects of decision making: (1) decision form (i.e., choosing between two objects to gain the greater reward or the lesser punishment), and (2) between-object reinforcement distance (i.e., the difference in reinforcements associated with the two objects). Blood oxygen level-dependent (BOLD) responses within the ACd and vmPFC were both related to decision form but differentially. Whereas ACd showed greater responses when deciding between objects to gain the lesser punishment, vmPFC showed greater responses when deciding between objects to gain the greater reward. Moreover, vmPFC was sensitive to reinforcement expectations associated with both the chosen and the forgone choice. In contrast, BOLD responses within ACd, but not vmPFC, related to between-object reinforcement distance, increasing as the distance between the reinforcements of the two objects decreased. These data are interpreted with reference to models of ACd and vmPFC functioning

Epidural Analgesia Decreases Narcotic Requirements in Low Level Spina Bifida Patients Undergoing Urologic Laparotomy for Neurogenic Bladder and Bowel

Purpose Concern of anatomical anomalies and worsening neurologic symptoms has prevented widespread use of epidural catheters in patients with low level spina bifida (LLSB). We hypothesize that thoracic epidural placement in the T9-T10 interspace is safe and decreases narcotic requirements in LLSB patients following major open lower urinary tract reconstruction (LUTR). Materials and Methods We reviewed consecutive LLSB patients who had LUTR and epidurals for post-operative pain control. Controls were LLSB patients who received single shot transversus abdominis plane (TAP) blocks with similar procedures. Complications from epidural placement, including changes in motor and sensory status were recorded. Opioid consumption was calculated utilizing equivalent IV morphine doses. Mean and maximum pain scores on post-operative day (POD) 0-3 were calculated. Results 10 LLSB patients who had lower urinary tract reconstruction and epidurals were matched to 10 LLSB patients who had lower urinary tract reconstruction and transverse abdominis plane blocks. Groups were demographically similar. All had full abdominal sensation and functional levels at or below L3. No epidural complications or changes in neurological status were noted. The epidural group had decreased opioid consumption on POD 0-3 (0.75 mg/kg vs. 1.29 mg/kg, p=0.04). Pain scores were similar or improved in the epidural group. Conclusions Thoracic epidural analgesia appears to be a safe and effective opioid sparing option to assist with post-operative pain management following lower urinary tract reconstruction in LLSB patients

Observations of X-rays and Thermal Dust Emission from the Supernova Remnant Kes 75

We present Spitzer Space Telescope and Chandra X-ray Observatory observations of the composite Galactic supernova remnant Kes 75 (G29.7-0.3). We use the detected flux at 24 microns and hot gas parameters from fitting spectra from new, deep X-ray observations to constrain models of dust emission, obtaining a dust-to-gas mass ratio M_dust/M_gas ~0.001. We find that a two-component thermal model, nominally representing shocked swept-up interstellar or circumstellar material and reverse-shocked ejecta, adequately fits the X-ray spectrum, albeit with somewhat high implied densities for both components. We surmise that this model implies a Wolf-Rayet progenitor for the remnant. We also present infrared flux upper limits for the central pulsar wind nebula.Comment: 7 pages, 2 tables, 4 figures, uses emulateapj. Accepted for publication in Ap

Switchable ErSc2N rotor within a C80 fullerene cage: An EPR and photoluminescence excitation study

Systems exhibiting both spin and orbital degrees of freedom, of which Er3+ is one, can offer mechanisms for manipulating and measuring spin states via optical excitations. Motivated by the possibility of observing photoluminescence and electron paramagnetic resonance from the same species located within a fullerene molecule, we initiated an EPR study of Er3+ in ErSc2N@C80. Two orientations of the ErSc2N rotor within the C80 fullerene are observed in EPR, consistent with earlier studies using photoluminescence excitation (PLE) spectroscopy. For some crystal field orientations, electron spin relaxation is driven by an Orbach process via the first excited electronic state of the 4I_15/2 multiplet. We observe a change in the relative populations of the two ErSc2N configurations upon the application of 532 nm illuminations, and are thus able to switch the majority cage symmetry. This photoisomerisation, observable by both EPR and PLE, is metastable, lasting many hours at 20 K.Comment: 4 pages, 4 figure

Higher Order Terms in the Melvin-Morton Expansion of the Colored Jones Polynomial

We formulate a conjecture about the structure of `upper lines' in the expansion of the colored Jones polynomial of a knot in powers of (q-1). The Melvin-Morton conjecture states that the bottom line in this expansion is equal to the inverse Alexander polynomial of the knot. We conjecture that the upper lines are rational functions whose denominators are powers of the Alexander polynomial. We prove this conjecture for torus knots and give experimental evidence that it is also true for other types of knots.Comment: 21 pages, 1 figure, LaTe

Bang-bang control of fullerene qubits using ultra-fast phase gates

Quantum mechanics permits an entity, such as an atom, to exist in a superposition of multiple states simultaneously. Quantum information processing (QIP) harnesses this profound phenomenon to manipulate information in radically new ways. A fundamental challenge in all QIP technologies is the corruption of superposition in a quantum bit (qubit) through interaction with its environment. Quantum bang-bang control provides a solution by repeatedly applying `kicks' to a qubit, thus disrupting an environmental interaction. However, the speed and precision required for the kick operations has presented an obstacle to experimental realization. Here we demonstrate a phase gate of unprecedented speed on a nuclear spin qubit in a fullerene molecule (N@C60), and use it to bang-bang decouple the qubit from a strong environmental interaction. We can thus trap the qubit in closed cycles on the Bloch sphere, or lock it in a given state for an arbitrary period. Our procedure uses operations on a second qubit, an electron spin, in order to generate an arbitrary phase on the nuclear qubit. We anticipate the approach will be vital for QIP technologies, especially at the molecular scale where other strategies, such as electrode switching, are unfeasible

What do patients really know? An evaluation of patients’ physical activity guideline knowledge within general practice

Background: Physical inactivity is well recognised as one of the leading causes of preventable death. However, little is known about the general public’s knowledge surrounding national physical activity guidelines, particularly within general practice (GP). Setting: Two GPs (York and Maidenhead, UK). Question: Are GP patients aware of the national physical guidelines? Also, are health care professionals routinely raising the issue of physical inactivity and would patients welcome support from health care professionals regarding inactivity? Methodology: A questionnaire was distributed in two GPs over a one-week period to evaluate patients knowledge of the national physical activity guidelines. Results: Ninety-four participants completed the questionnaire over one week (60 female; 34 male), with an average age of 54.2 (standard deviation: 19.9 years). 14% (95% Confidence Interval (CI): 8–22%) of the total participants correctly knew the recommended national guidelines for physical activity. 52% (95% CI: 42–63%) recalled being asked by a health care professional about their activity levels. 46% (95% CI: 35–56%) would welcome support from a health care professional around improving their activity levels. Discussion/Conclusion: Only 14% of responders correctly knew the current national minimum activity guidelines. Encouragingly 46% of participants in our study were interested in physical activity advice from a health care professional. Health care professionals need to be aware that many patients do not know the current physical activity guidelines and recognise that primary care may be an underutilised opportunity to educate and promote physical activity

Deforestation-induced climate change reduces carbon storage in remaining tropical forests

Biophysical effects from deforestation have the potential to amplify carbon losses but are often neglected in carbon accounting systems. Here we use both Earth system model simulations and satellite–derived estimates of aboveground biomass to assess losses of vegetation carbon caused by the influence of tropical deforestation on regional climate across different continents. In the Amazon, warming and drying arising from deforestation result in an additional 5.1 ± 3.7% loss of aboveground biomass. Biophysical effects also amplify carbon losses in the Congo (3.8 ± 2.5%) but do not lead to significant additional carbon losses in tropical Asia due to its high levels of annual mean precipitation. These findings indicate that tropical forests may be undervalued in carbon accounting systems that neglect climate feedbacks from surface biophysical changes and that the positive carbon–climate feedback from deforestation-driven climate change is higher than the feedback originating from fossil fuel emissions