A Phospho-SIM in the Antiviral Protein PML is Required for Its Recruitment to HSV-1 Genomes

Herpes simplex virus type 1 (HSV-1) is a significant human pathogen that infects a large portion of the human population. Cells deploy a variety of defenses to limit the extent to which the virus can replicate. One such factor is the promyelocytic leukemia (PML) protein, the nucleating and organizing factor of nuclear domain 10 (ND10). PML responds to a number of stimuli and is implicated in intrinsic and innate cellular antiviral defenses against HSV-1. While the role of PML in a number of cellular pathways is controlled by post-translational modifications, the effects of phosphorylation on its antiviral activity toward HSV-1 have been largely unexplored. Consequently, we mapped phosphorylation sites on PML, mutated these and other known phosphorylation sites on PML isoform I (PML-I), and examined their effects on a number of PML’s activities. Our results show that phosphorylation at most sites on PML-I is dispensable for the formation of ND10s and colocalization between PML-I and the HSV-1 regulatory protein, ICP0, which antagonizes PML-I function. However, inhibiting phosphorylation at sites near the SUMO-interaction motif (SIM) of PML-I impairs its ability to respond to HSV-1 infection. Overall, our data suggest that PML phosphorylation regulates its antiviral activity against HSV-1

Neural responses to facial and vocal expressions of fear and disgust

Neuropsychological studies report more impaired responses to facial expressions of fear than disgust in people with amygdala lesions, and vice versa in people with Huntington's disease. Experiments using functional magnetic resonance imaging (fMRI) have confirmed the role of the amygdala in the response to fearful faces and have implicated the anterior insula in the response to facial expressions of disgust. We used fMRI to extend these studies to the perception of fear and disgust from both facial and vocal expressions. Consistent with neuropsychological findings, both types of fearful stimuli activated the amygdala. Facial expressions of disgust activated the anterior insula and the caudate-putamen; vocal expressions of disgust did not significantly activate either of these regions. All four types of stimuli activated the superior temporal gyrus. Our findings therefore (i) support the differential localization of the neural substrates of fear and disgust; (ii) confirm the involvement of the amygdala in the emotion of fear, whether evoked by facial or vocal expressions; (iii) confirm the involvement of the anterior insula and the striatum in reactions to facial expressions of disgust; and (iv) suggest a possible general role for the perception of emotional expressions for the superior temporal gyrus

Confirmatory factor analysis of the Test of Performance Strategies (TOPS) among adolescent athletes

The aim of the present study was to examine the factorial validity of the Test of Performance Strategies (TOPS; Thomas et al., 1999) among adolescent athletes using confirmatory factor analysis. The TOPS was designed to assess eight psychological strategies used in competition (i.e. activation, automaticity, emotional control, goal-setting, imagery, negative thinking, relaxation and self-talk,) and eight used in practice (the same strategies except negative thinking is replaced by attentional control). National-level athletes (n = 584) completed the 64-item TOPS during training camps. Fit indices provided partial support for the overall measurement model for the competition items (robust comparative fit index = 0.92, Tucker-Lewis index = 0.88, root mean square error of approximation = 0.05) but minimal support for the training items (robust comparative fit index = 0.86, Tucker-Lewis index = 0.81, root mean square error of approximation = 0.06). For the competition items, the automaticity, goal-setting, relaxation and self-talk scales showed good fit, whereas the activation, emotional control, imagery and negative thinking scales did not. For the practice items, the attentional control, emotional control, goal-setting, imagery and self-talk scales showed good fit, whereas the activation, automaticity and relaxation scales did not. Overall, it appears that the factorial validity of the TOPS for use with adolescents is questionable at present and further development is required

Geographies of outer space: progress and new opportunities

Research into outer space has burgeoned in recent years, through the work of scholars in the social sciences, arts and humanities. Geographers have made a series of useful contributions to this emergent work, however scholarship remains fairly limited in comparison to other disciplinary fields. This Forum explains the scholarly roots of these new geographies of outer space, considering why and how geographies of outer space could make further important contributions. The Forum invites reflections from political, environmental, historical and cultural geographers to show how human geography can present future avenues to continued scholarship into outer space

Individual and joint trajectories of change in bone, lean mass and physical performance in older men.

BackgroundDeclines in bone, muscle and physical performance are associated with adverse health outcomes in older adults. However, few studies have described concurrent age-related patterns of change in these factors. The purpose of this study was to characterize change in four properties of muscle, physical performance, and bone in a prospective cohort study of older men.MethodsUsing repeated longitudinal data from up to four visits across 6.9 years from up to 4681 men (mean age at baseline 72.7 yrs. ±5.3) participating in the Osteoporotic Fractures in Men (MrOS) Study, we used group-based trajectory models (PROC TRAJ in SAS) to identify age-related patterns of change in four properties of muscle, physical performance, and bone: total hip bone mineral (BMD) density (g/m2) and appendicular lean mass/ht2 (kg/m2), by DXA; grip strength (kg), by hand dynamometry; and walking speed (m/s), by usual walking pace over 6 m. We also described joint trajectories in all pair-wise combinations of these measures. Mean posterior probabilities of placement in each trajectory (or joint membership in latent groups) were used to assess internal reliability of the model. The number of trajectories for each individual factor was limited to three, to ensure that the pair-wise determination of joint trajectories would yield a tractable number of groups as well as model fit considerations.ResultsThe patterns of change identified were generally similar for all measures, with three district groups declining over time at roughly similar rates; joint trajectories revealed similar patterns with no cross-over or convergence between groups. Mean posterior probabilities for all trajectories were similar and consistently above 0.8 indicating reasonable model fit to the data.ConclusionsOur description of trajectories of change with age in bone mineral density, grip strength, walking speed and appendicular lean mass found that groups identified by these methods appeared to have little crossover or convergence of change with age, even when considering joint trajectories of change in these factors

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

Lessons learnedThe addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.BackgroundThis randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.MethodsPatients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).ResultsOne hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen.ConclusionAddition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup

Exfoliated Nanocomposites Based on Polyaniline and Tungsten Disulfide

Nanocomposite materials consisting of polyaniline (PANI) and exfoliated WS2 were synthesized. The WS2 was prepared by reacting tungstic acid with thiourea at 500°C under nitrogen flow. Samples were prepared with a WS2 content of 1, 5, 7.5, 10, 12.5, 15, 20, 37, and 64% by mass. An improvement in the electronic conductivity value of the PANI was observed through the incorporation of exfoliated WS2. The electronic conductivity of PANI-15%WS2 was 24.5 S/cm, an eightfold increase when compared to pure PANI. Powder X-ray diffraction (XRD), transmission electron microscopy (TEM) and electron paramagnetic resonance (EPR) provided evidence that the nanocomposites are in an exfoliated state. XRD and TEM showed that the nanocomposites were completely amorphous, suggesting lack of structural order in these materials, while their EPR signals were considerably narrower compared to pure PANI, indicating the formation of genuine exfoliated systems. Furthermore, our research showed that WS2 can be used as a filler to improve activation energy of decomposition of the polymer. By using the Ozawa method, we studied the decomposition kinetics for the nanocomposites, as well as for the pure polymer. The activation energy for the decomposition of pure PANI was found to be 131.2 kJ/mol. Increasing the amount of WS2 to 12.5% in the PANI increases the activation energy of decomposition to 165.4 kJ/mol, an enhancement of 34.2 kJ/mol over the pure polymer

Stable Isotope-Resolved Metabolomics Shows Metabolic Resistance to Anti-Cancer Selenite in 3D Spheroids Versus 2D Cell Cultures

Conventional two-dimensional (2D) cell cultures are grown on rigid plastic substrates with unrealistic concentration gradients of O2, nutrients, and treatment agents. More importantly, 2D cultures lack cell–cell and cell–extracellular matrix (ECM) interactions, which are critical for regulating cell behavior and functions. There are several three-dimensional (3D) cell culture systems such as Matrigel, hydrogels, micropatterned plates, and hanging drop that overcome these drawbacks but they suffer from technical challenges including long spheroid formation times, difficult handling for high throughput assays, and/or matrix contamination for metabolic studies. Magnetic 3D bioprinting (M3DB) can circumvent these issues by utilizing nanoparticles that enable spheroid formation and growth via magnetizing cells. M3DB spheroids have been shown to emulate tissue and tumor microenvironments while exhibiting higher resistance to toxic agents than their 2D counterparts. It is, however, unclear if and how such 3D systems impact cellular metabolic networks, which may determine altered toxic responses in cells. We employed a Stable Isotope-Resolved Metabolomics (SIRM) approach with 13C6-glucose as tracer to map central metabolic networks both in 2D cells and M3DB spheroids formed from lung (A549) and pancreatic (PANC1) adenocarcinoma cells without or with an anti-cancer agent (sodium selenite). We found that the extent of 13C-label incorporation into metabolites of glycolysis, the Krebs cycle, the pentose phosphate pathway, and purine/pyrimidine nucleotide synthesis was largely comparable between 2D and M3DB culture systems for both cell lines. The exceptions were the reduced capacity for de novo synthesis of pyrimidine and sugar nucleotides in M3DB than 2D cultures of A549 and PANC1 cells as well as the presence of gluconeogenic activity in M3DB spheroids of PANC1 cells but not in the 2D counterpart. More strikingly, selenite induced much less perturbation of these pathways in the spheroids relative to the 2D counterparts in both cell lines, which is consistent with the corresponding lesser effects on morphology and growth. Thus, the increased resistance of cancer cell spheroids to selenite may be linked to the reduced capacity of selenite to perturb these metabolic pathways necessary for growth and survival

Recruitment of ethnic minority patients to a cardiac rehabilitation trial: The Birmingham Rehabilitation Uptake Maximisation (BRUM) study [ISRCTN72884263]

Background: Concerns have been raised about low participation rates of people from minority ethnic groups in clinical trials. However, the evidence is unclear as many studies do not report the ethnicity of participants and there is insufficient information about the reasons for ineligibility by ethnic group. Where there are data, there remains the key question as to whether ethnic minorities more likely to be ineligible (e.g. due to language) or decline to participate. We have addressed these questions in relation to the Birmingham Rehabilitation Uptake Maximisation (BRUM) study, a randomized controlled trial (RCT) comparing a home-based with a hospital-based cardiac rehabilitation programme in a multi-ethnic population in the UK. Methods: Analysis of the ethnicity, age and sex of presenting and recruited subjects for a trial of cardiac rehabilitation in the West-Midlands, UK. Participants: 1997 patients presenting post-myocardial infarction, percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery. Data collected: exclusion rates, reasons for exclusion and reasons for declining to participate in the trial by ethnic group. Results: Significantly more patients of South Asian ethnicity were excluded (52% of 'South Asian' v 36% 'White European' and 36% 'Other', p < 0.001). This difference in eligibility was primarily due to exclusion on the basis of language (i.e. the inability to speak English or Punjabi). Of those eligible, similar proportions were recruited from the different ethnic groups (white, South Asian and other). There was a marked difference in eligibility between people of Indian, Pakistani or Bangladeshi origin

Can we trust “Magnitude-based inference”?

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