Core binding factor (CBF) is required for Epstein-Barr virus EBNA3 proteins to regulate target gene expression

ChIP-seq performed on lymphoblastoid cell lines (LCLs), expressing epitope-tagged EBNA3A, EBNA3B or EBNA3C from EBV-recombinants, revealed important principles of EBNA3 binding to chromatin. When combined with global chromatin looping data, EBNA3-bound loci were found to have a singular character, each directly associating with either EBNA3-repressed or EBNA3-activated genes, but not with both. EBNA3A and EBNA3C showed significant association with repressed and activated genes. Significant direct association for EBNA3B loci could only be shown with EBNA3B-repressed genes. A comparison of EBNA3 binding sites with known transcription factor binding sites in LCL GM12878 revealed substantial co-localization of EBNA3s with RUNX3-a protein induced by EBV during B cell transformation. The beta-subunit of core binding factor (CBFβ), that heterodimerizes with RUNX3, could co-immunoprecipitate robustly EBNA3B and EBNA3C, but only weakly EBNA3A. Depletion of either RUNX3 or CBFβ with lentivirus-delivered shRNA impaired epitope-tagged EBNA3B and EBNA3C binding at multiple regulated gene loci, indicating a requirement for CBF heterodimers in EBNA3 recruitment during target-gene regulation. ShRNA-mediated depletion of CBFβ in an EBNA3C-conditional LCL confirmed the role of CBF in the regulation of EBNA3C-induced and -repressed genes. These results reveal an important role for RUNX3/CBF during B cell transformation and EBV latency that was hitherto unexplored

Strength of the dominant upper and lower extremities predicts skeletal muscle mass irrespective of age and gender

Background: Sarcopenia is characterised by losses in muscle mass, strength and function. It is a contributing factor to numerous non-communicable diseases and frailty. Screening for sarcopenia typically requires measurements of handgrip strength, functional performance, and skeletal muscle mass. However, available tools do not tend to measure strength of the lower extremities. The aim of this study was to investigate associations between these measures and lower extremity strength with skeletal muscle mass in healthy young and older adults. Methods: Fifty younger (mean ± SD age = 22.7 ± 5.4 years) and 50 older (age = 69.9 ± 4.3 years) individuals received the following measurements after an overnight fast: Skeletal Muscle Index (SMI) derived by dual-energy X-ray absorptiometry, gait speed, handgrip strength (HGS), and unilateral one-repetition maximum (1RM) leg extension strength. Muscle quality (MQ), was also determined as the ratio of grip strength to appendicular lean mass of the upper body. Results: One older female and one older male were pre-sarcopenic and sarcopenic. Upper extremity MQ was below established cutpoints in 21 older participants. SMI was positively associated with upper and lower extremity strength in all groups except older men, and negatively associated with upper extremity MQ in young males. By multiple regression analysis, dominant HGS and dominant leg extension 1RM strength predicted SMI in the complete sample, accounting for 70.3% of the variance (B = 0.469 and 0.421, respectively; P < 0.00001). The equation for SMI is as follows: 4.568 + 0.025 x dominant leg extension 1RM + 0.059 x dominant grip strength. Discussion: Since muscle mass is the foremost variable in determining sarcopenia, we support the inclusion of lower extremity strength testing in addition to that of handgrip strength to enable better prediction of SMI in both older and younger individuals. MQ determination is also recommended since established algorithms may fail to identify individuals with muscle weakness

Stress biomarker changes following a series of repeated static and dynamic apneas in non-divers

Purpose This study examined the magnitude of physiological strain imposed by repeated maximal static and dynamic apneas through assessing a panel of stress-related biomarkers. Methods Eleven healthy men performed on three separate occasions (≥72-h apart): a series of five repeated maximal (i) static (STA) or (ii) dynamic apneas (DYN) or (iii) a static eupneic protocol (CTL). Venous blood samples were drawn at 30, 90, and 180-min after each protocol to determine ischaemia modified albumin (IMA), neuron-specific enolase (NSE), myoglobin, and high sensitivity cardiac troponin T (hscTnT) concentrations. Results IMA was elevated after the apnoeic interventions (STA,+86%;DYN,+332%,p ≤ 0.047) but not CTL (p = 0.385). Myoglobin was higher than baseline (23.6 ± 3.9 ng/mL) 30-min post DYN (+70%,38.8 ± 13.3 ng/mL,p = 0.030). A greater myoglobin release was recorded in DYN compared with STA and CTL (p ≤ 0.035). No changes were observed in NSE (p = 0.207) or hscTnT (p = 0.274). Conclusions Five repeated maximal DYN led to a greater muscle injury compared with STA but neither elicited myocardial injury or neuronal-parenchymal damage

Amniotic fluid volume: Rapid MR-based assessment at 28-32 weeks gestation.

OBJECTIVES: This work evaluates rapid magnetic resonance projection hydrography (PH) based amniotic fluid volume (AFV) estimates against established routine ultrasound single deepest vertical pocket (SDVP) and amniotic fluid index (AFI) measurements, in utero at 28-32 weeks gestation. Manual multi-section planimetry (MSP) based measurement of AFV is used as a proxy reference standard. METHODS: Thirty-five women with a healthy singleton pregnancy (20-41 years) attending routine antenatal ultrasound were recruited. SDVP and AFI were measured using ultrasound, with same day MRI assessing AFV with PH and MSP. The relationships between the respective techniques were assessed using linear regression analysis and Bland-Altman method comparison statistics. RESULTS: When comparing estimated AFV, a highly significant relationship was observed between PH and the reference standard MSP (R(2) = 0.802, p < 0.001). For the US measurements, SDVP measurement related most closely to amniotic fluid volume, (R(2) = 0.470, p < 0.001), with AFI demonstrating a weaker relationship (R(2) = 0.208, p = 0.007). CONCLUSION: This study shows that rapid MRI based PH measurement is a better predictor of AFV, relating more closely to our proxy standard than established US techniques. Although larger validation studies across a range of gestational ages are required this approach could form part of MR fetal assessment, particularly where poly- or oligohydramnios is suspected. KEY POINTS: • MR projection hydrography can be used to estimate amniotic fluid volume. • MR projection hydrography relies on the T2w signal from amniotic fluid. • Amniotic fluid volume (AFV) is more accurately assessed than with ultrasound.This study was supported by the National Institute of Health Research, Cambridge Biomedical Research Centre. The authors also acknowledge the support of Addenbrooke’s Charitable Trust and thank the participants for their contribution to the study.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00330-015-4179-

Magnetic monopole density and antiferromagnetic domain control in spin-ice iridates.

Magnetically frustrated systems provide fertile ground for complex behaviour, including unconventional ground states with emergent symmetries, topological properties, and exotic excitations. A canonical example is the emergence of magnetic-charge-carrying quasiparticles in spin-ice compounds. Despite extensive work, a reliable experimental indicator of the density of these magnetic monopoles is yet to be found. Using measurements on single crystals of Ho2Ir2O7 combined with dipolar Monte Carlo simulations, we show that the isothermal magnetoresistance is highly sensitive to the monopole density. Moreover, we uncover an unexpected and strong coupling between the monopoles on the holmium sublattice and the antiferromagnetically ordered iridium ions. These results pave the way towards a quantitative experimental measure of monopole density and demonstrate the ability to control antiferromagnetic domain walls using a uniform external magnetic field, a key goal in the design of next-generation spintronic devices

Is transcranial sonography useful to distinguish scans without evidence of dopaminergic deficit patients from Parkinson's disease?

BACKGROUND: Approximately 10% of patients clinically diagnosed with early Parkinson's disease (PD) subsequently have normal dopaminergic functional imaging. Transcranial sonography (TCS) has been shown to detect midbrain hyperechogenicity in approximately 90% of Parkinson's disease (PD) patients and 10% of the healthy population. The aim of this study was to investigate the prevalence of midbrain hyperechogenicity in patients with suspected parkinsonism and scans without evidence of dopaminergic deficit (SWEDD), in comparison to PD patients. METHODS: TCS was performed in 14 patients with SWEDD and 19 PD patients. RESULTS: There was a significantly increased area of echogenicity in the PD group (0.24 ± 0.06 cm(2) ), compared to the group of patients with SWEDD (0.13 ± 0.06 cm(2) ; P < 0.001). One (9.1%) of these patients, compared to 14 (82.5%) of the PD patients, was found to have hyperechogenicity (P < 0.001). CONCLUSIONS: We conclude that TCS is useful to distinguish PD patients from patients with suspected parkinsonism and SWEDD

Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling

PK/PD integration data. (DOCX 7 kb

Skeletal muscle, haematological and splenic volume characteristics of elite breath-hold divers

Purpose The aim of the study was to provide an evaluation of the oxygen transport, exchange and storage capacity of elite breath-hold divers (EBHD) compared with non-divers (ND). Methods Twenty-one healthy males’ (11 EBHD; 10 ND) resting splenic volumes were assessed by ultrasound and venous blood drawn for full blood count analysis. Percutaneous skeletal muscle biopsies were obtained from the m. vastus lateralis to measure capillarisation, and fibre type-specific localisation and distribution of myoglobin and mitochondrial content using quantitative immunofluorescence microscopy. Results Splenic volume was not different between groups. Reticulocytes, red blood cells and haemoglobin concentrations were higher (+ 24%, p < 0.05; + 9%, p < 0.05; + 3%, p < 0.05; respectively) and mean cell volume was lower (− 6.5%, p < 0.05) in the EBHD compared with ND. Haematocrit was not different between groups. Capillary density was greater (+ 19%; p < 0.05) in the EBHD. The diffusion distance (R95) was lower in type I versus type II fibres for both groups (EBHD, p < 0.01; ND, p < 0.001), with a lower R95 for type I fibres in the EBHD versus ND (− 13%, p < 0.05). Myoglobin content was higher in type I than type II fibres in EBHD (+ 27%; p < 0.01) and higher in the type I fibres of EBHD than ND (+ 27%; p < 0.05). No fibre type differences in myoglobin content were observed in ND. Mitochondrial content was higher in type I than type II fibres in EBHD (+ 35%; p < 0.05), with no fibre type differences in ND or between groups. Conclusions In conclusion, EBDH demonstrate enhanced oxygen storage in both blood and skeletal muscle and a more efficient oxygen exchange capacity between blood and skeletal muscle versus ND