Human papillomavirus E2 regulates SRSF3 (SRp20) to promote capsid protein expression in infected differentiated keratinocytes

The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelial cell suggesting a sophisticated interplay between host cell metabolism and virus replication. Previously we demonstrated in differentiated keratinocytes in vitro and in vivo that HPV16 infection caused increased levels of the cellular SR splicing factors (SRSFs) SRSF1 (ASF/SF2), SRSF2 (SC35) and SRSF3 (SRp20). Moreover, the viral E2 transcription and replication factor that is expressed at high levels in differentiating keratinocytes could bind and control activity of the SRSF1 gene promoter. Here we reveal that E2 proteins of HPV16 and HPV31 control expression of SRSFs 1, 2 and 3 in a differentiation-dependent manner. E2 has the greatest trans-activation effect on expression of SRSF3. siRNA depletion experiments in two different models of the HPV16 life cycle (W12E and NIKS16) and one model of the HPV31 life cycle (CIN612-9E) revealed that only SRSF3 contributed significantly to regulation of late events in the virus life cycle. Increased levels of SRSF3 are required for L1 mRNA and capsid protein expression. Capsid protein expression was regulated specifically by SRSF3 and appeared independent of other SRSFs. Taken together these data suggest a significant role of the HPV E2 protein in regulating late events in the HPV life cycle through transcriptional regulation of SRSF3 expression. IMPORTANCE Human papillomavirus replication is accomplished in concert with differentiation of the infected epithelium. Virus capsid protein expression is confined to the upper epithelial layers so as to avoid immune detection. In this study we demonstrate that the viral E2 transcription factor activates the promoter of the cellular SRSF3 RNA processing factor. SRSF3 is required for expression of the E4̂L1 mRNA and so controls expression of the HPV L1 capsid protein. Thus we reveal a new dimension of virus-host interaction crucial for production of infectious virus. SRSF proteins are known drug targets. Therefore, this study provides an excellent basis for developing strategies to regulate capsid protein production in the infected epithelium and production of new virions

Berry phases for composite fermions: effective magnetic field and fractional statistics

The quantum Hall superfluid is presently the only viable candidate for a realization of quasiparticles with fractional Berry phase statistics. For a simple vortex excitation, relevant for a subset of fractional Hall states considered by Laughlin, non-trivial Berry phase statistics were demonstrated many years ago by Arovas, Schrieffer, and Wilczek. The quasiparticles are in general more complicated, described accurately in terms of excited composite fermions. We use the method developed by Kjonsberg, Myrheim and Leinaas to compute the Berry phase for a single composite-fermion quasiparticle, and find that it agrees with the effective magnetic field concept for composite fermions. We then evaluate the "fractional statistics", related to the change in the Berry phase for a closed loop caused by the insertion of another composite-fermion quasiparticle in the interior. Our results support the general validity of fractional statistics in the quantum Hall superfluid, while also giving a quantitative account of corrections to it when the quasiparticle wave functions overlap. Many caveats, both practical and conceptual, are mentioned that will be relevant to an experimental measurement of the fractional statistics. A short report on some parts of this article has appeared previously.Comment: 14 pages, 9 figure

Dosing regimen of meropenem for adults with severe burns : a population pharmacokinetic study with Monte Carlo simulations

Objectives To develop a population model to describe the pharmacokinetics (PK) of intravenous meropenem in adult patients with severe burns and investigate potential relationships between dosage regimens and antimicrobial efficacy.Patients and methods A dose of 1 g every 8 h was administered to adult patients with total body surface area burns of ≥15%. Doses for subsequent courses were determined using results from the initial course and the patient's clinical condition. Five plasma meropenem concentrations were typically measured over the dosage interval on one to four occasions. An open, two-compartment PK model was fitted to the meropenem concentrations using NONMEM and the effect of covariates on meropenem PK was investigated. Monte Carlo simulations investigated dosage regimens to achieve a target T>MIC for ≥40%, ≥60% or ≥80% of the dose interval.Results Data comprised 113 meropenem concentration measurements from 20 dosage intervals in 12 patients. The parameters were CL (L/h) = 0.196 L/h/kg × [1 − 0.023 × (age − 46)] × [1 − 0.049 × (albumin − 15)], V1 = 0.273 L/kg × [1 − 0.049 × (albumin − 15)], Q = 0.199 L/h/kg and V2 = 0.309 L/kg × [1 – 0.049 × (albumin − 15)]. For a target of ≥80% T>MIC, the breakpoint was 8 mg/L for doses of 1 g every 4 h and 2 g every 8 h given over 3 h, but only 4 mg/L if given over 5 min.Conclusions Although 1 g 8 hourly should be effective against Escherichia coli and CoNS, higher doses, ideally with a longer infusion time, would be more appropriate for empirical therapy, mixed infections and bacteria with MIC values ≥4 mg/L

Galaxy And Mass Assembly (GAMA) : stellar mass functions by Hubble type

This work was supported by the Austrian Science Foundation FWF under grant P23946. AWG was supported under the Australian Research Council's funding scheme FT110100263.We present an estimate of the galaxy stellar mass function and its division by morphological type in the local (0.025 < z < 0.06) Universe. Adopting robust morphological classifications as previously presented (Kelvin et al.) for a sample of 3727 galaxies taken from the Galaxy And Mass Assembly survey, we define a local volume and stellar mass limited sub-sample of 2711 galaxies to a lower stellar mass limit of M = 109.0 MΘ. We confirm that the galaxy stellar mass function is well described by a double-Schechter function given by Μ* = 1010.64 MΘ, α1 = 0.43, φ1* = 4.18 dex-1 Mpc-3, α2 = −1.50 and φ2* = 0.74 dex-1 Mpc-3. The constituent morphological-type stellar mass functions are well sampled above our lower stellar mass limit, excepting the faint little blue spheroid population of galaxies. We find approximately 71-4+3 per cent of the stellar mass in the local Universe is found within spheroid-dominated galaxies; ellipticals and S0-Sas. The remaining 29-3+4 per cent falls predominantly within late-type disc-dominated systems, Sab-Scds and Sd-Irrs. Adopting reasonable bulge-to-total ratios implies that approximately half the stellar mass today resides in spheroidal structures, and half in disc structures. Within this local sample, we find approximate stellar mass proportions for E : S0-Sa : Sab-Scd : Sd-Irr of 34 : 37 : 24 :5.Publisher PDFPeer reviewe

White matter abnormalities in active elite adult rugby players

The recognition, diagnosis and management of mild traumatic brain injuries is difficult and confusing. It is unclear how the severity and number of injuries sustained relate to brain injuries such as diffuse axonal injury, diffuse vascular injury and progressive neurodegeneration. Advances in neuroimaging techniques enable the investigation of neuropathologies associated with acute and long-term effects of injury. Head injuries are the most commonly reported injury seen during professional rugby. There is increased vigilance for the immediate effects of these injuries in matches, but there has been surprisingly little research investigating the longer-term effects of rugby participation. Here we present a longitudinal observational study investigating the relationship of exposure to rugby participation and sub-acute head injuries in professional adult male and female rugby union and league players using advanced MRI. Diffusion tensor imaging and susceptibility weighted imaging was used to assess white matter structure and evidence of axonal and diffuse vascular injury. We also studied changes in brain structure over time using Jacobian Determinant statistics extracted from serial volumetric imaging. We tested 41 male and 3 female adult elite rugby players, of whom 21 attended study visits after a head injury, alongside 32 non-sporting controls, 15 non-collision-sport athletic controls and 16 longitudinally assessed controls. 18 rugby players participated in the longitudinal arm of the study, with a second visit at least 6 months after their first scan. Neuroimaging evidence of either axonal injury or diffuse vascular injury was present in 23% (10/44) of players. In the non-acutely injured group of rugby players, abnormalities of fractional anisotropy and other diffusion measures were seen. In contrast, non-collision-sport athletic controls were not classified as showing abnormalities. A group level contrast also showed evidence of sub-acute injury using diffusion tensor imaging in rugby players. Examination of longitudinal imaging revealed unexpected reductions in white matter volume in the elite rugby players studied. These changes were not related to self-reported head injury history or neuropsychological test scores and might indicate excess neurodegeneration in white matter tracts affected by injury. Taken together, our findings suggest an association of participation in elite adult rugby with changes in brain structure. Further well-designed large scale studies are needed to understand the impact of both repeated sports related head impacts and head injuries on brain structure, and to clarify whether the abnormalities we have observed are related to an increased risk of neurodegenerative disease and impaired neurocognitive function following elite rugby participation

White matter abnormalities in active elite adult rugby players

The recognition, diagnosis and management of mild traumatic brain injuries are difficult and confusing. It is unclear how the severity and number of injuries sustained relate to brain injuries, such as diffuse axonal injury, diffuse vascular injury and progressive neurodegeneration. Advances in neuroimaging techniques enable the investigation of neuropathologies associated with acute and long-term effects of injury. Head injuries are the most commonly reported injury seen during professional rugby. There is increased vigilance for the immediate effects of these injuries in matches, but there has been surprisingly little research investigating the longer-term effects of rugby participation. Here, we present a longitudinal observational study investigating the relationship of exposure to rugby participation and sub-acute head injuries in professional adult male and female rugby union and league players using advanced MRI. Diffusion tensor imaging and susceptibility weighted imaging was used to assess white matter structure and evidence of axonal and diffuse vascular injury. We also studied changes in brain structure over time using Jacobian Determinant statistics extracted from serial volumetric imaging. We tested 41 male and 3 female adult elite rugby players, of whom 21 attended study visits after a head injury, alongside 32 non-sporting controls, 15 non-collision-sport athletic controls and 16 longitudinally assessed controls. Eighteen rugby players participated in the longitudinal arm of the study, with a second visit at least 6 months after their first scan. Neuroimaging evidence of either axonal injury or diffuse vascular injury was present in 23% (10/44) of players. In the non-acutely injured group of rugby players, abnormalities of fractional anisotropy and other diffusion measures were seen. In contrast, non-collision-sport athletic controls were not classified as showing abnormalities. A group level contrast also showed evidence of sub-acute injury using diffusion tensor imaging in rugby players. Examination of longitudinal imaging revealed unexpected reductions in white matter volume in the elite rugby players studied. These changes were not related to self-reported head injury history or neuropsychological test scores and might indicate excess neurodegeneration in white matter tracts affected by injury. Taken together, our findings suggest an association of participation in elite adult rugby with changes in brain structure. Further well-designed large-scale studies are needed to understand the impact of both repeated sports-related head impacts and head injuries on brain structure, and to clarify whether the abnormalities we have observed are related to an increased risk of neurodegenerative disease and impaired neurocognitive function following elite rugby participation

Galaxy And Mass Assembly (GAMA) : refining the local galaxy merger rate using morphological information

KRVS acknowledges the Science and Technology Facilities Council (STFC) for providing funding for this project, as well as the Government of Catalonia for a research travel grant (ref. 2010 BE-00268) to begin this project at the University of Nottingham. PN acknowledges the support of the Royal Society through the award of a University Research Fellowship and the European Research Council, through receipt of a Starting Grant (DEGAS-259586).We use the Galaxy And Mass Assembly (GAMA) survey to measure the local Universe mass-dependent merger fraction and merger rate using galaxy pairs and the CAS (concentration, asymmetry, and smoothness) structural method, which identifies highly asymmetric merger candidate galaxies. Our goals are to determine which types of mergers produce highly asymmetrical galaxies and to provide a new measurement of the local galaxy major merger rate. We examine galaxy pairs at stellar mass limits down to M* = 108 M⊙ with mass ratios of 4:1) the lower mass companion becomes highly asymmetric, whereas the larger galaxy is much less affected. The fraction of highly asymmetric paired galaxies which have a major merger companion is highest for the most massive galaxies and drops progressively with decreasing mass. We calculate that the mass-dependent major merger fraction is fairly constant at ∼1.3–2 per cent within 109.5 < M* < 1011.5 M⊙, and increases to ∼4 per cent at lower masses. When the observability time-scales are taken into consideration, the major merger rate is found to approximately triple over the mass range we consider. The total comoving volume major merger rate over the range 108.0 < M* < 1011.5 M⊙ is (1.2 ± 0.5) × 10−3 h370 Mpc−3 Gyr−1.Publisher PDFPeer reviewe

Gender differentials in the evolution of cigarette smoking habits in a general European adult population from 1993–2003

BACKGROUND: Describe the recent evolution of cigarette smoking habits by gender in Geneva, where incidence rates of lung cancer have been declining in men but increasing in women. METHODS: Continuous cross-sectional surveillance of the general adult (35–74 yrs) population of Geneva, Switzerland for 11 years (1993–2003) using a locally-validated smoking questionnaire, yielding a representative random sample of 12,271 individuals (6,164 men, 6,107 women). RESULTS: In both genders, prevalence of current cigarette smoking was stable over the 11-year period, at about one third of men and one quarter of women, even though smoking began at an earlier age in more recent years. Older men were more likely to be former smokers than older women. Younger men, but not women, tended to quit smoking at an earlier age. CONCLUSION: This continuous (1993–2003) risk factor surveillance system, unique in Europe, shows stable prevalence of smoking in both genders. However, sharp contrasts in age-specific prevalence of never and former smoking and of ages at smoking initiation indicate that smoking continues a long-term decline in men but has still not reached its peak in women

Effects of dietary salt on gene and protein expression in brain tissue of a model of sporadic small vessel disease

Background: The effect of salt on cerebral small vessel disease (SVD) is poorly understood. We assessed the effect of dietary salt on the cerebral tissue of the strokeprone spontaneously hypertensive rat (SHRSP) - a relevant model of sporadic SVD - at both the gene and protein level. Methods: Brains from 21 week old SHRSP and Wistar-Kyoto rats, half additionally salt-loaded (via a 3 week regime of 1% NaCl in drinking water) were split into 2 hemispheres and sectioned coronally – one hemisphere for mRNA microarray and qRT-PCR, the other for immunohistochemistry using a panel of antibodies targeting components of the neurovascular unit. Results: We observed differences in gene and protein expression affecting the acute phase pathway and oxidative stress (ALB, AMBP, APOH, AHSG and LOC100129193, up-regulated in salt-loaded WKY versus WKY, &gt;2-fold), active microglia (increased Iba-1 protein expression in salt-loaded SHRSP versus saltloaded WKY, p&lt;0.05), vascular structure (ACTB &amp; CTNNB, up-regulated in saltloaded SHRSP versus SHRSP, &gt;3-fold; CLDN-11,VEGF and VGF downregulated &gt;- 2-fold in salt-loaded SHRSP versus SHRSP) and myelin integrity (MBP downregulated in salt loaded WKY rats versus WKY, &gt;2.5-fold). Changes of salt-loading were more pronounced in SHRSP and occurred without an increase in blood pressure in WKY rats. Conclusion: Salt exposure induced changes in gene and protein expression in an experimental model of SVD and its parent rat strain in multiple pathways involving components of the glio-vascular unit. Further studies in pertinent experimental models at different ages would help clarify the short and long-term effect of dietary salt in SVD

Transformer-based out-of-distribution detection for clinically safe segmentation

In a clinical setting it is essential that deployed image processing systems are robust to the full range of inputs they might encounter and, in particular, do not make confidently wrong predictions. The most popular approach to safe processing is to train networks that can provide a measure of their uncertainty, but these tend to fail for inputs that are far outside the training data distribution. Recently, generative modelling approaches have been proposed as an alternative; these can quantify the likelihood of a data sample explicitly, filtering out any out-of-distribution (OOD) samples before further processing is performed. In this work, we focus on image segmentation and evaluate several approaches to network uncertainty in the far-OOD and near-OOD cases for the task of segmenting haemorrhages in head CTs. We find all of these approaches are unsuitable for safe segmentation as they provide confidently wrong predictions when operating OOD. We propose performing full 3D OOD detection using a VQ-GAN to provide a compressed latent representation of the image and a transformer to estimate the data likelihood. Our approach successfully identifies images in both the far- and near-OOD cases. We find a strong relationship between image likelihood and the quality of a model’s segmentation, making this approach viable for filtering images unsuitable for segmentation. To our knowledge, this is the first time transformers have been applied to perform OOD detection on 3D image data.</p