KSHV-TK is a tyrosine kinase that disrupts focal adhesions and induces Rho-mediated cell contraction.

This is the accepted manuscript. The final version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.15252/embj.201490358/abstract.Paradoxically, the thymidine kinase (TK) encoded by Kaposi sarcoma-associated herpesvirus (KSHV) is an extremely inefficient nucleoside kinase, when compared to TKs from related herpesviruses. We now show that KSHV-TK, in contrast to HSV1-TK, associates with the actin cytoskeleton and induces extensive cell contraction followed by membrane blebbing. These dramatic changes in cell morphology depend on the auto-phosphorylation of tyrosines 65, 85 and 120 in the N-terminus of KSHV-TK. Phosphorylation of tyrosines 65/85 and 120 results in an interaction with Crk family proteins and the p85 regulatory subunit of PI3-Kinase, respectively. The interaction of Crk with KSHV-TK leads to tyrosine phoshorylation of this cellular adaptor. Auto-phosphorylation of KSHV-TK also induces a loss of FAK and paxillin from focal adhesions, resulting in activation of RhoA-ROCK signalling to myosin II and cell contraction. In the absence of FAK or paxillin, KSHV-TK has no effect on focal adhesion integrity or cell morphology. Our observations demonstrate that by acting as a tyrosine kinase, KSHV-TK modulates signalling and cell morphology.This work was supported by Medical Research Council grant G0701185 to PGS and MBG. M.W is supported by Cancer Research UK

Ethnic differences in respiratory impairment

Objective Spirometric Z scores by lambda-mu-sigma (LMS) rigorously account for age-related changes in lung function. Recently, the Global Lung Function Initiative (GLI) expanded LMS spirometric Z scores to multiple ethnicities. Hence, in aging populations, the GLI provides an opportunity to rigorously evaluate ethnic differences in respiratory impairment, including airflow limitation and restrictive pattern. Methods Using data from the Third National Health and Nutrition Examination Survey, including participants aged 40-80, we evaluated ethnic differences in GLI-defined respiratory impairment, including prevalence and associations with mortality and respiratory symptoms. Results Among 3506 white Americans, 1860 African Americans and 1749 Mexican Americans, the prevalence of airflow limitation was 15.1% (13.9% to 16.4%), 12.4% (10.7% to 14.0%) and 8.2% (6.7% to 9.8%), and restrictive pattern was 5.6% (4.6% to 6.5%), 8.0% 6.9% to 9.0%) and 5.7% (4.5% to 6.9%), respectively. Airflow limitation was associated with mortality in white Americans, African Americans and Mexican Americans - adjusted HR (aHR) 1.66 (1.23 to 2.25), 1.60 (1.09 to 2.36) and 1.80 (1.17 to 2.76), respectively, but associated with respiratory symptoms only in white Americans - adjusted OR (aOR) 2.15 (1.70 to 2.73). Restrictive pattern was associated with mortality but only in white Americans and African Americans - aHR 2.56 (1.84 to 3.55) and 3.23 (2.06 to 5.05), and associated with respiratory symptoms but only in white Americans and Mexican Americans-aOR 2.16 (1.51 to 3.07) and .12 (1.45 to 3.08), respectively. Conclusions In an aging population, we found ethnic differences in GLI-defined respiratory impairment. In particular, African Americans had high rates of respiratory impairment that were associated with mortality but not respiratory symptoms

In vivo function of the murid herpesvirus-4 ribonucleotide reductase small subunit

The difficulty of eliminating herpesvirus carriage makes host entry a key target for infection control. However, its viral requirements are poorly defined. Murid herpesvirus-4 (MuHV-4) can potentially provide insights into gammaherpesvirus host entry. Upper respiratory tract infection requires the MuHV-4 thymidine kinase (TK) and ribonucleotide reductase large subunit (RNR-L), suggesting a need for increased nucleotide production. However, both TK and RNR-L are likely to be multifunctional. We therefore tested further the importance of nucleotide production by disrupting the MuHV-4 ribonucleotide reductase small subunit (RNR-S). This caused a similar attenuation to RNR-L disruption: despite reduced intra-host spread, invasive inoculations still established infection, whereas a non-invasive upper respiratory tract inoculation did so only at high dose. Histological analysis showed that RNR-S−, RNR-L− and TK− viruses all infected cells in the olfactory neuroepithelium but unlike wild-type virus then failed to spread. Thus captured host nucleotide metabolism enzymes, up to now defined mainly as important for alphaherpesvirus reactivation in neurons, also have a key role in gammaherpesvirus host entry. This seemed to reflect a requirement for lytic replication to occur in a terminally differentiated cell before a viable pool of latent genomes could be established

HTLV-III Serology in Hemophilia: Relationship with Immunologic Abnormalities

We investigated the relationship of the presence of antibodies to HTLV-III and immunologic abnormalities in patients with hemophilia. Serum antibodies to HTLV-III were analyzed by ELISA assay, immunoprecipitation of labeled cell extracts, and immunoprecipitation of purified HTLV-III p24. Thirty-four (61%) of the total group (n = 56) had antibody to HTLV-III; 34 (76%) of 45 patients given commercial factor VIII preparations were seropositive, compared with none of 11 patients treated exclusively with cryoprecipitate obtained from volunteer blood donors. Of patients who were seropositive for HTLV-III antibody, 94% had abnormal T4/T8 ratios, and 33% of those whose serum was antibody negative had abnormal T4/T8 ratios; five patients, each antibody positive, have lymphadenopathy syndrome. Sequential studies in a subset of patients indicate that there is a changing pattern of antibody production to HTLV-III antigens after seroconversion

HTLV-III Serology in Hemophilia: Relationship with Immunologic Abnormalities

We investigated the relationship of the presence of antibodies to HTLV-III and immunologic abnormalities in patients with hemophilia. Serum antibodies to HTLV-III were analyzed by ELISA assay, immunoprecipitation of labeled cell extracts, and immunoprecipitation of purified HTLV-III p24. Thirty-four (61%) of the total group (n = 56) had antibody to HTLV-III; 34 (76%) of 45 patients given commercial factor VIII preparations were seropositive, compared with none of 11 patients treated exclusively with cryoprecipitate obtained from volunteer blood donors. Of patients who were seropositive for HTLV-III antibody, 94% had abnormal T4/T8 ratios, and 33% of those whose serum was antibody negative had abnormal T4/T8 ratios; five patients, each antibody positive, have lymphadenopathy syndrome. Sequential studies in a subset of patients indicate that there is a changing pattern of antibody production to HTLV-III antigens after seroconversion

Copyright and cultural work: an exploration

This article first discusses the contemporary debate on cultural “creativity” and the economy. Second, it considers the current state of UK copyright law and how it relates to cultural work. Third, based on empirical research on British dancers and musicians, an analysis of precarious cultural work is presented. A major focus is how those who follow their art by way of “portfolio” work handle their rights in ways that diverge significantly from the current simplistic assumptions of law and cultural policy. Our conclusions underline the distance between present top-down conceptions of what drives production in the cultural field and the actual practice of dancers and musicians

CO2 enrichment and soil type additively regulate grassland productivity

The development of a predictive understanding of how atmospheric CO2 enrichment is affecting the primary productivity of the terrestrial biosphere is among the most pressing of ecological challenges. The terrestrial biosphere absorbs c. 25% of anthropogenic carbon (C) emissions (Le Quere et al., 2018). Uncertainty in CO2 effects on ecosystem C uptake is a major constraint in the prediction of C cycling and the provisioning of productivity- related ecosystem services. Grasslands cover c. 25% of the terrestrial area and are an important contributor to the global C balance (Sala et al., 1996). CO2 enrichment stimulates the aboveground net primary productivity (ANPP) of most water-limited grasslands by increasing plant water use efficiency (WUE; productivity per unit of transpiration; Morgan et al., 2004; Nowak et al., 2004; Fatichi et al., 2016), but grassland ANPP, as other ecosystem functions, is determined by drivers in addition to water availability which act simultaneously and often interactively with CO2 (Polley et al., 2011). CO2 enrichment usually shows greater stimulation of plant productivity when nitrogen (N) availability is relatively high (Owensby et al., 1994; Reich & Hobbie, 2013; Mueller et al., 2016), for example. Other drivers include precipitation timing (Hovenden et al., 2014), disturbance regimes (Newton et al., 2014), plant species composition (Langley & Megonigal, 2010; Fay et al., 2012; Polley et al., 2012) and soil properties (Epstein et al., 1997, 1998), including soil texture, which influences water availability to plants (Tor-Ngern et al., 2017)

CO2 enrichment and soil type additively regulate grassland productivity

The development of a predictive understanding of how atmospheric CO2 enrichment is affecting the primary productivity of the terrestrial biosphere is among the most pressing of ecological challenges. The terrestrial biosphere absorbs c. 25% of anthropogenic carbon (C) emissions (Le Quere et al., 2018). Uncertainty in CO2 effects on ecosystem C uptake is a major constraint in the prediction of C cycling and the provisioning of productivity- related ecosystem services. Grasslands cover c. 25% of the terrestrial area and are an important contributor to the global C balance (Sala et al., 1996). CO2 enrichment stimulates the aboveground net primary productivity (ANPP) of most water-limited grasslands by increasing plant water use efficiency (WUE; productivity per unit of transpiration; Morgan et al., 2004; Nowak et al., 2004; Fatichi et al., 2016), but grassland ANPP, as other ecosystem functions, is determined by drivers in addition to water availability which act simultaneously and often interactively with CO2 (Polley et al., 2011). CO2 enrichment usually shows greater stimulation of plant productivity when nitrogen (N) availability is relatively high (Owensby et al., 1994; Reich & Hobbie, 2013; Mueller et al., 2016), for example. Other drivers include precipitation timing (Hovenden et al., 2014), disturbance regimes (Newton et al., 2014), plant species composition (Langley & Megonigal, 2010; Fay et al., 2012; Polley et al., 2012) and soil properties (Epstein et al., 1997, 1998), including soil texture, which influences water availability to plants (Tor-Ngern et al., 2017)

Pain measurement in rheumatic and musculoskeletal diseases: where to go from here? Report from a Special Interest Group at OMERACT 2018

Objective: Establishing a research agenda on standardizing pain measurement in clinical trials in rheumatic and musculoskeletal diseases (RMDs). Methods: Discussion during a meeting at OMERACT 2018, prepared by a systematic review of existing core outcome sets and a patient online survey. Results: Several key questions were debated: is pain a symptom or a disease? are pain core (sub)domains consistent across RMDs? how to account for pain mechanistic descriptors (e.g. central sensitization) in pain measurement? Conclusion: Characterizing and assessing the spectrum of pain experience across RMDs in a standardized fashion is the future objective of the OMERACT pain working group

Status of MUSIC, the MUltiwavelength Sub/millimeter Inductance Camera

We present the status of MUSIC, the MUltiwavelength Sub/millimeter Inductance Camera, a new instrument for the Caltech Submillimeter Observatory. MUSIC is designed to have a 14', diffraction-limited field-of-view instrumented with 2304 detectors in 576 spatial pixels and four spectral bands at 0.87, 1.04, 1.33, and 1.98 mm. MUSIC will be used to study dusty star-forming galaxies, galaxy clusters via the Sunyaev-Zeldovich effect, and star formation in our own and nearby galaxies. MUSIC uses broadband superconducting phased-array slot-dipole antennas to form beams, lumpedelement on-chip bandpass filters to define spectral bands, and microwave kinetic inductance detectors to sense incoming light. The focal plane is fabricated in 8 tiles consisting of 72 spatial pixels each. It is coupled to the telescope via an ambient-temperature ellipsoidal mirror and a cold reimaging lens. A cold Lyot stop sits at the image of the primary mirror formed by the ellipsoidal mirror. Dielectric and metal-mesh filters are used to block thermal infrared and out-ofband radiation. The instrument uses a pulse tube cooler and ^(3)He/^(3)He/^(4)He closed-cycle cooler to cool the focal plane to below 250 mK. A multilayer shield attenuates Earth's magnetic field. Each focal plane tile is read out by a single pair of coaxes and a HEMT amplifier. The readout system consists of 16 copies of custom-designed ADC/DAC and IF boards coupled to the CASPER ROACH platform. We focus on recent updates on the instrument design and results from the commissioning of the full camera in 2012