Dynamic binding of Ku80, Ku70 and NF90 to the IL-2 promoter in vivo in activated T-cells

IL-2 gene expression in activated T-cells is initiated by chromatin remodeling at the IL-2 proximal promoter and conversion of a transcriptional repressor into a potent transcriptional activator. A purine-box regulator complex was purified from activated Jurkat T-cell nuclei based on sequence-specific DNA binding to the antigen receptor response element (ARRE)/nuclear factor of activated T-cells (NF-AT) target DNA sequence in the proximal IL-2 promoter. ARRE DNA-binding subunits were identified as NF90, NF45 and systemic lupus erythematosis autoantigens, Ku80 and Ku70. Monoclonal antibodies to Ku80, Ku70 and NF90 specifically inhibit constitutive and inducible ARRE DNA-binding activity in Jurkat T-cells. Ku80, Ku70 and NF90 bind specifically to the IL-2 gene promoter in vivo, as demonstrated by chromatin immunoprecipitation. Activation of Jurkat T-cells and mouse primary spleen cells induces binding of Ku80 and NF90 to the IL-2 promoter in vivo, and decreases binding of Ku70 to the IL-2 promoter in vivo, and these dynamic changes are inhibited by immunosuppressants cyclosporin A and triptolide. Dynamic changes in binding of Ku80, Ku70 and NF90 to the IL-2 proximal promoter in vivo correlate with chromatin remodeling and transcriptional initiation in activated T-cells

Prevalence of Small-scale Jets from the Networks of the Solar Transition Region and Chromosphere

As the interface between the Sun's photosphere and corona, the chromosphere and transition region play a key role in the formation and acceleration of the solar wind. Observations from the Interface Region Imaging Spectrograph reveal the prevalence of intermittent small-scale jets with speeds of 80-250 km/s from the narrow bright network lanes of this interface region. These jets have lifetimes of 20-80 seconds and widths of 300 km or less. They originate from small-scale bright regions, often preceded by footpoint brightenings and accompanied by transverse waves with ~20 km/s amplitudes. Many jets reach temperatures of at least ~100000 K and constitute an important element of the transition region structures. They are likely an intermittent but persistent source of mass and energy for the solar wind.Comment: Figs 1-4 & S1-S5; Movies S1-S8; published in Science, including the main text and supplementary materials. Reference: H. Tian, E. E. DeLuca, S. R. Cranmer, et al., Science 346, 1255711 (2014

How common is chronic fatigue syndrome; how long is a piece of string?

Commentary o

The X-ray Afterglows of GRB 020813 and GRB 021004 with Chandra HETGS: Possible Evidence for a Supernova Prior to GRB 020813

We report on the detection of an emission line near 1.3 keV, which we associate with blue-shifted hydrogen-like sulfur (S XVI), in a 76.8 ksec Chandra HETGS spectrum of the afterglow of GRB 020813. The line is detected at 3.3 sigma significance. We also find marginal evidence for a line possibly due to hydrogen-like silicon (Si XIV) with the same blue-shift. A line from Fe is not detected, though a very low significance Ni feature may be present. A thermal model fits the data adequately, but a reflection model may provide a better fit. There is marginal evidence that the equivalent width of the S XVI line decrease as the burst fades. We infer from these results that a supernova likely occurred >~ 2 months prior to the GRB. We find no discrete or variable spectral features in the Chandra HETGS spectrum of the GRB 021004 afterglow.Comment: 26 pages, 11 figures, submitted to Ap

Autoantibodies Define a Family of Proteins with Conserved Double-stranded RNA-binding Domains as Well as DNA Binding Activity

Cellular responses to viral infection are signaled by double-stranded (ds) RNA, which is not found in substantial amounts in uninfected cells. Although cellular dsRNA-binding proteins have been described, their characterization is incomplete. We show that dsRNA-binding proteins are prominent autoantigens. Sera from B6 and B10.S mice with pristane-induced lupus and human autoimmune sera immunoprecipitated a novel set of 130-, 110-, 90-, 80-, and 45-kDa proteins. The proteins were all major cellular poly(IC)-binding factors. N-terminal amino acid sequences of p110 and p90 were identical and matched nuclear factor (NF) 90 and M phase phosphoprotein 4. p45 and p90 were identified as the NF45.NF90 complex, which binds the interleukin-2 promoter as well as certain highly structured viral RNAs. NF90.NF45 and M phase phosphoprotein 4 belong to a large group of proteins with conserved dsRNA-binding motifs. Besides binding dsRNA, NF90.NF45, p110, and p130 had single-stranded and dsDNA binding activity. Some sera contained autoantibodies whose binding was inhibited by poly(IC) but not single-stranded DNA or vice versa, suggesting that the DNA- and RNA-binding sites are different. These autoantibodies will be useful probes of the function of dsRNA-binding proteins. Their interaction with dsRNA, an immunological adjuvant, also could promote autoimmunity

Large-scale rollout of extension training in Bangladesh: Challenges and opportunities for gender-inclusive participation

Despite the recognized importance of women’s participation in agricultural extension services, research continues to show inequalities in women’s participation. Emerging capacities for conducting large-scale extension training using information and communication technologies (ICTs) now afford opportunities for generating the rich datasets needed to analyze situational factors that affect women’s participation. Data was recorded from 1,070 video-based agricultural extension training events (131,073 farmers) in four Administrative Divisions of Bangladesh (Rangpur, Dhaka, Khulna, and Rajshahi). The study analyzed the effect of gender of the trainer, time of the day, day of the week, month of the year, Bangladesh Administrative Division, and venue type on (1) the expected number of extension event attendees and (2) the odds of females attending the event conditioned on the total number of attendees. The study revealed strong gender specific training preferences. Several factors that increased total participation, decreased female attendance (e.g., male-led training event held after 3:30 pm in Rangpur). These findings highlight the dilemma faced by extension trainers seeking to maximize attendance at training events while avoiding exacerbating gender inequalities. The study concludes with a discussion of ways to mitigate gender exclusion in extension training by extending data collection processes, incorporating machine learning to understand gender preferences, and applying optimization theory to increase total participation while concurrently improving gender inclusivity

Hot Explosions in the Cool Atmosphere of the Sun

The solar atmosphere was traditionally represented with a simple one-dimensional model. Over the past few decades, this paradigm shifted for the chromosphere and corona that constitute the outer atmosphere, which is now considered a dynamic structured envelope. Recent observations by IRIS (Interface Region Imaging Spectrograph) reveal that it is difficult to determine what is up and down even in the cool 6000-K photosphere just above the solar surface: this region hosts pockets of hot plasma transiently heated to almost 100,000 K. The energy to heat and accelerate the plasma requires a considerable fraction of the energy from flares, the largest solar disruptions. These IRIS observations not only confirm that the photosphere is more complex than conventionally thought, but also provide insight into the energy conversion in the process of magnetic reconnection.Comment: published in Science 346, 1255726 (2014), 30 pages, 13 figures; for associated movie, see http://www2.mps.mpg.de/data/outgoing/peter/papers/2014-iris-eb/fig1-movie.mo

Impact of the HIV-1 env Genetic Context outside HR1–HR2 on Resistance to the Fusion Inhibitor Enfuvirtide and Viral Infectivity in Clinical Isolates

Resistance mutations to the HIV-1 fusion inhibitor enfuvirtide emerge mainly within the drug's target region, HR1, and compensatory mutations have been described within HR2. The surrounding envelope (env) genetic context might also contribute to resistance, although to what extent and through which determinants remains elusive. To quantify the direct role of the env context in resistance to enfuvirtide and in viral infectivity, we compared enfuvirtide susceptibility and infectivity of recombinant viral pairs harboring the HR1–HR2 region or the full Env ectodomain of longitudinal env clones from 5 heavily treated patients failing enfuvirtide therapy. Prior to enfuvirtide treatment onset, no env carried known resistance mutations and full Env viruses were on average less susceptible than HR1–HR2 recombinants. All escape clones carried at least one of G36D, V38A, N42D and/or N43D/S in HR1, and accordingly, resistance increased 11- to 2800-fold relative to baseline. Resistance of full Env recombinant viruses was similar to resistance of their HR1–HR2 counterpart, indicating that HR1 and HR2 are the main contributors to resistance. Strictly X4 viruses were more resistant than strictly R5 viruses, while dual-tropic Envs featured similar resistance levels irrespective of the coreceptor expressed by the cell line used. Full Env recombinants from all patients gained infectivity under prolonged drug pressure; for HR1–HR2 viruses, infectivity remained steady for 3/5 patients, while for 2/5 patients, gains in infectivity paralleled those of the corresponding full Env recombinants, indicating that the env genetic context accounts mainly for infectivity adjustments. Phylogenetic analyses revealed that quasispecies selection is a step-wise process where selection of enfuvirtide resistance is a dominant factor early during therapy, while increased infectivity is the prominent driver under prolonged therapy

New Oldowan locality Sare-Abururu (ca. 1.7 Ma) provides evidence of diverse hominin behaviors on the Homa Peninsula, Kenya

The Homa Peninsula, in southwestern Kenya, continues to yield insights into Oldowan hominin landscape behaviors. The Late Pliocene locality of Nyayanga (∼3–2.6 Ma) preserves some of the oldest Oldowan tools. At the Early Pleistocene locality of Kanjera South (∼2 Ma) toolmakers procured a diversity of raw materials from over 10 km away and strategically reduced them in a grassland-dominated ecosystem. Here, we report findings from Sare-Abururu, a younger (∼1.7 Ma) Oldowan locality approximately 12 km southeast of Kanjera South and 18 km east of Nyayanga. Sare-Abururu has yielded 1754 artifacts in relatively undisturbed low-energy silts and sands. Stable isotopic analysis of pedogenic carbonates suggests that hominin activities were carried out in a grassland-dominated setting with similar vegetation structure as documented at Kanjera South. The composition of a nearby paleo-conglomerate indicates that high-quality stone raw materials were locally abundant. Toolmakers at Sare-Abururu produced angular fragments from quartz pebbles, representing a considerable contrast to the strategies used to reduce high quality raw materials at Kanjera South. Although lithic reduction at Sare-Abururu was technologically simple, toolmakers proficiently produced cutting edges, made few mistakes and exhibited a mastery of platform management, demonstrating that expedient technical strategies do not necessarily indicate a lack of skill or suitable raw materials. Lithic procurement and reduction patterns on the Homa Peninsula appear to reflect variation in local resource contexts rather than large-scale evolutionary changes in mobility, energy budget, or toolmaker cognition

General practitioners' experience and benefits from patient evaluations

<p>Abstract</p> <p>Background</p> <p>It has now for many years been recognised that patient evaluations should be undertaken as an integral part of the complex task of improving the quality of general practice care. Yet little is known about the general practitioners' (GPs') benefit from patient evaluations. Aim 1 was to study the impact on the GPs of a patient evaluation and subsequent feedback of results presented at a plenary session comprising a study guide for the results and group discussions. Aim 2 was to study possible facilitators and barriers to the implementations of the results raised by the patient evaluation process.</p> <p>Methods</p> <p>A patient evaluation survey of 597 voluntarily participating GPs was performed by means of the EUROPEP questionnaire. Evaluation results were fed back to the GPs as written reports at a single feedback meeting with group discussions of the results. Between 3 and 17 months after the feedback, the 597 GPs received a questionnaire with items addressing their experience with and perceived benefit from the evaluations.</p> <p>Results</p> <p>79.4% of the GPs responded. 33% of the responding GPs reported that the patient evaluation had raised their attention to the patient perspective on the quality of general practice care. Job satisfaction had improved among 26%, and 21% had developed a more positive attitude to patient evaluations. 77% of the GPs reported having learnt from the evaluation. 54% had made changes to improve practice, 82% would recommend a patient evaluation to a colleague and 75% would do another patient evaluation if invited. 14% of the GPs had become less positive towards patient evaluations, and job satisfaction had decreased among 3%.</p> <p>Conclusions</p> <p>We found a significant impact on the GPs regarding satisfaction with the process and attitude towards patient evaluations, GPs' attention to the patients' perspective on care quality and their job satisfaction. Being benchmarked against the average seemed to raise barriers to the concept of patient evaluations and difficulties interpreting the results may have formed a barrier to their implementation which was partly overcome by adding qualitative data to the quantitative results. The GPs' significant willingness to share and discuss the results with others may have served as a facilitator.</p