Redundant Function of REV-ERBα and β and Non-Essential Role for Bmal1 Cycling in Transcriptional Regulation of Intracellular Circadian Rhythms

The mammalian circadian clockwork is composed of a core PER/CRY feedback loop and additional interlocking loops. In particular, the ROR/REV/Bmal1 loop, consisting of ROR activators and REV-ERB repressors that regulate Bmal1 expression, is thought to “stabilize” core clock function. However, due to functional redundancy and pleiotropic effects of gene deletions, the role of the ROR/REV/Bmal1 loop has not been accurately defined. In this study, we examined cell-autonomous circadian oscillations using combined gene knockout and RNA interference and demonstrated that REV-ERBα and β are functionally redundant and are required for rhythmic Bmal1 expression. In contrast, the RORs contribute to Bmal1 amplitude but are dispensable for Bmal1 rhythm. We provide direct in vivo genetic evidence that the REV-ERBs also participate in combinatorial regulation of Cry1 and Rorc expression, leading to their phase-delay relative to Rev-erbα. Thus, the REV-ERBs play a more prominent role than the RORs in the basic clock mechanism. The cellular genetic approach permitted testing of the robustness of the intracellular core clock function. We showed that cells deficient in both REV-ERBα and β function, or those expressing constitutive BMAL1, were still able to generate and maintain normal Per2 rhythmicity. Our findings thus underscore the resilience of the intracellular clock mechanism and provide important insights into the transcriptional topologies underlying the circadian clock. Since REV-ERB function and Bmal1 mRNA/protein cycling are not necessary for basic clock function, we propose that the major role of the ROR/REV/Bmal1 loop and its constituents is to control rhythmic transcription of clock output genes

Redesign and initial validation of an instrument to assess the motivational qualities of music in exercise: The Brunel Music Rating Inventory-2

In the present study, a measure to assess the motivational qualities of music in exercise was redesigned, extending previous research efforts (Karageorghis et al., 1999). The original measure, the Brunel Music Rating Inventory (BMRI), had shown limitations in its factor structure and its applicability to non-experts in music selection. Redesign of the BMRI used in-depth interviews with eight participants (mean age 31.9 years, s¼8.9 years) to establish the initial item pool, which was examined using a series of confirmatory factor analyses. A single-factor model provided a good fit across three musical selections with different motivational qualities (comparative fit index, CFI: 0.95 – 0.98; standardized root mean residual, SRMR: 0.03 – 0.05). The single-factor model also demonstrated acceptable fit across two independent samples and both sexes using one piece of music (CFI: 0.86 – 1.00; SRMR: 0.04 – 0.07). The BMRI was designed for experts in selecting music for exercise (e.g. dance aerobic instructors), whereas the BMRI-2 can be used both by exercise instructors and participants. The psychometric properties of the BMRI-2 are stronger than those of the BMRI and it is easier to use. The BMRI-2 provides a valid and internally consistent tool by which music can be selected to accompany a bout of exercise or a training session. Furthermore, the BMRI-2 enables researchers to standardize music in experimental protocols involving exercise-related tasks

GPs' use of problem solving therapy for depression: a qualitative study of barriers to and enablers of evidence based care

BACKGROUND: Depression is a major health concern, predominantly treated by general practitioners (GPs). Problem solving therapy (PST) is recognised as an effective treatment for depression that is not widely used by GPs. This research aims to explore barriers and enablers that may influence GPs use of this treatment. METHOD: Qualitative methodology was used including individual and focus group interviews of GPs, PST experts and consumers. Analysis was undertaken using the Theory of Planned Behaviour (TPB) as a framework. RESULTS: A spectrum of potential influences, on GPs' use of PST emerged. Both barriers and enablers were identified. PST was perceived as being close to current practice approaches and potentially beneficial to both doctor and patient. In addition to a broadly positive attitude to PST, expressed by those with previous experience of its use, potential solutions to perceived barriers emerged. By contrast some GPs expressed fear that the use of PST would result in loss of doctor control of consultations and associated potential adverse patient outcomes. Patient expectations, which emerged as not always coinciding with GPs' perception of those expectations, were identified as a potential influence on GPs' decision concerning adoption of PST. In addition specific factors, including GP skill and confidence, consultation time constraints and technical issues related to PST were noted as potential concerns. CONCLUSION: This research contributes to our knowledge of the factors that may influence GPs' decisions regarding use of PST as a treatment for depression. It recognises both barriers and enablers. It suggests that for many GPs, PST is viewed in a positive light, providing encouragement to those seeking to increase the provision of PST by GPs. In identifying a number of potential barriers, along with associated options to address many of these barriers, it provides insights which may assist in the planning of GP training in PST

Using functional genomics to decipher the complexity of microbial pathogenicity

From the first identification of bacteria as a causative agent of disease, researchers have been developing methods and techniques to understand their pathogenic processes. For decades, this work has been limited to looking at a small number of genetically manipulatable isolates in in vitro assays or animal models of infection. Despite these limitations such work has facilitated the development of successful therapeutic strategies, most notably vaccines that target specific virulence-related features. There are however many antimicrobial resistant pathogens for which vaccination strategies have not worked, as we simply do not know enough about how they cause disease. We are however at the dawn of a new era in the study of microbial pathogenicity, where large collections of bacteria isolated directly from human infections can be sequenced and assayed to identify the bacterial features that affect disease severity in humans. Here, we describe our attempt to perform such a study focussed on the major human pathogen Staphylococcus aureus, which demonstrates the step changes such approaches can make to understanding microbial pathogenicity

Consolidation of Belief in Two Logics of Evidence

Recently, several logics have emerged with the goal of modelling evidence in a more relaxed sense than that of justifications. Here, we explore two of these logics, one based on neighborhood models and the other being a four-valued modal logic. We establish grounds for comparing these logics, finding, for any model, a counterpart in the other logic which represents roughly the same evidential situation. Then we propose operations for consolidation, answering our central question: What should the doxastic state of a rational agent be in a given evidential situation? These operations map evidence models to Kripke models. We then compare the consolidations in the two logics, finding conditions under which they are isomorphic. By taking this dynamic perspective on belief formation we pave the way for, among other things, a study of the complexity, and an AGM-style analysis of rationality of these belief-forming processes

Why are flare ribbons associated with the spines of magnetic null points generically elongated?

Coronal magnetic null points exist in abundance as demonstrated by extrapolations of the coronal field, and have been inferred to be important for a broad range of energetic events. These null points and their associated separatrix and spine field lines represent discontinuities of the field line mapping, making them preferential locations for reconnection. This field line mapping also exhibits strong gradients adjacent to the separatrix (fan) and spine field lines, that can be analysed using the `squashing factor', $Q$. In this paper we make a detailed analysis of the distribution of $Q$ in the presence of magnetic nulls. While $Q$ is formally infinite on both the spine and fan of the null, the decay of $Q$ away from these structures is shown in general to depend strongly on the null-point structure. For the generic case of a non-radially-symmetric null, $Q$ decays most slowly away from the spine/fan in the direction in which $|{\bf B}|$ increases most slowly. In particular, this demonstrates that the extended, elliptical high-$Q$ halo around the spine footpoints observed by Masson et al. (Astrophys. J., 700, 559, 2009) is a generic feature. This extension of the $Q$ halos around the spine/fan footpoints is important for diagnosing the regions of the photosphere that are magnetically connected to any current layer that forms at the null. In light of this, we discuss how our results can be used to interpret the geometry of observed flare ribbons in `circular ribbon flares', in which typically a coronal null is implicated. We conclude that both the physics in the vicinity of the null and how this is related to the extension of $Q$ away from the spine/fan can be used in tandem to understand observational signatures of reconnection at coronal null points.Comment: Pre-print version of article accepted for publication in Solar Physic

Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children

Large-scale Bright Fronts in the Solar Corona: A Review of "EIT waves"

``EIT waves" are large-scale coronal bright fronts (CBFs) that were first observed in 195 \AA\ images obtained using the Extreme-ultraviolet Imaging Telescope (EIT) onboard the \emph{Solar and Heliospheric Observatory (SOHO)}. Commonly called ``EIT waves", CBFs typically appear as diffuse fronts that propagate pseudo-radially across the solar disk at velocities of 100--700 km s$^{-1}$ with front widths of 50-100 Mm. As their speed is greater than the quiet coronal sound speed ($c_s\leq$200 km s$^{-1}$) and comparable to the local Alfv\'{e}n speed ($v_A\leq$1000 km s$^{-1}$), they were initially interpreted as fast-mode magnetoacoustic waves ($v_{f}=(c_s^2 + v_A^2)^{1/2}$). Their propagation is now known to be modified by regions where the magnetosonic sound speed varies, such as active regions and coronal holes, but there is also evidence for stationary CBFs at coronal hole boundaries. The latter has led to the suggestion that they may be a manifestation of a processes such as Joule heating or magnetic reconnection, rather than a wave-related phenomena. While the general morphological and kinematic properties of CBFs and their association with coronal mass ejections have now been well described, there are many questions regarding their excitation and propagation. In particular, the theoretical interpretation of these enigmatic events as magnetohydrodynamic waves or due to changes in magnetic topology remains the topic of much debate.Comment: 34 pages, 19 figure

Fine-scale Explosive Energy Release at Sites of Prospective Magnetic Flux Cancellation in the Core of the Solar Active Region Observed by Hi-C 2.1, IRIS, and SDO

The second Hi-C flight (Hi-C 2.1) provided unprecedentedly high spatial and temporal resolution (~250 km, 4.4 s) coronal EUV images of Fe ix/x emission at 172 Å of AR 12712 on 2018 May 29, during 18:56:21–19:01:56 UT. Three morphologically different types (I: dot-like; II: loop-like; III: surge/jet-like) of fine-scale sudden-brightening events (tiny microflares) are seen within and at the ends of an arch filament system in the core of the AR. Although type Is (not reported before) resemble IRIS bombs (in size, and brightness with respect to surroundings), our dot-like events are apparently much hotter and shorter in span (70 s). We complement the 5 minute duration Hi-C 2.1 data with SDO/HMI magnetograms, SDO/AIA EUV images, and IRIS UV spectra and slit-jaw images to examine, at the sites of these events, brightenings and flows in the transition region and corona and evolution of magnetic flux in the photosphere. Most, if not all, of the events are seated at sites of opposite-polarity magnetic flux convergence (sometimes driven by adjacent flux emergence), implying likely flux cancellation at the microflare's polarity inversion line. In the IRIS spectra and images, we find confirming evidence of field-aligned outflow from brightenings at the ends of loops of the arch filament system. In types I and II the explosion is confined, while in type III the explosion is ejective and drives jet-like outflow. The light curves from Hi-C, AIA, and IRIS peak nearly simultaneously for many of these events, and none of the events display a systematic cooling sequence as seen in typical coronal flares, suggesting that these tiny brightening events have chromospheric/transition region origin