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Programmed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.5-encoded viral mitochon-drial inhibitor of apoptosis (vMIA), a BAX suppressor that functions in concert with M41.1-encoded viral inhibitor of BAK oligomerization (vIBO), (ii) M36-encoded viral inhibitor of caspase-8 activation (vICA), and (iii) M45-encoded viral inhibitor of RIP/RHIM activation (vIRA). Following infection of bone marrow-derived macrophages, the virus initially deflected receptor-interacting protein kinase (RIPK)3-dependent necroptosis, the most potent of the three cell death pathways. This process remained independent of caspase-8, although suppression of this apoptotic protease en-hances necroptosis in most cell types. Second, the virus deflected TNF-mediated extrinsic apoptosis, a pathway dependent on autocrine TNF production by macrophages that proceeds independently of mitochondrial death machinery or RIPK3. Third, cytomegalovirus deflected BCL-2 family protein-dependent mitochondrial cell death through combined TNF-dependent and-independent signaling even in the absence of RIPK1, RIPK3, and caspase-8. Furthermore, each of these cell death pathways dictated a distinct pattern of cytokine and chemokine activation. Therefore, cytomegalovirus employs sequential, non-redundant suppression strategies to specifically modulate the timing and execution of necroptosis, extrinsic apoptosis, and intrinsic apoptosis within infected cells to orchestrate virus control and infection-dependent inflammation. Virus-encoded death suppressors together hold control over an intricate network that upends host defense and sup

Several studies have documented periodic and quasi-periodic signals from the time series of dMe flare stars and other stellar sources. Such periodic signals, observed within quiescent phases (i.e., devoid of larger-scale microflare or flare activity), range in period from $1-1000$ seconds and hence have been tentatively linked to ubiquitous $p$-mode oscillations generated in the convective layers of the star. As such, most interpretations for the observed periodicities have been framed in terms of magneto-hydrodynamic wave behavior. However, we propose that a series of continuous nanoflares, based upon a power-law distribution, can provide a similar periodic signal in the associated time series. Adapting previous statistical analyses of solar nanoflare signals, we find the first statistical evidence for stellar nanoflare signals embedded within the noise envelope of M-type stellar lightcurves. Employing data collected by the Next Generation Transit Survey (NGTS), we find evidence for stellar nanoflare activity demonstrating a flaring power-law index of $3.25 \pm 0.20 $, alongside a decay timescale of $200 \pm 100$ s. We also find that synthetic time series, consistent with the observations of dMe flare star lightcurves, are capable of producing quasi-periodic signals in the same frequency range as $p$-mode signals, despite being purely comprised of impulsive signatures. Phenomena traditionally considered a consequence of wave behaviour may be described by a number of high frequency but discrete nanoflare energy events. This new physical interpretation presents a novel diagnostic capability, by linking observed periodic signals to given nanoflare model conditions., Comment: 22 Pages, 8 figures, accepted for publication by ApJ

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (-)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.

TLR2 promotes NLRP3 inflammasome activation via an early MyD88-IRAK1-dependent pathway that provides a priming signal (signal 1) necessary for activation of the inflammasome by a second potassium-depleting signal (signal 2). Here we show that TLR3 binding to dsRNA promotes post-translational inflammasome activation through intermediate and late TRIF/RIPK1/FADD-dependent pathways. Both pathways require the scaffolding but not the catalytic function of caspase-8 or RIPK1. Only the late pathway requires kinase competent RIPK3 and MLKL function. Mechanistically, FADD/caspase-8 scaffolding function provides a post-translational signal 1 in the intermediate pathway, whereas in the late pathway it helps the oligomerization of RIPK3, which together with MLKL provides both signal 1 and 2 for inflammasome assembly. Cytoplasmic dsRNA activates NLRP3 independent of TRIF, RIPK1, RIPK3 or mitochondrial DRP1, but requires FADD/caspase-8 in wildtype macrophages to remove RIPK3 inhibition. Our study provides a comprehensive analysis of pathways that lead to NLRP3 inflammasome activation in response to dsRNA.

This paper draws on a recent research project into high-level key skills links between HE and employment. The project has worked with groups in several universities and companies to explore how the developmental model embedded in the QCA key skills national standards can be used to support learning and assessment of higher level (QCA levels 4 and 5) key skills. Employers increasingly value skills such as teamworking, communicating effectively with partners and customers, and being able to adapt to new situations and develop new capabilities. Within organisations individuals may be expected to move from project to project and job to job. They may be expected to identify their own particular training needs, work within the company business goals and develop their own individual skills portfolio to satisfy professional recognition requirements. HE currently appears to offer relatively little support or training to develop the key skills needed in such environments. As part of the project students in HE have used a framework of planning, monitoring progress, presenting outcomes and reviewing progress to develop their skills. The model encourages learners to recognise and articulate their own capabilities more clearly, and offers an assessment structure for profiling achievement. It is this 'meta-skills' approach that is used to bridge the gap between HE and employment by encouraging learners to be actively aware of the context in which they are currently situated, and to make connections with experience, skills and knowledge they have gained elsewhere. The paper presents some preliminary findings and comments from the project.

The Open University (OU) is the United Kingdom's only university devoted to distance learning. It is also the UK's largest university with over 200,000 students overall. Around 150,000 students are studying undergraduate level courses. Over the last decade major policy changes have impacted on UK higher education. Following the recommendations of the National Committee of Inquiry into Higher Education (Dearing Report, 1997) and the establishment of the Quality Assurance Agency, all UK universities have been required to define learning outcomes for their programmes and link learning outcomes to teaching and assessment. This major pedagogic shift led the OU to establish the Learning Outcomes and their Assessment (LOTA) project to re-examine the ways its courses are planned, designed, delivered and assessed, and to initiate necessary institution-wide changes. Explicitly linking outcomes, assessment and teaching, actively using assessment for learning, and supporting academic staff development are key elements in enhancing student learning.

The Open University (OU) is the United Kingdom's only university devoted to distance learning. It is also the UK's largest university with over 200,000 students overall. Around 150,000 students are studying undergraduate level courses. Over the last decade major policy changes have impacted on UK higher education. Following the recommendations of the National Committee of Inquiry into Higher Education (Dearing Report, 1997) and the establishment of the Quality Assurance Agency, all UK universities have been required to define learning outcomes for their programmes and link learning outcomes to teaching and assessment. This major pedagogic shift led the OU to establish the Learning Outcomes and their Assessment (LOTA) project to re-examine the ways its courses are planned, designed, delivered and assessed, and to initiate necessary institution-wide changes. Explicitly linking outcomes, assessment and teaching, actively using assessment for learning, and supporting academic staff development are key elements in enhancing student learning.

This paper draws on a recent research project into high-level key skills links between HE and employment. The project has worked with groups in several universities and companies to explore how the developmental model embedded in the QCA key skills national standards can be used to support learning and assessment of higher level (QCA levels 4 and 5) key skills. Employers increasingly value skills such as teamworking, communicating effectively with partners and customers, and being able to adapt to new situations and develop new capabilities. Within organisations individuals may be expected to move from project to project and job to job. They may be expected to identify their own particular training needs, work within the company business goals and develop their own individual skills portfolio to satisfy professional recognition requirements. HE currently appears to offer relatively little support or training to develop the key skills needed in such environments. As part of the project students in HE have used a framework of planning, monitoring progress, presenting outcomes and reviewing progress to develop their skills. The model encourages learners to recognise and articulate their own capabilities more clearly, and offers an assessment structure for profiling achievement. It is this 'meta-skills' approach that is used to bridge the gap between HE and employment by encouraging learners to be actively aware of the context in which they are currently situated, and to make connections with experience, skills and knowledge they have gained elsewhere. The paper presents some preliminary findings and comments from the project.