Reducing Poverty in California…Permanently

If California were to seriously commit to equalizing opportunity and reducing poverty, how might that commitment best be realized? This is of course a hypothetical question, as there is no evidence that California is poised to make such a serious commitment, nor have many other states gone much beyond the usual lip-service proclamations. There are many reasons for California’s complacency, but an important one is that most people think that poverty is intractable and that viable solutions to it simply don’t exist. When Californians know what needs to be done, they tend to go forward and get it done. When, for example, the state’s roads are in disrepair, there are rarely paralyzing debates about exactly how to go about fixing them; instead we proceed with the needed repairs as soon as the funds to do so are appropriated. The same type of sure and certain prescription might appear to be unavailable when it comes to reducing poverty. It is hard not to be overwhelmed by the cacophony of voices yielding a thick stream of narrow-gauge interventions, new evaluations, and piecemeal proposals.1 Although the research literature on poverty is indeed large and may seem confusing, recent advances have in fact been so fundamental that it is now possible to develop a science-based response to poverty. In the past, the causes of poverty were not well understood, and major interventions, such as the War on Poverty, had to be built more on hunch than science. It is an altogether different matter now. The causes of poverty are well established, and the effects of many possible policy responses to poverty are likewise well established. The simple purpose of this essay is to assemble these advances into a coherent plan that would, if implemented, reduce poverty in California substantially

100% complete assignment of non-labile 1H, 13C, and 15N signals for calcium-loaded calbindin D9k P43G

Here we present the 100% complete assignment chemical shift of non-labile 1H, 15N and 13C nuclei of Calbindin D9k P43G. The assignment includes all non-exchangeable side chain nuclei, including ones that are rarely reported, such as LysNζ as well as the termini. NMR experiments required to achieve truly complete assignments are discussed. To the best of our knowledge our assignments for Calbindin D9k extend beyond previous studies reaching near-completeness (Vis et al. in Biochem 33:14858–14870, 1994; Yamazaki et al. in J Am Chem Soc 116:6464–6465, 1994; Yamazaki et al. in Biochem 32:5656–5669, 1993b)

Bioreactor technologies to support liver function in vitro

Liver is a central nexus integrating metabolic and immunologic homeostasis in the human body, and the direct or indirect target of most molecular therapeutics. A wide spectrum of therapeutic and technological needs drives efforts to capture liver physiology and pathophysiology in vitro, ranging from prediction of metabolism and toxicity of small molecule drugs, to understanding off-target effects of proteins, nucleic acid therapies, and targeted therapeutics, to serving as disease models for drug development. Here we provide perspective on the evolving landscape of bioreactor-based models to meet old and new challenges in drug discovery and development, emphasizing design challenges in maintaining long-term liver-specific function and how emerging technologies in biomaterials and microdevices are providing new experimental models.National Institutes of Health (U.S.) (R01 EB010246)National Institutes of Health (U.S.) (P50-GM068762-08)National Institutes of Health (U.S.) (R01-ES015241)National Institutes of Health (U.S.) (P30-ES002109)5UH2TR000496-02National Science Foundation (U.S.). Emergent Behaviors of Integrated Cellular Systems (CBET-0939511)United States. Defense Advanced Research Projects Agency. Microphysiological Systems Program (W911NF-12-2-0039

An individually randomised controlled multi-centre pragmatic trial with embedded economic and process evaluations of early vocational rehabilitation compared with usual care for stroke survivors: study protocol for the RETurn to work After stroKE (RETAKE) trial

Background: Return to work (RTW) is achieved by less than 50% of stroke survivors. The rising incidence of stroke among younger people, the UK economic forecast, and clinical drivers highlight the need for stroke survivors to receive support with RTW. However, evidence for this type of support is lacking. This randomised controlled trial (RCT) will investigate whether Early Stroke Specialist Vocational Rehabilitation (ESSVR) plus usual care (UC) (i.e., usual NHS rehabilitation) is more clinically and cost effective for supporting post-stroke RTW, than UC alone. Methods: 760 stroke survivors and their carers will be recruited from approximately 20 NHS stroke services. A 5:4 allocation ratio will be employed to randomise participants to receive ESSVR plus UC, or UC alone. The individually tailored ESSVR intervention will commence within 12 weeks of stroke onset and be delivered for up to 12 months as necessary by trained RETAKE occupational therapists in the community, participants’ homes or workplaces, outpatient/inpatient therapy settings, via telephone, email or SMS text message. Outcome data will be collected via self-report questionnaires administered by post or online at 3, 6, and 12 months follow-up. The primary outcome will be self-reported RTW and job retention at 12 months (minimum 2 hours/week). Secondary outcomes will include: mood; function; participation; health-related quality of life; confidence; intervention compliance; health and social care resource use; and mortality. An embedded economic evaluation will estimate cost-effectiveness and cost-utility analyses from National Health Service (NHS) and Personal Social Services (PSS) perspectives. An embedded process evaluation will employ a mixed methods approach to explore ESSVR implementation, contextual factors linked to outcome variation, and factors affecting NHS roll-out. Discussion: This article describes the protocol for a multi-centre RCT evaluating the clinical- and cost-effectiveness of an early vocational rehabilitation intervention aimed at supporting adults to return to work following a stroke. Evidence favouring the ESSVR intervention would support its roll-out in NHS settings. Trial registration: ISRCTN, ISRCTN12464275. Registered on 26th February 2018, http://www.isrctn.com/ISRCTN12464275

Pilgrimage and Visual Genre: The Architecture of Twentieth-Century Roman Catholic Pilgrimage in Scotland

As Roman Catholics gained confidence in twentieth-century Scotland, they revived pre-Reformation shrines and pilgrimages and created new shrines with transnational connections to the modern Catholic world. Three sites in this campaign were Carfin, a new pilgrimage center based on Lourdes; Whithorn, site of medieval pilgrimages to Saint Ninian; and Dunfermline, associated with the canonized Queen Margaret of Scotland. Each had different meanings for Scottish Catholicism. The landscapes of these shrines included proposed new buildings, completed buildings, including shrines and churches, and existing features, notably caves or grottoes and medieval ruins. Whether found, professionally designed, or made by the clergy and their congregations, these sites framed and ordered pilgrimage rituals and lent them meaning. Seeing common architectural, visual features across these pilgrimages, and drawing on new archival research, we suggest that the employment of recognizable visual genres was a key way of creating a consensus amongst the faithful. International symbols of saintly presence were remade for the local context, with intertwined religious and political intentions, giving tangible expression to a revived Catholicism in Scotland, and promoting a new vision of Scotland as a Catholic nation

RETurn to work After stroKE (RETAKE) Trial: protocol for a mixed-methods process evaluation using normalisation process theory

Objectives: This mixed-method process evaluation underpinned by normalisation process theory aims to measure fidelity to the intervention, understand the social and structural context in which the intervention is delivered and identify barriers and facilitators to intervention implementation. Setting: RETurn to work After stroKE (RETAKE) is a multicentre individual patient randomised controlled trial to determine whether Early Stroke Specialist Vocational Rehabilitation (ESSVR) plus usual care is a clinically and cost-effective therapy to facilitate return to work after stroke, compared with usual care alone. This protocol paper describes the embedded process evaluation. Participants and outcome measures: Intervention training for therapists will be observed and use of remote mentor support reviewed through documentary analysis. Fidelity will be assessed through participant questionnaires and analysis of therapy records, examining frequency, duration and content of ESSVR sessions. To understand the influence of social and structural contexts, the process evaluation will explore therapists’ attitudes towards evidence-based practice, competency to deliver the intervention and evaluate potential sources of contamination. Longitudinal case studies incorporating non-participant observations will be conducted with a proportion of intervention and usual care participants. Semistructured interviews with stroke survivors, carers, occupational therapists, mentors, service managers and employers will explore their experiences as RETAKE participants. Analysis of qualitative data will draw on thematic and framework approaches. Quantitative data analysis will include regression models and descriptive statistics. Qualitative and quantitative data will be independently analysed by process evaluation and Clinical Trials Research Unit teams, respectively. Linked data, for example, fidelity and describing usual care will be synthesised by comparing and integrating quantitative descriptive data with the qualitative findings. Ethics and dissemination: Approval obtained through the East Midlands—Nottingham 2 Research Ethics Committee (Ref: 18/EM/0019) and the National Health ServiceResearch Authority. Dissemination via journal publications, stroke conferences, social media and meetings with national Stroke clinical leads. Trial registration number: ISRCTN12464275

Apical Function in Neocortical Pyramidal Cells: A Common Pathway by Which General Anesthetics Can Affect Mental State

It has been argued that general anesthetics suppress the level of consciousness, or the contents of consciousness, or both. The distinction between level and content is important because, in addition to clarifying the mechanisms of anesthesia, it may help clarify the neural bases of consciousness. We assess these arguments in the light of evidence that both the level and the content of consciousness depend upon the contribution of apical input to the information processing capabilities of neocortical pyramidal cells which selectively amplify relevant signals. We summarize research suggesting that what neocortical pyramidal cells transmit information about can be distinguished from levels of arousal controlled by sub-cortical nuclei and from levels of prioritization specified by interactions within the thalamocortical system. Put simply, on the basis of the observations reviewed, we hypothesize that when conscious we have particular, directly experienced, percepts, thoughts, feelings and intentions, and that general anesthetics affect consciousness by interfering with the subcellular processes by which particular activities are selectively amplified when relevant to the current context

Elevated Proteasome Capacity Extends Replicative Lifespan in Saccharomyces cerevisiae

Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS–related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans

Chikungunya Disease: Infection-Associated Markers from the Acute to the Chronic Phase of Arbovirus-Induced Arthralgia

At the end of 2005, an outbreak of fever associated with joint pain occurred in La Réunion. The causal agent, chikungunya virus (CHIKV), has been known for 50 years and could thus be readily identified. This arbovirus is present worldwide, particularly in India, but also in Europe, with new variants returning to Africa. In humans, it causes a disease characterized by a typical acute infection, sometimes followed by persistent arthralgia and myalgia lasting months or years. Investigations in the La Réunion cohort and studies in a macaque model of chikungunya implicated monocytes-macrophages in viral persistence. In this Review, we consider the relationship between CHIKV and the immune response and discuss predictive factors for chronic arthralgia and myalgia by providing an overview of current knowledge on chikungunya pathogenesis. Comparisons of data from animal models of the acute and chronic phases of infection, and data from clinical series, provide information about the mechanisms of CHIKV infection–associated inflammation, viral persistence in monocytes-macrophages, and their link to chronic signs

Effect of variable transmission rate on the dynamics of HIV in sub-Saharan Africa

<p>Abstract</p> <p>Background</p> <p>The cause of the high HIV prevalence in sub-Saharan Africa is incompletely understood, with heterosexual penile-vaginal transmission proposed as the main mechanism. Heterosexual HIV transmission has been estimated to have a very low probability; but effects of cofactors that vary in space and time may substantially alter this pattern.</p> <p>Methods</p> <p>To test the effect of individual variation in the HIV infectiousness generated by co-infection, we developed and analyzed a mathematical sexual network model that simulates the behavioral components of a population from Malawi, as well as the dynamics of HIV and the co-infection effect caused by other infectious diseases, including herpes simplex virus type-2, gonorrhea, syphilis and malaria.</p> <p>Results</p> <p>The analysis shows that without the amplification effect caused by co-infection, no epidemic is generated, and HIV prevalence decreases to extinction. But the model indicates that an epidemic can be generated by the amplification effect on HIV transmission caused by co-infection.</p> <p>Conclusion</p> <p>The simulated sexual network demonstrated that a single value for HIV infectivity fails to describe the dynamics of the epidemic. Regardless of the low probability of heterosexual transmission per sexual contact, the inclusion of individual variation generated by transient but repeated increases in HIV viral load associated with co-infections may provide a biological basis for the accelerated spread of HIV in sub-Saharan Africa. Moreover, our work raises the possibility that the natural history of HIV in sub-Saharan Africa cannot be fully understood if individual variation in infectiousness is neglected.</p