Folding of a single domain protein entering the endoplasmic reticulum precedes disulfide formation

The relationship between protein synthesis, folding and disulfide formation within the endoplasmic reticulum (ER) is poorly understood. Previous studies have suggested pre-existing disulfide links are absolutely required to allow protein folding and, conversely, that protein folding occurs prior to disulfide formation. To address the question of what happens first within the ER; that is, protein folding or disulfide formation, we studied folding events at the early stages of polypeptide chain translocation into the mammalian ER using stalled translation intermediates. Our results demonstrate that polypeptide folding can occur without complete domain translocation. Protein disulfide isomerase (PDI) interacts with these early intermediates, but disulfide formation does not occur unless the entire sequence of the protein domain is translocated. This is the first evidence that folding of the polypeptide chain precedes disulfide formation within a cellular context and highlights key differences between protein folding in the ER and refolding of purified proteins

Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1α, 25-dihydroxyvitamin D3

Background: Allergen immunotherapy (SIT) is the only treatment for allergic disease capable of modifying disease long term. To reduce the risk of anaphylaxis from SIT, allergen-extracts have been modified by polymerisation with glutaraldehyde to reduce IgE binding. It is suggested that these allergoid extracts also have reduced T cell activity, which could compromise clinical efficacy. Effective SIT is thought to act through regulatory T cells (Tregs) rather than activation of effector T cells. There is no published data on the activity of modified extracts on Tregs.Results: We compared the capacity of modified (depigmented-polymerised) versus unmodified (native) allergen extracts of grass pollen and house dust mite to stimulate proliferation/cytokine production and to modulate Treg/effector T cell frequency in cultures of peripheral blood mononuclear cells (PBMC), from volunteers sensitised to both allergens in vitro. Depigmented-polymerised allergen extracts stimulated less proliferation of PBMC, and reduced effector cell numbers after 7 days in culture than did native extracts. However, the frequency of Foxp3+ Tregs in cultures were similar to those seen with native extract so that ratios of regulatory to effector T cells were significantly increased in cultures stimulated with depigmented-polymerised extracts. Addition of 1 alpha, 25-dihydroxyvitamin D3 further favoured Treg, and reduced effector cytokine production, but not interleukin-10.Conclusions: Depigmented-polymerised allergen extracts appear to favour Treg expansion over activation of effector T cells and this may relate to their demonstrated efficacy and safety in SIT. 1 alpha, 25-dihydroxyvitamin D3 further reduces effector T cell activation by allergen extracts and may be a useful adjuvant for SIT.</p

TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy

Significance Alzheimer’s disease (AD) is the most common cause of dementia and is a major public health problem for which there is currently no disease-modifying treatment. There is an urgent need for greater understanding of the molecular mechanisms underlying neurodegeneration in patients to create better therapeutic options. Recently, genetic studies uncovered novel AD risk variants in the microglial receptor, triggering receptor expressed on myeloid cells 2 (TREM2). Previous studies suggested that loss of TREM2 function worsens amyloid-β (Aβ) plaque-related toxicity. In contrast, we observe TREM2 deficiency mitigates neuroinflammation and protects against brain atrophy in the context of tau pathology. These findings indicate dual roles for TREM2 and microglia in the context of amyloid versus tau pathology, which are important to consider for potential treatments targeting TREM2.</jats:p

Mapping Alternative Impact: Alternative approaches to impact from co-produced research

No abstract available

The perceived impact of childhood parental divorce on young adults

This qualitative study examines perceptions and meanings of childhood parental divorce and its impact through the eyes of adult children of divorce. There were three primary objectives in this study. They include (a) capturing the retrospective childhood meaning of parental divorce through the eyes of the young adult participants, (b) describing how they believe the process of divorce is influencing their views of themselves in terms of the roles of husband or wife, and father or mother, and (c) understanding the meaning of parental divorce as it is perceived currently by young adults. In-depth interviews were conducted with 21 young adults between the ages of 20 and 30 whose parents divorced when they were 10 years old or younger. From these interviews, seven themes emerged: retrospective perception of parents\u27 relationship with each other, current perception of parents\u27 relationship, perceptions of marriage and parenthood, perceptions of single-parent families; perceptions of remarriage, perceptions of sibling relationships, and perceptions of extended family relationships. Results indicated that three crucial factors seemed to influence the effects of the divorce experience of the participants: first, the quality of life experienced in the single-parent family; second, the quality of the relationship with the non-custodial parent; and third, the way in which parental remarriage is experienced. In addition, a particularly intriguing finding was that often siblings were separated and reared in separate households. Sometimes this physical separation precipitates an emotional distancing as well. This finding has not been noted in earlier studies. Further, because of the tremendous within group variation of the divorce experience, there is no consistent method of characterizing the child of divorce. Additionally, participants\u27 perceptions of their own marital roles and their roles as parents yielded striking results in that they had the added task of turning away from the marital behavior modeled by their parents and often from the parenting model as well

Current child Care Strategies of Twenty-Five states and Summary Recommendations for Future Child Care Services in Utah based on Recommendations from the Governor\u27s Task Force on Child Care

Social and employment changes have occurred in the United States over the past twenty years that have had a drastic impact on the traditional American family. Americans now live in an era of inflation and economic change in which a second family income is often a necessity just to maintain.an adequate standard of living. Mothers\u27 are no longer waiting until their youngest child enters elementary school to enter or re-enter the labor force. By 1985, 57% of mothers\u27 of children under the age of six were in the labor force, whereas in 1950, only 12% were employed (Department of Labor, 1988)

A Study to Determine the Effectiveness of Manipulative Mathematics on Student Learning Outcomes as Compared to Textbook Practices

The hypothesis of this study was: 1. There would be no significant difference in the learning outcomes of the students who were exposed to the manipulative mathematics curriculum as compared to those who were exposed only to textbook practices

Do the Opportunities Offered during the School Day Provide the Recommended Physical Activity Levels for Children?: An Assessment of the Upson County Pre-Kindergarten and Elementary School Physical Activity Occurrences

Problem Statement: Almost 90% of students do not meet the national recommendations for physical activity in school. The purpose of this study was to determine the need for school policy changes to incorporate classroom-based physical activity programs in an effort to increase school physical activity levels for children in grades pre-kindergarten through five by assessing the levels of and the barriers/facilitators to physical activity engagement. Methods: This was a sequential explanatory mixed methods study utilizing school board members, principals, and teachers in the Upson County School System as participants. The online survey was adapted from the School Health Policies and Practices Study Physical Education School and Classroom questionnaires (National Center for Chronic Disease and Health Promotion). Interview questions were developed based upon survey results. The study sought to answer the following questions: 1. Do the current physical activity opportunities provide 60 minutes of physical activity daily? 2. What are the barriers/facilitators associated with increasing physical activity in school? 3. What is the most effective method to increase physical activity for the public school system? Results: The findings showed that at least 60 minutes of physical activity per day are neither required by the school system nor achieved by children in grades pre-kindergarten through fifth grade in Upson County. These students have physical education class twice weekly for approximately 45 minutes each day. Barriers to providing the recommended levels included lack of resources such as administrative support and assistance in developing lesson plans that incorporate physical activity. According to participants, the most effective method to increase physical activity for the school system is a classroombased physical activity curriculum. Conclusion: Policy change to incorporate physical activity into the core subjects that students engage in daily, such as math, and science, will increase the activity levels of the children and allow them to meet the recommendations of 60 minutes of physical activity per day as described by the American College of Sports Medicine and the American Heart Association. Integration also would help movement towards the Healthy People 2020 goals and objectives related to school policies requiring daily physical education for all student

Development of NASA's Small Fission Power System for Science and Human Exploration

Exploration of our solar system has brought many exciting challenges to our nations scientific and engineering community over the past several decades. As we expand our visions to explore new, more challenging destinations, we must also expand our technology base to support these new missions. NASAs Space Technology Mission Directorate is tasked with developing these technologies for future mission infusion and continues to seek answers to many existing technology gaps. One such technology gap is related to compact power systems (1 kWe) that provide abundant power for several years where solar energy is unavailable or inadequate. Below 1 kWe, Radioisotope Power Systems have been the workhorse for NASA and will continue to be used for lower power applications similar to the successful missions of Voyager, Ulysses, New Horizons, Cassini, and Curiosity. Above 1 kWe, fission power systems become an attractive technology offering a scalable modular design of the reactor, shield, power conversion, and heat transport subsystems. Near term emphasis has been placed in the 1-10kWe range that lies outside realistic radioisotope power levels and fills a promising technology gap capable of enabling both science and human exploration missions. History has shown that development of space reactors is technically, politically, and financially challenging and requires a new approach to their design and development. A small team of NASA and DOE experts are providing a solution to these enabling FPS technologies starting with the lowest power and most cost effective reactor series named Kilopower that is scalable from approximately 1-10 kWe

The Bottom Line: Investing for Impact on Economic Mobility in the U.S.

There is no greater challenge in the United States today than income inequality. It has been 50 years since the War on Poverty began. We have made progress but not enough. More than 32 million children live in low-income families, and racial and gender gaps persist. For the first time, Americans do not believe life will be better for the next generation. We have both a moral and an economic imperative to fuel social and economic mobility in this country.The Aspen Institute was founded in 1950 as a place to address the critical issues of our time. Today, ensuring that the American dream can be a possibility for all and be passed from one generation to the next is that issue. This commitment is at the heart of the work of many policy programs at the Aspen Institute. Ending the cycle of poverty requires leadership and hard work across all sectors, from nonprofit organizations, philanthropies, and academia to the government and private sector. This report recognizes the importance of learning from all sectors in tackling any challenge. Specifically, it builds on opportunities in the growing impact investment field. The report draws on the lessons from market-based approaches to identify tools and strategies that can help move the needle on family economic security. In this report, you will find the following: Case studies -- An opportunity to go under the hood on deals with the Bank of America, W.K. Kellogg Foundation, Acelero Learning, and others; Point of view essays -- Insights and lessons from leaders in the field; Deals at a glance -- Snapshots of impact investors and what they have learned, including the Kresge Foundation, Living Cities, and the MacArthur Foundation; and Survey results and lessons learned -- Trends among active and emerging players in the U.S. impact investment field and the lessons that can be applied to economic mobility in the U.S. We are pleased to offer this expanded perspective on impact investing in the U.S. and the lessons for investors, philanthropists, and non-profits working to build strong and prosperous families and communities