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  1. Abstract

    Human acyl protein thioesterases (APTs) catalyze the depalmitoylation ofS‐acylated proteins attached to the plasma membrane, facilitating reversible cycles of membrane anchoring and detachment. We previously showed that a bacterial APT homologue, FTT258 from the gram‐negative pathogenFrancisella tularensis, exists in equilibrium between a closed and open state based on the structural dynamics of a flexible loop overlapping its active site. Although the structural dynamics of this loop are not conserved in human APTs, the amino acid sequence of this loop is highly conserved, indicating essential but divergent functions for this loop in human APTs. Herein, we investigated the role of this loop in regulating the catalytic activity, ligand binding, and protein folding of human APT1, a depalmitoylase connected with cancer, immune, and neurological signaling. Using a combination of substitutional analysis with kinetic, structural, and biophysical characterization, we show that even in its divergent structural location in human APT1 that this loop still regulates the catalytic activity of APT1 through contributions to ligand binding and substrate positioning. We confirmed previously known roles for multiple residues (Phe72 and Ile74) in substrate binding and catalysis while adding new roles in substrate selectivity (Pro69), in catalytic stabilization (Asp73 and Ile75), and in transitioning between the membrane binding β‐tongue and substrate‐binding loops (Trp71). Even conservative substitution of this tryptophan (Trp71) fulcrum led to complete loss of catalytic activity, a 13°C decrease in total protein stability, and drastic drops in ligand affinity, indicating that the combination of the size, shape, and aromaticity of Trp71 are essential to the proper structure of APT1. Mixing buried hydrophobic surface area with contributions to an exposed secondary surface pocket, Trp71 represents a previously unidentified class of essential tryptophans within α/β hydrolase structure and a potential allosteric binding site within human APTs.

     
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  2. null (Ed.)
    Studies have shown that in the U.S., Black, Hispanic, and women entrepreneurs are given a tiny fraction of venture capital funding, which is vastly disproportionate to their representation in the population. This investment discrepancy is not only socially unjust, but it also deprives the U.S. of the advantages in innovation and global competitiveness that could stem from increasing the participation of these groups in innovative sectors. This is particularly true within transdisciplinary startups, including those focused on smart energy, biomedical, and nanomedical technologies, all of which require cross-disciplinary experts. Every new enterprise in these fields experiences challenges in finding adequate support. These challenges exist at a time in the 21st century when U.S. innovation is facing unprecedented pressures in competition for primacy. In 1960, U.S. R&D expenditure for defense and private industries was approximately 69 percent of global spending on R&D [1]; whereas in 2016, the U.S. share of global R&D expenditure had decreased to just 28 percent [2], due to China’s substantial advances in R&D. If this trend continues, both China’s GDP and R&D expenditure measured by GDP will outperform those of the U.S. by 2030 [3]. To ensure that the U.S. remains a world leader in R&D, the National Science Foundation (NSF) launched the Innovative Postdoctoral Entrepreneurial Research Fellowship (I-PERF) program. I-PERF facilitates the professional development of Black, Hispanic and female research fellows, who are typically underrepresented within STEM fields, by offering them invaluable experience within research and technology companies. The program’s goal is to enhance diversity in the startup and entrepreneurial landscapes, improve opportunities for researchers from underserved groups, and increase the number of highly competent entrepreneurs within the U.S. STEM community. The startup companies involved in the program, which are also supported by the NSF, comprise a variety of new, mixed STEM fields that were unknown just a few decades ago. 
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  3. Berg, N. ; Bagnall, N. ; Deeprose, C. (Ed.)
    Statistics suggest that Hispanic, Black, and female entrepreneurs receive a disproportionately tiny portion of total venture capital funds in the United States. With this in mind, the National Science Foundation created the I-PERF program. I-PERF supports the professional development of research fellows from underserved groups, offering them hands-on experience within promising research and technology companies, with the goal of increasing diversity in the start-up and entrepreneurial landscape. The program is managed by Dr Teddy Ivanitzki, Rashida Johnson, Rachel Levitin and their colleagues at the American Society for Engineering Education. Women and individuals from underserved minority groups often face additional difficulties when trying to secure funding for their businesses compared to white males. Every year, the US Small Business Administration (SBA) awards over 5,000 grants to entrepreneurs, for a total of over $3.5 billion. According to the SBA’s 2013 Annual Report, only 15% of these funds were awarded to firms owned by individuals from underrepresented minority groups, despite the fact that these groups make up about one-third of the US population. A similar pattern can also be observed in the venture capital market. In 2019, a non-profit collaboration aimed at increasing diversity in the venture industry, called Diversity VC, released a report outlining the results of a study that polled 10,000 start-up founders. They found that 77% of venture-fund recipients were white, while only 1% were African Americans and 9% were women. Initiatives aimed at supporting the professional development and business endeavors of individuals from underrepresented minority groups are of crucial importance, as they could ensure that these individuals’ talent is recognized, valued, and does not go to waste. Over the past few years, the National Science Foundation (NSF) has introduced and funded a number of projects aimed at supporting start-ups and businesses founded by individuals from underserved minorities, including the Small Business Postdoctoral Research Diversity Fellowship (SBPRDF) program, which started in 2010. The SBPRDF program allowed postdoctoral fellows specialized in STEM disciplines to acquire real-life research experience in entrepreneurial settings and apply their skills within the technology sector. The program placed a total of 79 fellows in companies for periods of two years, 40% of which were women and individuals from underserved minorities. The vast majority of those who participated felt that they had significantly benefitted from the program. The positive feedback offered by those who participated encouraged the NSF to introduce an extension of the SBPRDF program, called the Innovative Postdoctoral Entrepreneurial Research Fellowship, or ‘I-PERF’. The primary mission of the I-PERF program, which was created in 2019 and is managed by the American Society for Engineering Education (ASEE), is to support the professional development of research fellows from underrepresented minorities 
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  4. Miller, E. (Ed.)
    On the list of racial and ethnic injustices requiring attention in the U.S., venture capital funding is probably not top-of-mind for many. But it is an area needing reform in order to diversify the leadership of companies fueling innovation in the country. Hispanic or Black entrepreneurs receive just 1 percent of venture capital, according to former administrator of the Small Business Administration Maria Contreras-Sweet. “Does anyone honestly believe these communities are the source of just 1 percent of our best business ideas?”. To expand overall entrepreneurship, accelerate innovation, and increase the participation of underrepresented groups in new startup research and high-tech entrepreneurship, the National Science Foundation selected ASEE to manage the Innovative Postdoctoral Entrepreneurial Research Fellowship (IPERF) program in 2019. The goals: emphasize the professional development of underrepresented research Fellows, advance best practices in postdoctoral programs, and expand the participation of underrepresented scholars in innovative research and technology entrepreneurship 
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  5. Teacher preparation relies primarily on classroom and field experiences including content and pedagogical practices. To comprehensively address areas which impact students’ lives, a broader vision is needed. This means reaching out to community mentors and including them in the educational experience of the student and making them an integral and specific part that experience. By doing so we can truly impact social justice and develop life-long agents of social change. Community-Engaged Teacher preparation is the catalyst and essence of social justice. 
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  6. null (Ed.)
  7. Free, publicly-accessible full text available January 22, 2025