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6. How to Minimize TOO for Bricking Machines

Author

Harding, Heather

Subjects
Architecture and design industries, Business, Construction and materials industries
Abstract

For refractory installation, it's critical to have a dependable bricking machine that efficiently delivers a high-quality result, reduces planned downtime and virtually eliminates emergency repairs. When looking to buy equipment [...]

Published
2023

10. GDF15 mediates the effects of metformin on body weight and energy balance

Author

Coll, Anthony P., Chen, Michael, Taskar, Pranali, Rimmington, Debra, Patel, Satish, Tadross, John A., Cimino, Irene, Yang, Ming, Welsh, Paul, Virtue, Samuel, Goldspink, Deborah A., Miedzybrodzka, Emily L., Konopka, Adam R., Esponda, Raul Ruiz, Huang, Jeffrey T.-J., Tung, Y. C. Loraine, Rodriguez-Cuenca, Sergio, Tomaz, Rute A., Harding, Heather P., Melvin, Audrey, Yeo, Giles S. H., Preiss, David, Vidal-Puig, Antonio, Vallier, Ludovic, Nair, K. Sreekumaran, Wareham, Nicholas J., Ron, David, Gribble, Fiona M., Reimann, Frank, Sattar, Naveed, Savage, David B., Allan, Bernard B., and O’Rahilly, Stephen

Published
2020
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14. Revolutionizing Refractory Maintenance

Author

Lindgren, Lars and Harding, Heather

Subjects
Architecture and design industries, Business, Construction and materials industries
Abstract

Refractory maintenance, though vital, can often be a logistical and financial burden. This is especially true for large facilities that rely on kilns, coolers, preheater towers and risers for day-to-day [...]

Published
2022

24. Substrate recruitment via eIF2γ enhances catalytic efficiency of a holophosphatase that terminates the integrated stress response.

Author

Yahui Yan, Shetty, Maithili, Harding, Heather P., George, Ginto, Zyryanova, Alisa, Labbé, Katherine, Mafi, Amirhossein, Qi Hao, Sidrauski, Carmela, and Ron, David

Subjects
PHOSPHOPROTEIN phosphatases, PEPTIDES, MOLECULAR dynamics, X-ray crystallography, DEEP learning
Abstract

Dephosphorylation of pSer51 of the α subunit of translation initiation factor 2 (eIF2αP ) terminates signaling in the integrated stress response (ISR). A trimeric mammalian holophosphatase comprised of a protein phosphatase 1 (PP1) catalytic subunit, the conserved C-terminally located ~70 amino acid core of a substrate-specific regulatory subunit (PPP1R15A/GADD34 or PPP1R15B/CReP) and G-actin (an essential cofactor) efficiently dephosphorylate eIF2αP in vitro. Unlike their viral or invertebrate counterparts, with whom they share the conserved 70 residue core, the mammalian PPP1R15s are large proteins of more than 600 residues. Genetic and cellular observations point to a functional role for regions outside the conserved core of mammalian PPP1R15A in dephosphorylating its natural substrate, the eIF2 trimer. We have combined deep learning technology, all-atom molecular dynamics simulations, X-ray crystallography, and biochemistry to uncover binding of the γ subunit of eIF2 to a short helical peptide repeated four times in the functionally important N terminus of human PPP1R15A that extends past its conserved core. Binding entails insertion of Phe and Trp residues that project from one face of an α-helix formed by the conserved repeats of PPP1R15A into a hydrophobic groove exposed on the surface of eIF2γ in the eIF2 trimer. Replacing these conserved Phe and Trp residues with Ala compromises PPP1R15A function in cells and in vitro. These findings suggest mechanisms by which contacts between a distant subunit of eIF2 and elements of PPP1R15A distant to the holophosphatase active site contribute to dephosphorylation of eIF2αP by the core PPP1R15 holophosphatase and to efficient termination of the ISR in mammals. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Infancy-onset diabetes caused by de-regulated AMPylation of the human endoplasmic reticulum chaperone BiP

Author

Perera, Luke A, Hattersley, Andrew T, Harding, Heather P, Wakeling, Matthew N, Flanagan, Sarah E, Mohsina, Ibrahim, Raza, Jamal, Gardham, Alice, Ron, David, De Franco, Elisa, Perera, Luke A [0000-0002-0032-1176], Hattersley, Andrew T [0000-0001-5620-473X], Harding, Heather P [0000-0002-7359-7974], Ron, David [0000-0002-3014-5636], De Franco, Elisa [0000-0002-1437-7891], and Apollo - University of Cambridge Repository

Subjects
nucleotidyltransferases, endoplasmic reticulum chaperone, Cricetulus, post-translational, Cricetinae, diabetes mellitus, Animals, Humans, Infant, mutation, Endoplasmic Reticulum Chaperone BiP, Protein Processing, Post-Translational, Adenosine Monophosphate
Abstract

Dysfunction of the endoplasmic reticulum (ER) in insulin-producing beta cells results in cell loss and diabetes mellitus. Here we report on five individuals from three different consanguineous families with infancy-onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in FICD. The FICD gene encodes a bifunctional Fic domain-containing enzyme that regulates the ER Hsp70 chaperone, BiP, via catalysis of two antagonistic reactions: inhibitory AMPylation and stimulatory deAMPylation of BiP. Arg371 is a conserved residue in the Fic domain active site. The FICDR371S mutation partially compromises BiP AMPylation in vitro but eliminates all detectable deAMPylation activity. Overexpression of FICDR371S or knock-in of the mutation at the FICD locus of stressed CHO cells results in inappropriately elevated levels of AMPylated BiP and compromised secretion. These findings, guided by human genetics, highlight the destructive consequences of de-regulated BiP AMPylation and raise the prospect of tuning FICD's antagonistic activities towards therapeutic ends., Supported by a Wellcome Trust Principal Research Fellowship to D.R. (Wellcome 200848/Z/16/Z). A Diabetes UK RD Lawrence fellowship to E.D.F. (Grant number 19_0005971), and a Wellcome Trust Senior Research Fellowship to S.E.F. (105636/Z/14/Z). M.N.W. is in receipt of an Independent Fellowship from the Exeter Diabetes Centre of Excellence funded by Research England’s Expanding Excellence in England (E3) fund

Published
2022
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29. Flexibility of the Rotavirus NSP2 C-Terminal Region Supports Factory Formation via Liquid-Liquid Phase Separation

Author

Nichols, Sarah L, Nilsson, Emil M, Brown-Harding, Heather, LaConte, Leslie EW, Acker, Julia, Borodavka, Alexander, McDonald Esstman, Sarah, McDonald Esstman, Sarah [0000-0002-4004-7343], Apollo - University of Cambridge Repository, Acker, Julia [0000-0002-6422-6514], and Borodavka, Alexander [0000-0002-5729-2687]

Subjects
viral factory, Rotavirus, viroplasm, Virology, Insect Science, NSP5, Immunology, NSP2, LLPS, Phosphorylation, Viral Nonstructural Proteins, Virus Replication, Microbiology
Abstract

Many viruses sequester the materials needed for their replication into discrete subcellular factories. For rotaviruses (RVs), these factories are called viroplasms, and they are formed in the host cell cytosol via the process of liquid-liquid phase separation (LLPS). The nonstructural protein 2 (NSP2) and its binding partner, nonstructural protein 5 (NSP5), are critical for viroplasm biogenesis. Yet it is not fully understood how NSP2 and NSP5 cooperate to form factories. The C-terminal region (CTR) of NSP2 (residues 291 to 317) is flexible, allowing it to participate in domain-swapping interactions that promote interoctamer interactions and, presumably, viroplasm formation. Molecular dynamics simulations showed that a lysine-to-glutamic acid change at position 294 (K294E) reduces NSP2 CTR flexibility in silico. To test the impact of reduced NSP2 CTR flexibility during infection, we engineered a mutant RV bearing this change (rRV-NSP2K294E). Single-cycle growth assays revealed a >1.2-log reduction in endpoint titers for rRV-NSP2K294E versus the wild-type control (rRV-WT). Using immunofluorescence assays, we found that rRV-NSP2K294E formed smaller, more numerous viroplasms than rRV-WT. Live-cell imaging experiments confirmed these results and revealed that rRV-NSP2K294E factories had delayed fusion kinetics. Moreover, NSP2K294E and several other CTR mutants formed fewer viroplasm-like structures in NSP5 coexpressing cells than did control NSP2WT. Finally, NSP2K294E exhibited defects in its capacity to induce LLPS droplet formation in vitro when incubated alongside NSP5. These results underscore the importance of NSP2 CTR flexibility in supporting the biogenesis of RV factories. IMPORTANCE Viruses often condense the materials needed for their replication into discrete intracellular factories. For rotaviruses, agents of severe gastroenteritis in children, factory formation is mediated in part by an octameric protein called NSP2. A flexible C-terminal region of NSP2 has been proposed to link several NSP2 octamers together, a feature that might be important for factory formation. Here, we created a change in NSP2 that reduced C-terminal flexibility and analyzed the impact on rotavirus factories. We found that the change caused the formation of smaller and more numerous factories that could not readily fuse together like those of the wild-type virus. The altered NSP2 protein also had a reduced capacity to form factory-like condensates in a test tube. Together, these results add to our growing understanding of how NSP2 supports rotavirus factory formation-a key step of viral replication.

Published
2023

31. Publisher Correction: GDF15 mediates the effects of metformin on body weight and energy balance

Author

Coll, Anthony P., Chen, Michael, Taskar, Pranali, Rimmington, Debra, Patel, Satish, Tadross, John A., Cimino, Irene, Yang, Ming, Welsh, Paul, Virtue, Samuel, Goldspink, Deborah A., Miedzybrodzka, Emily L., Konopka, Adam R., Esponda, Raul Ruiz, Huang, Jeffrey T.-J., Tung, Y. C. Loraine, Rodriguez-Cuenca, Sergio, Tomaz, Rute A., Harding, Heather P., Melvin, Audrey, Yeo, Giles S. H., Preiss, David, Vidal-Puig, Antonio, Vallier, Ludovic, Nair, K. Sreekumaran, Wareham, Nicholas J., Ron, David, Gribble, Fiona M., Reimann, Frank, Sattar, Naveed, Savage, David B., Allan, Bernard B., and O’Rahilly, Stephen

Published
2020
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35. Teach for America: Leading for Change

Author

Harding, Heather

Abstract

Ending educational inequality requires not only an army of teachers who do whatever it takes to overcome the challenges facing children in low-income communities but also an army of leaders, working both in and outside school, who will change our inequitable system. Teach for America's mission is to help build this force. The organization's development model centers on empowering carefully selected recruits to have a transformational effect on students' lives. During the five-week summer institute followed by two years plus in the classroom, recruits learn how to plan lessons; check for understanding during instruction; design assessments; and build relationships with students, families, and colleagues. A large and growing body of research shows that corps members achieve academic gains equal to or larger than teachers from other preparation programs. (Contains 2 endnotes.)

Published
2012

36. A Study of the Effectiveness of Supplemental Educational Services for Title I Students in Baltimore City Public Schools

Author

Harding, Heather R., Harrison-Jones, Lois, and Rebach, Howard M.

Abstract

The authors of the "No Child Left Behind Act of 2001" anticipated that a majority of school districts or schools would not be able to attain state and national achievement standards without assistance. Consequently, the Act created a major tenet known as Supplemental Educational Services (SES) programs to improve the learning outcomes of students placed "at-risk" and to hold public schools accountable for increasing the proficiency levels of students in reading and mathematics. This study examined whether provision of supplemental educational services significantly improved academic achievement of students in Baltimore City Public Schools after they received supplemental services. A quasi-experimental research design was utilized in this study to compare SES participants and non-participants. (Contains 5 tables.)

Published
2012

37. Contextual Influences on Inquiries into Effective Teaching and Their Implications for Improving Student Learning

Author

Bryk, Anthony S., Harding, Heather, and Greenberg, Sharon

Abstract

In this article, Anthony Bryk, Heather Harding, and Sharon Greenberg report on a roundtable jointly sponsored by Teach For America and the Carnegie Foundation for the Advancement of Teaching. The authors brought together a group of scholars and practitioners with a broad range of perspectives and asked them to explore several questions related to the emerging national narrative on effective teachers: What is an effective teacher? How do we leverage this moment of enormous energy in producing more effective teaching to advance meaningful improvements at scale? Where are the current sites of success? What can we learn from what is working? The article is organized around the edited transcript of the roundtable discussion and is supplemented by author commentaries. The authors seek to illuminate and reimagine the current "nonsystem" in order to accelerate progress toward a wholly new approach to developing the teaching force our nation and our children need. (Contains 11 notes.)

Published
2012

38. An Examination of Supplemental Educational Services and Student Performance in Baltimore City Public Schools

Author

Harding, Heather R.

Abstract

The authors of the No Child Left Behind (NCLB 107-110) Act of 2001 anticipated that a majority of school districts or schools would not be able to attain state and national achievement standards without assistance. Consequently, the Act created a major tenet known as Supplemental Educational Services (SES) programs to improve the learning outcomes of students placed "at-risk" and to hold public schools accountable for increasing the proficiency levels of students in reading and mathematics. This study examined whether provision of supplemental educational services significantly improved academic achievement of selected third, fifth, and eighth grade students in Baltimore City Public Schools after they received supplemental services. A quasi-experimental research design was utilized in this study to compare SES participants and non-participants. Consistent with a quasi-experimental design, subjects were not randomly assigned to treatment groups. The experimental groups are students who participated in SES, and the comparison groups are students who did not participate. The results of the study showed that the level of student participation was correlated significantly and positively with students' 06-07 MSA reading and math scores when their 05-06 MSA reading and math scores were controlled. School level showed a significant influence on the level of participation of students during the 2006-2007, and students who went to schools that met Adequate Yearly Progress (AYP) showed a higher level of participation than students who were in schools that did not meet AYP. A major implication in this study is that while correlations coefficients shown were statistically significant, they were often quite small. For instance, a positive and statistically significant correlation was found between hours of participation and MSA score; however, the correlation coefficients were small. As is well known, small correlations can become statistically significant as "N" (i.e., sample size) grows large. In this case, an "N" of over 2,000 cases enabled a small correlation to be statistically significant. It is difficult to assess whether the correlations found are behaviorally or socially significant enough to be a basis for major policy recommendations. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Published
2009

41. Cultural Studies and Education: Perspectives on Theory, Methodology, and Practice. Harvard Educational Review Reprint Series No. 38

Author

Gaztambide-Fernandez, Ruben A., Harding, Heather, Sorde-Marti, Tere, Gaztambide-Fernandez, Ruben A., Harding, Heather, and Sorde-Marti, Tere

Abstract

This book portrays the intersection of two impressive currents in contemporary intellectual life, cultural studies and educational research. Despite important contributions from a number of scholars, commerce between these two fields has, until recently, been disappointingly scarce. Yet as the rich array of essays in this volume suggests, fruitful collaborations between cultural and educational studies have begun to appear. Moreover, these essays suggest that such collaborations can greatly enrich both fields. For education scholars and practitioners in particular, encounters with various aspects of the cultural studies enterprise have already begun to open up new approaches and insights in their research and their schools.

Published
2004

43. A homozygous p.(Arg371Ser) mutation in FICD de-regulates AMPylation of the human endoplasmic reticulum chaperone BiP causing infancy-onset diabetes and severe neurodevelopmental delay

Author

Perera, Luke A., primary, Hattersley, Andrew T., additional, Harding, Heather P., additional, Wakeling, Matthew N., additional, Flanagan, Sarah E., additional, Moshina, Ibrahim, additional, Raza, Jamal, additional, Gardham, Alice, additional, Ron, David, additional, and De Franco, Elisa, additional

Published
2022
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