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AWARD PURPOSE TO PREPARE JUSTICE-INVOLVED YOUTH AND YOUNG ADULTS, 18 TO 24 YEARS, FOR THE WORLD OF WORK WITH PAID WORK E...

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Department of Labor

AWARD PURPOSE TO PREPARE JUSTICE-INVOLVED YOUTH AND YOUNG ADULTS, 18 TO 24 YEARS, FOR THE WORLD OF WORK WITH PAID WORK EXPERIENCES, PROVIDE EDUCATIONAL AND OCCUPATIONAL SKILLED TRAINING IN IN-DEMAND INDUSTRIES SUCH AS CONSTRUCTION, AND HEALTH, AND PROVIDE MENTORSHIP, CONFLICT RESOLUTION, AND LEADERSHIP DEVELOPMENT THAT WILL STRENGTHEN THEIR OPPORTUNITIES FOR EMPLOYMENT AND POST-SECONDARY OPPORTUNITIES. ACTIVITIES PERFORMED THE PROGRAM COMPONENTS ARE OCCUPATIONAL SKILLED TRAINING, PAID WORK EXPERIENCE, EMPLOYMENT AND CAREER SERVICES, LEADERSHIP TRAINING, MENTORSHIP, EDUCATION, SUPPORTIVE SERVICE, AND FOLLOW-UP. OCCUPATIONAL SKILLED TRAINING WILL CONSIST OF ON-SITE CONSTRUCTION TRAINING, CONSTRUCTION THEORY FOR THE OBTAINMENT OF CERTIFICATIONS. THE ON-SITE TRAINING WILL OCCUR AT GJA, AND EMPLOYER PARTNERS WORK SITES. PARTICIPANTS WILL ALSO HAVE AN OPPORTUNITY TO ENROLL IN THE ADVANCED OCCUPATIONAL SKILLED CERTIFICATE PROGRAM AT CCAC. THE CERTIFICATE SKILLED TRAINING AT CCAC IS WELDING, PLUMBING, AND FACILITIES MAINTENANCE TECHNOLOGY. FOR HEALTH, PARTICIPANTS WILL RECEIVE CNA TRAINING FROM CCAC. THE TRAINING IS 24 DAYS WHERE THEY EARN A CNA CERTIFICATION. EMPLOYMENT AND CAREER SERVICES SUCH AS JOB PREPARATION, CAREER EXPLORATION, WORK READINESS, ALLOWS PARTICIPANTS TO EXPLORE CAREER OPPORTUNITIES TO ADDRESS SPECIFIC WORKFORCE CHALLENGES AND BARRIERS FACED BY YOUTH OFFENDERS TO PREPARE THEM FOR JOBS. LEADERSHIP TRAINING WILL BE PROMOTED IN ALL ASPECTS OF THE PROGRAM AND CAPTURES THE UNDERLYING PRINCIPLE THAT PARTICIPANTS ARE OUR FUTURE LEADERS. MENTORSHIP WILL BE PROVIDED; SERVICE OF MENTORS IS THE BACKBONE OF THE PROGRAM TO YOUTH. THEY CAN HELP YOUTH AS THEY GO THROUGH CHALLENGING LIFE TRANSITIONS, INCLUDING DEALING WITH STRESSFUL CHANGES AT HOME, RE-ENTRY FROM THE SYSTEM, OR TO ADULTHOOD. THE STRUCTURE OF THE MENTORSHIP PROGRAM IS ONE YEAR DURATION, ONE-ON-ONE MENTORING, AND SCREENING, TRAINING, AND ON-GOING SUPPORT OF MENTORS. SELECTION OF MENTORS WILL CONSIST OF CARING ADULTS OR INDIVIDUALS WHO HAVE LIVE INCARCERATION AND COMMUNITY VIOLENCE EXPERIENCES. PARTICIPANTS WILL HAVE THE OPPORTUNITY TO RECEIVE HIGH SCHOOL/GED PREPARATION. THEY WILL ALSO RECEIVE POST-SECONDARY EDUCATION INFORMATION FROM CCAC. POSTSECONDARY EDUCATION IS A STRONG FEATURE THROUGHOUT THE PROGRAM SO THAT PARTICIPANTS CAN MASTER SUCCESS WHILE THEY ARE IN COLLEGE. GROWTH FOCUSED CASE MANAGEMENT, SUPPORTIVE SERVICES, FOLLOW-UP, AND RETENTION WILL BE PROVIDED TO HELP YOUTH MASTER SUCCESS IN COMPLETING THE PROGRAM AND MAINTAINING EMPLOYMENT OR ADVANCE TRAINING. DELIVERABLES 70% EDUCATION AND EMPLOYMENT RATE FOR SECOND QUARTER AFTER EXIT; 60% EDUCATION AND EMPLOYMENT RATE FOURTH QUARTER AFTER EXIT; $5,750 MEDIAN EARNINGS SECOND QUARTER AFTER EXIT; 50% CREDENTIAL ATTAINMENT; 70% MEASURABLE SKILL GAINS. INTENDED BENEFICIARY YOUTH, THE COMMUNITIES, PARENTS, SCHOOLS, ETC. SUBRECIPIENT ACTIVITIES N/A

Up to $1.6M

Deadline: 2026-12-31

EducationHealth

Bacterial Regulation of Acid Resistance and Amino Acid Metabolism

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NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Bacteria have successfully colonized almost every niche on this planet, and their success is driven in large part by their ability to adapt to and survive environmental challenges. One example is excessive protons (or acidity, low pH), which can damage lipids, nucleic acids, and proteins. Bacteria that colonize the human body contend with many different pH gradients, especially in the gastrointestinal system. One way that bacteria survive this stress is by using amino acid catabolism to de-acidify their environment. We discovered that the bacterial second messenger c-di-GMP regulates both amino acid metabolism and acid resistance in the gastrointestinal bacteria E. coli and Shigella. One of these amino acids is isoleucine, and we have found that E. coli, but not Shigella, catabolizes isoleucine to resist acid stress. Bacterial isoleucine-mediated acid resistance has not been previously reported. In this application, we will investigate how isoleucine contributes to acid resistance, how c- di-GMP regulates acid resistance in these two organisms, and how these pathways are impacted by the evolutionary process of pathoadaptation. Methodologies proposed here are accessible for undergraduate researchers, who will complete the experiments outlined in this proposal. Because many bacteria use amino acid metabolism to resist acid stress, and because c-di-GMP signaling is so widely conserved, findings from this study will be widely generalizable for other gastrointestinal bacteria. Understanding how gastrointestinal bacteria adapt to pH stress is critical for many aspects of human health, including protecting our food supply chain, promoting symbiotic bacteria, and controlling human pathogens.

Up to $533K

Deadline: 2029-01-31

Health

BH UWC Consolidated Grant Program

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Baldwin Hills Conservancy

The Consolidated Grant Program guidelines prioritizes project which directly and meaningfully benefit Disadvantaged Communities and Vulnerable Populations. BH UWC Community and Climate Resilience Framework is integral to effective and equitable grant making is the strategic funding of projects & programs that deliver tangible and/or measurable benefits to a population, in direct response to a demonstrated need or vulnerability. As a conservancy within of the California Natural Resources Agency tasked with addressing key regional climate hazards and disparities in community access to parks, green spaces, and other recreational facilities, the BH UWC has developed a grant making framework that enables strategic investment in high‐impact projects that deliver direct multiple benefits to vulnerable populations and communities, hereinafter referred to as the BH UWC Community and Climate Resilience Framework. Developed to fortify the Conservancy’s grant funding decision‐making process, the BH UWC Community and Climate Resilience Framework establishes a method for: Identifying multi‐benefit / high‐impact projects that address key regional climate‐related vulnerabilities, disproportionate exposure to climate hazards, and disparities in community access to recreational spaces; and Prioritizing funding for projects that serve or directly benefit vulnerable populations, frontline communities, or communities of color that have faced historical disinvestment. Comprised of four (4) key elements, this systematic funding framework ensures effective and equitable grant making through: 1. Establishment of Strategic Agency Goals to Enhance Community and Climate Resilience 2. Identifying Priority Projects for Agency Funding 3. Utilization of Novel Tools to Evaluate a Proposed Project’s Benefits / Impact; and 4. Allocation of Funding for Proposed Projects Based on Strategic Alignment, Potential Project Impacts & Benefits, and Implementation Urgency.

Deadline: Rolling

disadvantaged communities; environment & water; parks & recreation

Biogenesis of hERG1a/1b ion channels in health and disease model cardiomyocytes

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NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Cardiac IKr is a critical repolarizing potassium current shaping the human ventricular action potential. It is conducted by heteromeric assemblies of the human ether-à-go-go-related gene (hERG1) 1a and 1b subunits. These subunits are encoded by alternate transcripts of the hERG/KCNH2 gene and differ only in their amino- terminal regions. hERG1a/1b heteromerization is vital for normal CM function, as the imbalance of subunit expression and/or function results in cellular pro-arrhythmic behaviors. hERG1a/1b assembly is mediated by the co-translational association of the encoding mRNAs in HEK293 cells, cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs), and human myocardium. Evidence suggests that interaction between the nascent proteins is not required for the co-translational complex assembly. This grant's preliminary findings indicate that this complex assembly occurs post-transcriptionally and is promoted by direct interactions between hERG1a and 1b mRNAs governed by their secondary structures. In preliminary studies, RNA binding proteins DDX3X and DDX5 were identified as part of the complex, and purified DDX3X promoted hERG1a/1b mRNAs' association in vitro. In the K99 phase, I will define the mRNA structural features promoting the co-translational association and determine the affinity and energies of the RNA/RNA interaction using in vitro systems, isothermal calorimetry (ITC), mutagenesis, hybrid protein-RNA immunoprecipitation (RIP), and live-cell imaging. I will also determine whether DDX3X and DDX5 affect hERG1a and 1b mRNAs stability, translation, and association in hiPSC-CMs using qPCR, electrophysiology, Western Blot, ribosome profiling, RIP, and single molecule fluorescent in situ hybridization (smFISH). I will use quantitative ITC and in vitro reconstitution approaches to determine the specificity, affinity, and energies of the interaction between purified DDX3X and DDX5 with hERG1a and 1b mRNAs. I will also evaluate if DDX3X and DDX5 promote the association of the mRNAs in in vitro systems. In the R00 phase, I will determine whether the stability, translation, and association of hERG1a and 1b mRNAs are impaired in arrhythmias associated with type 2 long QT syndrome (LQT2). I will use hiPSC-CM disease models to evaluate half-life, translation rate, and association of the mRNAs with qPCR, ribosome profiling, RIP, and smFISH. These experiments will contribute to understanding ion channel biogenesis and elucidate molecular mechanisms underlying LQT2 related arrhythmias. This proposal is designed to fulfill my short-term goals of expanding my skills in cardiovascular research and biophysics and transitioning into the independent phase of my career. This will ultimately allow me to obtain my long-term purpose of linking RNA and ion channel biophysics to translational cardiovascular research.

Up to $249K

Deadline: 2029-01-31

Health

Biophysical constraints on antibody affinity maturation to SARS-CoV-2

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NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT The objective of this proposal is to develop a quantitative understanding of how the biophysical properties of antibodies impact their capacity to evolve affinity to divergent SARS-CoV-2 spike variants. Though there is substantial evidence that mutations acquired during affinity maturation impact antibody expression, affinity for distinct viral variants, and self-reactivity, we lack a quantitative understanding of (1) how mutations impact these biophysical properties and (2) how these properties, and trade-offs between them, collectively determine the fate of the corresponding B-cell lineage. Here, we propose three Aims to test our hypothesis that mutations differentially impact antibody expression, affinity, and self-reactivity, resulting in biophysical trade-offs that constrain the evolution of antibodies that bind divergent SARS-CoV-2 spike variants. In Aim 1, we quantitate the biophysical effects of mutations in anti-SARS-CoV-2 spike antibodies, using high-throughput mammalian cell- display methods we recently developed. By measuring the expression, affinity, and self-reactivity for millions of anti-spike antibodies, including broadly neutralizing antibodies (bnAbs) that bind divergent spike variants, their evolutionary predecessors, and systematically mutagenized antibody sequences, we will unveil biophysical constraints that shape affinity maturation to rapidly evolving viral antigens. In Aim 2, we evaluate the contributions of antibody biophysical properties to B-cell fitness, or proliferation, using longitudinally-sampled patient B-cells following exposure to divergent strains of SARS-CoV-2. This approach will reveal the relative importance of distinct antibody biophysical properties in driving B-cell evolutionary dynamics in human repertoires and enable development of quantitative models for predicting the outcomes of affinity maturation. In Aim 3, we define the impact of selection pressure during affinity maturation on the biophysical properties of the resulting antibodies, focusing on selection regimes known to favor the maturation of bnAbs that bind distinct spike variants. To this end, we leverage a B-cell directed evolution platform that mimics the mutagenic load of somatic hypermutation, enables fine-tuning of the antibody selection conditions, and supports longitudinal B-cell sampling to profile the evolutionary dynamics of the B-cell response and the biophysical properties of the corresponding antibody lineages. The resulting data will be used to define the impact of the selection regime on the biophysical determinants of B-cell fitness. Successful completion of these Aims will yield quantitative insight into (1) how antibody biophysical properties change during affinity maturation, (2) how they collectively determine B-cell fate in human repertoires, and (3) how their relative importance varies across distinct selection regimes. Thus, this work will advance our fundamental understanding of the biophysical mechanisms that shape antibody affinity maturation to rapidly evolving pathogens like SARS-CoV-2, supporting efforts to design and elicit antibodies that bind existing and novel viral variants.

Up to $816K

Deadline: 2031-01-31

Health

BMP2/6 ligand formation and function in development and iron homeostasis

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NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT Bone morphogenetic proteins (BMPs) play critical roles in development and adult tissue homeostasis. Class I (BMP2 and 4) and class II (BMP5-7) BMPs are the dominant players in specifying cell fate, embryonic patterning and organ morphogenesis. We previously showed that liver endothelial cell (LEC)-derived BMP2 and BMP6 also have a key role to regulate systemic homeostasis of the essential nutrient iron by controlling expression of the liver hormone hepcidin. Indeed, iron homeostasis regulation is the major non-redundant function of BMP6 in vivo, and impaired BMP signaling is the main cause of the iron overload disorder hereditary hemochromatosis. BMPs are dimeric proteins that are made as precursors comprised of a non-signaling prodomain and an active ligand released by proteolytic cleavage. Our work and others' have shown that prodomains play critical roles in ligand folding, dimerization, activation, and receptor interactions. Moreover, many ligand functions are carried out by heterodimers (comprised of 2 different ligands) rather than homodimers. Notably, little is known about BMP2 or BMP6 dimerization, proteolytic processing, and prodomain function. Moreover, BMP6 prodomain mutations are linked to altered hepcidin regulation and iron overload in humans, but the mechanisms are uncertain. Here, we will show that 1) LEC-secreted BMP2 and BMP6 must work together to regulate hepcidin and iron homeostasis in vivo; 2) co-expressed BMP2 and BMP6 form heterodimers that signal more strongly vs homodimers; 2) BMP2 and BMP6 proteolytic maturation and/or subcellular trafficking differ from their closest homologues BMP4 and BMP7; 3) BMP2 prodomain is essential to generate active BMP6 homodimers or BMP2/6 heterodimers in Xenopus embryos, whereas cognate prodomains are essential in LECs; and 4) BMP6 prodomain mutations linked to iron overload impair ligand activity and hepcidin induction in vitro. We hypothesize that BMP2/6 heterodimers are a key ligand for hepcidin and iron homeostasis regulation and that prodomains have critical roles in BMP2/6 maturation and function. In this proposal, we aim to use structural modeling, Xenopus embryos, a human LEC-hepatocyte cell culture system, and novel knock-in mice to elucidate how BMP2 and BMP6 prodomains, and the process of proteolytic maturation, contribute to heterodimer and/or homodimer formation and function, and how BMP6 prodomain mutations impact these processes to impair hepcidin regulation and cause iron overload. Our long-term goals are to understand how BMP signaling is regulated to control hepcidin expression and systemic iron homeostasis, how this process is perturbed in iron disorders, and ultimately to develop new treatments for iron disorders. We will also gain fundamental insights into BMP ligand maturation and prodomain function that will have broader impacts for many other fields where BMP signaling is important, including developmental biology.

Up to $814K

Deadline: 2030-11-30

Health

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