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National Institutes of Health

Through this funding opportunity announcement (FOA), the National Cancer Institute (NCI) invites applications for P50 Research Center Grants for Specialized Programs of Research Excellence (SPORE). The program will fund P50 SPORE grants to support state-of-the-art investigator-initiated translational research that will contribute to improved prevention, early detection, diagnosis, and treatment of an organ-specific cancer or a highly related group of cancers. For the purpose of this FOA, a group of highly related cancers are those that are derived from the same organ system, such as gastrointestinal, neuroendocrine, head and neck, and other cancers. Other programmatically appropriate groups of cancers may include those centered around a common biological mechanism critical for promoting tumorigenesis and/or cancer progression in organ sites that belong to different organ systems. For example, a SPORE may focus on cancers caused by the same infectious agent or cancers promoted and sustained by dysregulation of a common signaling pathway. In addition, a SPORE may focus on cross-cutting themes such as pediatric cancers or cancer health disparities. The research supported through this program must be translational and must stem from research on human biology using cellular, molecular, structural, biochemical, and/or genetic experimental approaches. SPORE projects must have the goal of reaching a translational human endpoint within the project period of the grant.

National Institutes of Health

<p>Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) invites applications for P50 Research Center Grants for Specialized Programs of Research Excellence (SPORE). This is a re-issuance of <a href="https://grants.nih.gov/grants/guide/pa-files/PAR-23-284.html">PAR-23-284</a>. The program will fund P50 SPORE grants to support state-of-the-art investigator-initiated translational research that will contribute to improved prevention, early detection, diagnosis, and treatment of an organ-specific cancer or a highly related group of cancers. For the purpose of this NOFO, a group of highly related cancers are those that are derived from the same organ system, such as gastrointestinal, neuroendocrine, head and neck, and other cancers. Other programmatically appropriate groups of cancers may include those centered around a common biological mechanism critical for promoting tumorigenesis and/or cancer progression in organ sites that belong to different organ systems. For example, a SPORE may focus on cancers caused by the same infectious agent or cancers promoted and sustained by dysregulation of a common signaling pathway. In addition, a SPORE may focus on cross-cutting themes such as pediatric cancers or epigenetics. The research supported through this program must be translational and must stem from research on human biology using cellular, molecular, structural, biochemical, and/or genetic experimental approaches. SPORE projects must have the goal of reaching a translational human endpoint within the project period of the grant.</p>

National Institutes of Health

Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) invites applications for P50 Research Center Grants for Specialized Programs of Research Excellence (SPORE). This is a re-issuance of PAR-23-284. The program will fund P50 SPORE grants to support state-of-the-art investigator-initiated translational research that will contribute to improved prevention, early detection, diagnosis, and treatment of an organ-specific cancer or a highly related group of cancers. For the purpose of this NOFO, a group of highly related cancers are those that are derived from the same organ system, such as gastrointestinal, neuroendocrine, head and neck, and other cancers. Other programmatically appropriate groups of cancers may include those centered around a common biological mechanism critical for promoting tumorigenesis and/or cancer progression in organ sites that belong to different organ systems. For example, a SPORE may focus on cancers caused by the same infectious agent or cancers promoted and sustained by dysregulation of a common signaling pathway. In addition, a SPORE may focus on cross-cutting themes such as pediatric cancers or epigenetics. The research supported through this program must be translational and must stem from research on human biology using cellular, molecular, structural, biochemical, and/or genetic experimental approaches. SPORE projects must have the goal of reaching a translational human endpoint within the project period of the grant.

OD - NIH Office of the Director

PROJECT SUMMARY/ABSTRACT: This S10 Shared Instrumentation Grant application from Washington University (WashU) in St. Louis requests funds in partial support of the purchase of a Sybmia Pro.specta X3 scanner (Siemens Medical Solutions USA). This hybrid single photon emission computed tomography and x-ray computed tomography (SPECT/CT) system will be housed in a dedicated Nuclear Medicine research facility for the non-invasive assessment of therapeutic and diagnostic (theranostic) radiopharmaceuticals. This state-of-the-art instrument will be a critical, broadly used resource for the clinical and translational neuroscience, cardiovascular and oncology research programmes at WashU. The requested SPECT/CT will be the only research dedicated SPECT/CT system across the WashU clinical enterprise. At present, WashU through its affiliated Hospitals, has access to 7 SPECT/CT scanners across the medical campus. These are dedicated for standard of care and clinical trial workflows, 1 of them being at the Children’s hospital (out-of-reach for research), and 2 of the SPECT scanners are obsolete and only used for planar imaging. These systems are all >10 yr, and they are heavily utilized, at nearly 8 h of scan time per day average (utilization >85%), which does not include protocol development and maintenance. Access for research is highly restricted and there is no support for the special attention required for clinical research. Additionally, in the greater St. Louis region beyond WashU there is no research SPECT/CT hardware, and the nearest research SPECT/CT scanners are located at University of Missouri Veterinary Health Center (2.5 h drive), dedicated for non-human use. The Symbia Pro.specta incorporates advanced workflows including advanced iterative data driven motion correction features are critical for advanced quantitative imaging-; a redesigned quantitative framework for therapeutic absorbed dose assessment; and best-in-the-field collimators. The requested SPECT/CT scanner will anchor major new research efforts in theranostics for cancer, cardiovascular disease and neuroscience at WashU. Towards this end, Pamela Woodard, Radiology Chair and MIR Director, and Timothy Eberlein, Director, Alvin J. Siteman Cancer Center, have made substantial financial and administrative commitments to ensure the successful utilization of this instrument. These include funds for (1) installation and renovation costs, (2) adjacent radioactive handling and patient-administration space, (3) maintenance for the instrument, (4) pilot funds for protocol development and (5) personnel support. A new Section of Medical Physics is being established to harness the outstanding imaging science and translational radiopharmaceutical expertise at WashU that will be co-located with this centerpiece scanner. The combination of advanced instrumentation and robust support from our institution will enable groundbreaking discoveries and innovations that will benefit both our research community and patients, reflecting our dedication to excellence in scientific inquiry and healthcare.

ATSDR - Agency for Toxic Substances and Disease Registry

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with no cure, and although inflammation plays a significant role in the disease, gaps remain in leveraging this knowledge for personalized clinical outcome models and personalized therapeutics. Peripheral blood immune profiles—defined as the total numbers and activation states of specific peripheral immune cells—reflect overall inflammation, but methodologic gaps exist to characterize these immune profiles given limitations in conventional flow cytometry, hampering its widespread use for ALS. The long-term goal is to leverage immune profiles to identify dysregulated immune pathways that can be treated to slow or stop ALS progression. The overall objective in this proposal, being submitted in response to RFA-TS-25-036 Funding Option A, is to establish spectral flow cytometry as the state-of-the-art approach to characterize peripheral immune profiles in ALS. The central hypothesis is that spectral flow cytometry will yield rigor and reproducibility with fresh and frozen blood samples and will identify pro-inflammatory immune profiles for ALS clinical outcome prediction. The rationale is that establishing rigorous protocols for the widespread multicenter use of spectral flow cytometry in ALS will unlock the complex, but vast, potential of the immune system for improving diagnosis, prognosis, and drug development for all persons with ALS. The central hypothesis will be tested by pursuing two specific aims: 1) Utilize spectral flow cytometry to quantify inflammation in ALS peripheral blood biosamples and determine the consistency of immune markers between samples processed fresh versus frozen to inform multisite ALS studies; and 2) Determine the natural history, diagnostic, and prognostic significance of comprehensive longitudinal spectral flow cytometry immune profiles as an ALS inflammatory signature. Under the first Aim, spectral flow cytometry protocols will be optimized to characterize ALS inflammation in fresh and frozen samples, paving the way for its use in multisite ALS studies. Under the second Aim, immune profiles will be associated with important ALS clinical outcomes, such as case status and disease progression. The research proposed in this application is innovative, in the applicant’s opinion, because it moves the field in a new direction—bridging both mechanistic and knowledge gaps—by bringing the transformational potential of spectral flow cytometry to ALS, establishing the rigor needed to make the technology widely available to the ALS community, leveraging the resulting data to better understand the role of comprehensive immune profiles for ALS, and providing the foundation for future multisite studies. The proposed research is significant because peripheral blood immunophenotyping will enable improved ALS clinical outcome associations, and eventually therapeutic target identification, testing, and responder analysis.

NIDCD - National Institute on Deafness and Other Communication Disorders

PROJECT SUMMARY Although hearing aids and cochlear implants (CIs) improve the ability of people with sensorineural hearing loss (SNHL) to communicate, performance remains stubbornly low, particularly in noisy backgrounds. This is a critical health issue, not least because of the strong association between hearing abilities and cognitive decline with age. Older adults, even those with typical hearing (TH), also experience deficits understanding speech in noise in ways that remain poorly understood. Our long-term goal is to uncover the mechanisms that limit auditory and speech perception under challenging acoustic conditions in adults with and without hearing loss across the lifespan. This goal is addressed under three specific aims that explore interlinked aspects of the spectro-temporal encoding of auditory and speech sounds. Under Aim 1, the fundamental mechanisms that allow us to detect and identify speech and non-speech sounds in noise are explored. A new hypothesis involving the processing of amplitude fluctuations across frequency is compared with the classic hypothesis involving the processing of energy changes across frequency. Empirical results in adults with SNHL, CIs, and TH across the lifespan will be compared with predictions from state-of-the-art computational models of the auditory periphery and midbrain. Under Aim 2, the relative contributions of peripheral and more central factors to deficits in speech perception in noise with hearing loss and age are studied using a novel intervention approach, rather than more traditional correlational methods. By manipulating the degree of peripheral spectral resolution and temporal fine structure cues available in the speech sounds themselves, the experiments test the hypothesis that the bulk of age effects for speech in noise can be accounted for by changes in peripheral representations. Under Aim 3, auditory and speech perception is studied with respect to the influence of spectral contrast and context effects. Perception is critically dependent on the surrounding context in which the sensory signals are received, but we know little about how these dependencies are altered by either age or hearing loss. The implication is that any changes in our ability to make use of sensory context may be impacted by sensory loss or age in ways that are not detected by standard clinical tests. Our experiments will provide both behavioral and neurophysiological measures of auditory and speech context effects in TH and SNHL across the adult lifespan to test the hypothesis that changes in peripheral processing with hearing loss and age can radically affect how our perception adjusts to the surrounding context, and therefore contributes to the unexplained difficulties in communication faced by older people with and without hearing loss in dynamic acoustic environments. Overall, the results of this project will shed new light on critical perceptual issues surrounding speech understanding in challenging acoustic environments and will contribute to developing new approaches to the diagnosis, treatment, and management of hearing loss.

NINDS - National Institute of Neurological Disorders and Stroke

Spreading Depolarization (SD) is associated with migraine aura and is recognized as a novel mechanism of injury in stroke and brain trauma patients. SDs are waves of sustained depolarization of neurons and glia that propagate the breakdown of transmembrane ion gradients, distortion of synaptic circuitry, and cytotoxic edema. Yet, the fundamental question of the molecular mechanism of rapid water entry into depolarized neurons remains an enigma. Passive osmotically obligated water flux following cations influx during SD is problematic because pyramidal neurons are highly resilient to osmotic swelling due to a lack of aquaporins in their membrane. Based on our preliminary data and the literature, it is plausible that volume-regulated Cl-/anion channels (VRAC) are involved in SD-induced neuronal swelling and recovery. In neurons lacking aquaporins, VRAC may either promote neuronal swelling during strong depolarization as a route for swelling-aggravating Cl- influx or assist in neuronal volume recovery during repolarization, providing a conduit for Cl- efflux. Thus, by serving as a major anionic pathway, VRAC plays a dual reciprocal role in neuronal volume regulation, and it conducts water. Aim 1 will reveal the role of VRAC in SD-induced neuronal edema and recovery. SD could lead to cell death in the energy-deprived cortex, but not all neurons die. Little is known about the cause of this variability across depolarized but viable neurons. It is feasible that the variation in the increased levels and duration of mitochondrial Ca2+ during SD could underlie this variability. However, in vivo mitochondrial Ca2+ levels in SD were never quantified, and cells were never followed in real-time until their death or recovery. Aim 2 will address these unresolved questions. Blood and plasma are released into the brain parenchyma during neurologic emergencies, and even without SD, many blood components can contribute to cell injury. The role of excitatory amino acids in triggering excitotoxicity cascades has been extensively studied. Surprisingly, our novel results reveal that non-excitatory amino acids induce severe damage to neurons in hypoxic brain tissue. Astroglial VRAC appears to mediate this injury, and this hypothesis will be tested in Aim 3. The specific aims are: 1) To test the hypothesis that the activation of neuronal VRAC is the mechanism implicated in SD-induced neuronal swelling and recovery. 2) To test the hypothesis that the increase in mitochondrial Ca2+ caused by SD is the mechanism underlying the “commitment point” marking the switch between cell death and recovery from SD. 3) To test the hypothesis that astroglial VRAC activity mediates neuronal injury by non-excitatory amino acids during hypoxic- ischemic conditions. Various classic and state-of-the-art technologies such as viral expression, mouse genetics, intravital imaging, and in vivo FRET-based 2-photon quantitative mitochondrial Ca2+ imaging will be used while simultaneously monitoring the occurrence of SD with electrophysiology. When applicable, intravital 2-photon imaging will be followed by ultrastructural analyses with serial section transmission electron microscopy. The results will bring new insight into mechanisms of acute cellular injury in SD-associated neurologic emergencies.

Dept of the Army -- Materiel Command

The ARO is soliciting proposals for Staff Research Program opportunities. The purpose of the program is to enable ARO scientific staff to maintain and expand professional competence in support of fulfilling the ARO mission through the conduct of hands-on, basic research. The staff research will be performed collaboratively with institutions external to ARO. Staff research efforts will involve scientific study directed toward advancing the state-of-the-art or increasing knowledge and scientific understanding in engineering, physical, life and information sciences, when there is an intersection with the interests and capabilities of the participating external institutions in these basic research areas.Protection of Mission Integrity: The primary role of the ARO scientific staff is to objectively assess and fund extramural research at numerous institutions across the U.S. and throughout the world. Since it is vitally important that the ARO be impartial in its actions, ARO scientists cannot engage in activities that could compromise the perceived objectivity of that scientist with respect to the institution, or with respect to the areas of science/engineering that they are responsible for as Program Managers. Consequently, ARO Program Managers will be disqualified from taking official actions regarding any institution at which that PM conducts Staff Research.Staff research will be conducted, directed and managed by an ARO scientist at the institution's laboratory facilities or field research sites, in collaboration with a PI designated by the institution. ARO scientists will not be named as a PI on any proposal or resulting award. Results of the Staff Research Program may include publication or co-authorship of research results and presentation at scientific forums, and contribute to the education and training of students, in accordance with the terms of the cooperative agreement.NOTE: ARO scientific staff will seek out a collaborating institution to engage in staff research as opportunities arise and at the discretion of ARO.

Stark Community Foundation

Stark Community Foundation ($200M in assets) supports nonprofits in OH through grants focused on education, community development, health, arts. Awards range from $1,000 to $50,000.

OD - NIH Office of the Director

Project summary/abstract: This application proposes to replace an end-of-life Philips research 3T MRI in the MRI Service Center at Johns Hopkins University (JHU) with a state-of-the-art Philips MR7700 3T MRI system. The proposed MRI scanner will benefit NIH-funded investigators across JHU and beyond. The current Philips research 3T MRI system has supported numerious NIH-funded projects over the past 20 years but is now reaching its end-of-life. The vendor, Philips Healthcare, has informed us that, due to the age of the hardware and the scarcity of this model among their customers, service contracts or replacement parts will no longer be available for this system beyond December 31, 2025. Therefore, the replacement with a new research 3T is both timely and imperative. JHU’s MRI technical group is one of the largest in the nation (>150 people). Therefore, considerable technical expertise is available among the Center personnel and other investigators at Johns Hopkins Radiology. Furthermore, JHU is known for its translational research and many clinicians have a strong need for reseach MRI as part of their NIH-funded studies. The long-term objectives of the proposed new research MRI are therefore to support NIH-funded projects at JHU across a wide range of disciplines, facilitating improved understanding of diseases and searching for a potential cure. For this application, we have assembled 12 Major Users and 5 Other Users consisting of different organs or clinical conditions (from 8 different NIH ICs). The proposed new research 3T is a Philips MR7700. This decision was made after a careful survey of similar systems by other vendors and a thorough assessment of sequence compatibility and continuity, especially the needs of our Major and Other Users. The new system has several important features when compared to the old system and other products on the market. The system is equipped with digital Stream (dStream) technology in which digital sampling occurs in the RF coil. This results in a SNR increase by 40% which will benefit all Major and Other Users’ projects. The new system has a 70cm bore which is less claustrophobic for patients, causes less discomfort, can accommodate larger patients, and allows a greater field-of-view. This is especially important for Major Users’ projects that involve vulnerable or high-BMI patients. The new MRI system uses a zero-boil off magnet and requires 0 refill of helium. Thus this system is environmentally more sustainable and reduces costs in maintainence and service contract. The new system is equipped with AI and deep learning technology are included in protocol suggestion, automatic planning, and image reconstruction. This improved efficiency in workflow will give all Major Users more time for actual scanning, allowing higher SNR or resolution. Simultaneous multi-slice (SMS) technology will allow faster fMRI and diffusion acquisitions, which are particularly beneficial for brain MRI studies. Collectively, these improved technologies and new features will significantly enhanced the projects of our Major and Other Users.

National Park Service

United States Department of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This posting is to provide public notice of the NPS' intention to fund the following project activities without full and open competition: Task Agreement P16AC01594 under Cooperative Agreement P13AC00676 with the Regents of the University of California, Berkeley, a partner under the Californian Cooperative Ecosystem Studies Unit, for the project titled, "State-of-the-art Searchable Web Interface for American WWII Home Front Oral History Collection."

Stavros Niarchos Foundation

Major international philanthropist funding arts, education, health, and social welfare with $3B+ in grants.

Kids and Paper

Kids and Paper has served children ages 5-12 with afterschool and summer program through homework help, SEL development through creative arts, healthy meals, and recreational activities at Magnuson Community Center, located at 7110 62nd Ave NE Seattle, WA. We are now looking to expand our educational impact by adding a new element to our program, specific STEM focused activities and tutoring that expose children to topics and hands-on learning. This will help students connect what they are learning with real-world applications. We will offer the new STEM program through the summer of 2023 and anticipate closing this project on September 30, 2023.

U.S. Mission to Uzbekistan

The U.S. Department of State's Embassy Tashkent announces an open competition for a cooperative agreement to implement " Storytelling to Safeguard Cultural Identity and Sovereignty: Bolstering the Tourism Industry" in Uzbekistan. This program aims to maximize the impact of U.S. investments in cultural heritage preservation and Ambassadors Fund for Cultural Preservation (AFCP) projects amplifying shared civilizational values and U.S. linkages while enhancing tourism experiences and building capacity for story-telling and content creation related to AFCP-supported heritage sites across Uzbekistan. The selected implementer will work in partnership with the Art and Culture Development Foundation (ACDF), Cultural Heritage Agency of the Republic of Uzbekistan (CHA), National Tourism Committee, National Content Creation Center, and local creative industry partners to deliver an integrated training program targeting two key audiences: tourism professionals and tour guides, and content creators (bloggers, journalists, filmmakers, and digital creators). The program will establish a specialized lab Heritage Content Creation &amp; Storytelling Lab to develop practical skills and increase quality of heritage-related storytelling in different formats and platforms. This program will enhance the visibility and impact of U.S. cultural preservation investments while strengthening U.S.-Uzbekistan cultural cooperation in support of a Joint Statement of Intent in the Field of Cultural Heritage declared during a C5+1 meeting in November 2025.

NIDA - National Institute on Drug Abuse

Homelessness and housing instability represent critical public health challenges in the US with more than 650,000 people experiencing homelessness (PEH) nightly. PEH experience differential health effects across various conditions, including chronic disease, substance use, and HIV, compared to their housed counterparts. An astounding 65% of PEH report having used illicit drugs regularly in their lifetime with 37% reporting regular drug use in previous 6 months. Homelessness and illicit substance use, in isolation and in combination, continue to be significant drivers of poor HIV outcomes and are highlighted as key priority targets under the Ending the HIV Epidemic (EHE) Initiative. EHE has identified evidence-based interventions, including rapid HIV testing, antiretroviral therapy (ART), low barrier clinics, and PrEP that need to be implemented, scaled, and sustained within communities most affected by HIV. To maximize the effectiveness of these interventions among PEH who use drugs and to address the HIV, overdose and homelessness syndemic, comprehensive healthcare models need to be developed, tested, and deployed where they are in comfortable environments that simultaneously address a key driver of HIV, namely untreated substance use disorders (SUD). The HIV Medicine Association has called for the scale-up of street medicine (delivering health services directly to unsheltered individuals where they are), counseling and differentiated service delivery to end the HIV epidemic. We developed, refined, and pilot tested Status Neutral Tele-Health ConcieRge (SN-THR), a telehealth-based, multicomponent care model originally designed for people with who inject drugs (PWID) with HIV then adapted it to include PWID without HIV for prevention via PrEP and MOUD. We hypothesize that SN-THR will increase access to HIV care (testing, prevention, treatment), SUD services, and mental health services through telehealth to augment street-based primary care (i.e. street medicine). We propose to test the efficacy, cost-effectiveness, and implementation of an innovative integrated HIV, addiction, and primary care model—SN-THR—in a street-based setting using a hybrid type I effectiveness-implementation approach. The specific aims are 1) Evaluate the efficacy of SN-THR vs. standard of care (patient navigation to off-site clinic) on HIV treatment and prevention adherence; 2) Perform an economic evaluation of SN-THR and estimate the cost-effectiveness of SN-THR; and 3) Assess the drivers of SN-THR implementation and their impact on implementation outcomes. We hypothesize that more participants in the SN-THR intervention condition will be adherent to ART for treatment or prevention than those in the control condition across 12-month follow-up This application is directly responsive to the priorities of NIDA’s RFA-DA-25-072 by testing a novel telehealth-based, status-neutral care model for integrating HIV and SUD services into street-based primary care for PEH who use drugs.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Despite decades of research effort, the HIV-1 retrovirus remains a major global public health crisis. To date, there is no cure for HIV-1, with an infected individual requiring continuous antiretroviral therapy (ART) to thwart the onset of AIDS. When ART is ceased, there is a rebound of viremia that originates from the pool of latently infected CD4+ T cells. This rebound within a latently infected cell begins with transcriptional reactivation of the HIV-1 genome, and the Transactivator of transcription (Tat) protein lies at the heart of HIV-1 gene expression. Tat activates gene expression by recruiting the kinase Positive Transcription Elongation Factor b (P-TEFb) to a paused RNA Polymerase II (RNAP II), ultimately promoting RNAP II pause release. Specifically, Tat recruits P- TEFb to the nascent Transactivation Response (TAR) RNA element, with Tat positioning P-TEFb for phosphorylation of the RNAP II C-terminal domain and transcription factors to promote RNAP II pause escape. Importantly, a major cellular reservoir of P-TEFb is held inactive by the dimeric Hexim1 (or less commonly Hexim2) protein within the 7SK ribonucleoprotein (RNP), and prior work supports that Tat “hijacks” P-TEFb from 7SK RNP for subsequent P-TEFb recruitment to TAR. However, the molecular mechanisms underpinning this hijacking remain uncharacterized, posing a fundamental barrier to targeting Tat transactivation as an HIV-1 eradication strategy. A potential route to Tat removal of P-TEFb is by competing with Hexim1 for 7SK RNA binding, since one of the Hexim1 binding sites on 7SK RNA mimics the Tat recognition site on TAR RNA. Therefore, Aim 1 proposes to define the competition between Tat and Hexim1 for binding to 7SK RNA in vitro by NMR, ITC, and EMSA experiments, building upon recent work from the Feigon lab that successfully employed these same methods to identify Hexim1 binding sites on and affinities for 7SK RNA. Aim 2 proposes to purify and biochemically characterize a Tat-bound 7SK RNP from mammalian cells, since this complex is a proposed intermediate prior to Tat–P-TEFb handover to TAR. Specifically, the complex will be characterized with mass photometry, mass spectrometry, and SHAPE-/DMS-MaP. Lastly, Aim 3 describes how the structure of a Tat– 7SK RNP will be determined by cryoEM and how structure-derived hypotheses will be tested on Tat transactivation in a cell line model of HIV-1 latency. The proposed work is supported by the Feigon lab’s excellent track record of combining NMR and cryoEM to study challenging, dynamic RNPs and, all the necessary facilities and equipment are available to execute this work. Together, the goal of this fellowship proposal is to uncover the structural and mechanistic basis of Tat “hijacking” of P-TEFb from the 7SK RNP, providing new insights to aid design of HIV-1 therapeutics and offering a rich training in structural biology methods.

NHLBI - National Heart Lung and Blood Institute

Summary/Abstract: The multifunctional cytokine TGF-β is a central mediator of the chronic inflammatory and fibrotic pathologic processes that leads to lung and airway fibrosis. Our long-term goals for this project are to acquire a deeper understanding of how TGF-β function is regulated, and to leverage that understanding to develop new strategies and treatments for fibrosing lung disease. There is an urgent need for effective therapies to treat chronic fibrosing and inflammatory diseases of the lung. Clinical trials targeting TGF-β itself or its receptors has faced challenges, most notably, toxicities. More understanding of how TGF-β functions is clearly needed to develop better and more specific methods to more effectively target the pathologic effects of TGF-β. Since TGF-β is always produced in an inactive form that must be activation to function, methods targeting its activation may more specifically target the local effects of TGF-β thus avoiding systemic toxicities. TGF-β is activated by binding to several integrins. What exactly happens biologically after these integrins bind to TGF-β remains largely speculative. Because of this lack of biologic understanding it has long been assumed that TGF-β must be released from LAP so that free TGF-β can operate as a paracrine factor and diffuse and bind its receptors on target cells. Based on our recent structural data obtained using single particle electron cryomicroscopy (cryo-EM), we have developed a new hypothesis where integrins can bind to L-TGF-β on cells presenting the L-TGF-β on their cell surface and induce autocrine signaling without release and diffusion of TGF-β. We have recently verified that such an autocrine mechanism is sufficient to maintain the essential functions of TGF-β1 in mice, and that paracrine TGF-β1 signaling is dispensable. We now have structural and cell-based data that provides a new hypothesis for TGF-β1 activation: The inherent disorder (entropy) present in specific domains of TGF-β1 and integrin αvβ8 is redistributed upon binding of L-TGF-β1 to αvβ8 which is sufficient to cause exposure of mature TGF-β1 to its receptors. Here in three aims, we address three critical questions concerning this new model of L-TGF-β activation. (1) Can entropy redistribution of the L-TGF-β/αvβ8 complex be predicted by structural methods, and if so can it be biochemically and therapeutically manipulated? (2) How does a native membrane environment affect entropy redistribution of the L-TGF-β/αvβ8 complex? (3) Can the entropy redistribution hypothesis be applied to other integrins and can it be harnessed to be therapeutically useful to treat lung fibrosis? To answer these questions, we will establish and employ state-of- the-art techniques including cryo-EM coupled to orthogonal spectroscopic, and analytical techniques to more quantitatively assess protein thermodynamics, protein engineering, recombinant antibodies to affect local protein conformational dynamics and finally testing of those antibodies in lung fibrosis models in vivo. Together, these studies will improve mechanistic understanding of TGF-β activation and therapeutic targeting strategies to inhibit it.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Lipoproteins (LPs) are heterogeneous macromolecular nanoparticles that play a central role in transporting lipids and cholesterol between the gut, liver, and other tissues. Apolipoprotein B (apoB), one of the largest proteins known, serves three main functions: (1) coordinating the synthesis of LP particles; (2) acting as the primary structural component of all non-high-density LPs to maintain particle integrity; and (3) providing the binding domain for receptors, enabling cellular uptake. Dysregulation of apoB-containing LP metabolism and mutations in apoB contribute to atherosclerosis, metabolic diseases, and a range of inherited lipid disorders. Despite its pivotal role in fundamental lipid biochemistry and physiology, significant gaps remain in our understanding of apoB structure and function, hindering progress toward a comprehensive understanding of lipid and cholesterol metabolism and associated disease mechanisms. Progress toward understanding apoB's structure and function has been slow due to its large size, complex membrane associations, and the inherent heterogeneity of LPs. The Berndsen group recently made a seminal contribution by solving the structure of apoB, revealing an unexpected multi-domain architecture and complex arrangement on the LP surface. This breakthrough uniquely positions us to address some of the most pressing unanswered questions about apoB, including: How does apoB change conformation to accommodate LPs of varying size and composition, and how do these changes influence its interactions with receptors? What roles do the individual apoB domains play in its three primary functions? How do naturally occurring genetic variants impact apoB’s structure and function? Our approach will be primarily biophysical, with a focus on state-of-the-art electron microscopy, including both single-particle analysis and tomographic techniques, which were instrumental in resolving the apoB structure. Secondary objectives include the continued development and dissemination of these experimental methods, as well as the application of advanced computational modeling techniques. To probe the structure- function relationship of apoB, we will build on insights gained from our recently solved structure and leverage extensive resources cataloging the phenotypes of naturally occurring mutations. We will determine the structure of apoB from heterogeneous LPs isolated from human serum and mutant apoB-containing LPs generated through recombinant expression, both alone and in complex with their cellular receptor. To complement these structural studies, we will measure LP size, mass, lipid composition, receptor-binding thermodynamics, and the efficiency of cellular assembly and secretion to construct a comprehensive understanding apoB function. The outcomes of these experiments and the technologies we develop will advance our fundamental understanding of apoB structure and LP metabolism, provide valuable tools and knowledge to the broader research community, and yield critical insights into the molecular mechanisms underlying various diseases.

National Foundation on the Arts and the Humanities

The Institute of Museum and Library Services (IMLS) announces the following information collection has been submitted to the Office of Management and Budget (OMB) for review and approval in accordance with the Paperwork Reduction Act. This law helps to ensure that requested data is provided in the desired format, reporting burden (time and financial resources) is minimized, collection instruments are clearly understood, and the impact of collection requirements on respondents can be properly assessed. This Notice proposes the clearance of the Guidelines for IMLS Grants to States Five-Year Evaluation. A copy of the proposed information collection request can be obtained by contacting the individual listed below in the FOR FURTHER INFORMATION CONTACT section of this Notice.

NIH

Background and Innovation: Clostridioides difficile is the most common pathogen causing healthcare-associated infections in the United States. Recent reports have raised concern that C. difficile strains with reduced susceptibility to the primary treatments for C. difficile infection (CDI) (i.e., fidaxomicin and vancomycin) are emerging. However, the extent of the problem is uncertain as surveillance for antimicrobial resistance in C. difficile is very limited in the United States. To address this unmet need, we will conduct a 3-year multicenter surveillance study for emergence of reduced susceptibility to vancomycin or fidaxomicin in the VA Healthcare System. The study will be conducted in 7 VA facilities in collaboration with VA co-investigators with expertise in C. difficile (5 sites) and with the Veterans Affairs Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD) biorepository (2 sites). Several aspects of our approach will be innovative, including correlation of susceptibility results with clinical outcomes, timely processing of specimens providing the ability to act on emerging resistance trends in real-time, use of state-of-the-art molecular studies to identify genes or mutations associated with reduced susceptibility, and use of an established mouse model to determine if reduced susceptibility to fidaxomicin or vancomycin impacts the ability of C. difficile isolates to colonize the intestinal tract and/or reduces the response to treatment with these agents. Significance and Impact to Veterans Healthcare: CDI is a substantial cause of morbidity and mortality in the VA Healthcare System, particularly among older Veterans and those in VA community-living centers. Emergence of C. difficile isolates with reduced susceptibility to CDI treatments could have a significant adverse impact on the care of Veterans. At the Cleveland VA, we have recovered C. difficile isolates with reduced susceptibility to fidaxomicin from 6% of CDI patients who failed to respond to fidaxomicin or had recurrent infections after fidaxomicin. This proposal will address the unmet need for surveillance for antimicrobial resistance in C. difficile in the VA Healthcare System and will provide evidence that can be used to inform treatment. Path to translation/implementation: The work proposed will establish a 3-year state-of-the-art multicenter surveillance program for detection of antimicrobial resistance in C. difficile in the VA Healthcare System. The findings will provide high-quality data on current trends in C. difficile susceptibility to vancomycin and fidaxomicin and will clarify whether reduced susceptibility impacts the effectiveness of these agents for CDI treatment. The information gained will be used to inform treatment algorithms for CDI in the VA and in non-VA healthcare settings. The results will be significant because CDI is an important clinical challenge and there is an urgent need for improved surveillance for emergence of resistance.

Swarovski Foundation

Funds creative arts, culture, and environmental conservation through luxury philanthropy.

National Institutes of Health

Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) intends to support research projects that employ state-of-the-art cancer biology approaches and preclinical model systems to investigate the biological effects of radiation emitted by radionuclides used in radiopharmaceutical therapy (RPT). The focus of this initiative is to advance mechanistic understanding of how different forms of radionuclide-emitted radiation affect normal tissues, tumor cells, and the tumor microenvironment, and how these effects can be leveraged to improve therapeutic outcomes. This NOFO will support the Systematic Testing of Radionuclides in Preclinical Experiments (STRIPE) program. The overarching goal of STRIPE is to stimulate multidisciplinary research that integrates cancer biology, radiation biology, radiochemistry, imaging, dosimetry, and preclinical modeling. Funded projects are expected to generate fundamental biological insights that can serve as the foundation for the development of new targeting strategies, optimized treatment regimens, and innovative combination approaches for RPT, ultimately leading to more effective and precise anticancer therapies.This NOFO consolidates prior exploratory/developmental and research project funding mechanisms to streamline the application process and sustain momentum in this critical research area. The applicants have the option of submitting either for exploratory/developmental research projects with a project period of up to 2 years or for research projects with a project period of 4 to 5 years. Collectively, the STRIPE program is intended to broaden the scientific base of RPT research, lower barriers to entry for cancer biology investigators, and accelerate the generation of reproducible, mechanistically informed data that will enable more effective and personalized use of radiopharmaceutical therapies in cancer care.

National Institutes of Health

<p>Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) intends to support research projects that employ state-of-the-art cancer biology approaches and preclinical model systems to investigate the biological effects of radiation emitted by radionuclides used in radiopharmaceutical therapy (RPT). The focus of this initiative is to advance mechanistic understanding of how different forms of radionuclide-emitted radiation affect normal tissues, tumor cells, and the tumor microenvironment, and how these effects can be leveraged to improve therapeutic outcomes. This NOFO will support the&nbsp;<strong>Systematic Testing of Radionuclides in Preclinical Experiments (STRIPE)</strong>&nbsp;program. The overarching goal of STRIPE is to stimulate multidisciplinary research that integrates cancer biology, radiation biology, radiochemistry, imaging, dosimetry, and preclinical modeling. Funded projects are expected to generate fundamental biological insights that can serve as the foundation for the development of new targeting strategies, optimized treatment regimens, and innovative combination approaches for RPT, ultimately leading to more effective and precise anticancer therapies.</p><p>This NOFO consolidates prior exploratory/developmental and research project funding mechanisms to streamline the application process and sustain momentum in this critical research area. The applicants have the option of submitting either for exploratory/developmental research projects with a project period of up to 2 years or for research projects with a project period of 4 to 5 years. Collectively, the STRIPE program is intended to broaden the scientific base of RPT research, lower barriers to entry for cancer biology investigators, and accelerate the generation of reproducible, mechanistically informed data that will enable more effective and personalized use of radiopharmaceutical therapies in cancer care.</p>

NIGMS - National Institute of General Medical Sciences

Summary The goal of our research is to discover the central principles that govern cellular adaptation. We aim to understand how cells achieve adaptive gene-expression states, both during short-term physiological adaptation and long-term adaptive evolution. We investigate these phenomena on a systems-level, often necessitating observations, perturbations, or analyses that are beyond the scale and precision of existing methods. Thus, our laboratory also develops new enabling technologies and computational methods. In this R35 application, we seek support for three NIGMS-related projects: (1) Cellular adaptation by stochastic tuning of gene expression. We have discovered a powerful new mechanism, that we call stochastic tuning, by which eukaryotic cells adapt to extreme or novel challenges. During stochastic tuning, cells utilize transcriptional noise to randomly change the expression of individual genes, and to actively reinforce those changes that improve the overall health of the cell. Stochastic tuning therefore enables cells to prospectively explore novel gene expression states that enable adaption to challenges in real time—including conditions never previously encountered—thereby bypassing the need for pre-determined hardwired regulatory programs. We have compelling new evidence that stochastic tuning is the key underlying mechanism for non-mutational cancer chemotherapy resistance, recognized as a major barrier to effective cancer therapies. We are utilizing CRISPR-interference and largescale reporter assays to define the critical protein and DNA effectors of stochastic tuning in yeast and to mechanistically determine their roles using chemical/genetic/optogenetic perturbations of single cells in well-controlled microfluidic experiments. (2) Genetic basis of microbial habitat adaptations. We have developed a versatile computational framework to conduct genotype-habitat association at the tree-of-life scale, enabling discovery of genes that underlie microbial colonization of specific habitats. By applying this analysis to the gut microbiome, we have discovered many highly conserved factors that strongly contribute to gut colonization. We are using functional genomics technologies to efficiently determine the molecular mechanisms by which these factors enable gut colonization. In addition, we are developing state-of-the-art deep learning and protein language models to improve the sensitivity/specificity of genotype-habitat association, enabling large-scale microbial engineering for diverse biomedical applications. (3) Global mapping of all-against-all molecular interactions in a single tube. We have recently developed a powerful technology for coupling in vivo expressed proteins to their encoding messenger RNAs, enabling a diverse array of proteomic assays to be performed by using DNA- sequencing as a readout. We propose to develop this platform to enable routine comprehensive all-against-all protein-protein and protein-DNA interaction studies on the timescale of days. This technology promises to transform our ability to rapidly map molecular network interactions under dynamic physiological conditions, an essential capability in the era of AI-enabled biology.