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Tasveer

Tasveer will organize the 3rd South Asian International Documentary Festival February 11 - 12, 2017.  It will bring people together to engage with the cultural, artistic and activist work of the South Asian region and people. Documentaries and art will inspire conversations and actions about issues relevant to the South Asian people.

OD - NIH Office of the Director

Project Summary A group of NIH-supported investigators requests funds to purchase an NMR console to replace an outdated 500 MHz NMR spectrometer. This equipment will significantly increase access to small molecule characterization for an existing shared spectrometer that is housed in the NMR Laboratory of the UCLA Molecular Instrumentation Center Core Facility. Specifically, we request funds to purchase a broadband Bruker i-Probe and replace an outdated Bruker DRX NMR console that was installed in 1999, with an Avance Neo 500 High Performance Digital console. The new workhorse spectrometer will allow more users than now to have instant access to NMR characterization and alleviate oversaturation usage on the two most sensitive spectrometers in the facility. The new equipment will provide an extended variable temperature range, provide a wide range of nuclei, and allow complex heteronuclear coupling elucidation with a triple-resonance probe. Experienced Ph.D. staff scientists will be in charge of maintenance, repair and user training. Also, as part of this grant, UCLA will allocate funds to refurbish the magnet that supports our most sensitive equipment and prevent the complex situation of losing this critical resource, showing our institutional commitment to excellence in research supported by state-of-the-art instrumentation.

National Foundation on the Arts and the Humanities

The National Endowment for the Arts (NEA), as part of its continuing effort to reduce paperwork and respondent burden, conducts a preclearance consultation program to provide the general public and federal agencies with an opportunity to comment on proposed and/or continuing collections of information in accordance with the Paperwork Reduction Act of 1995. This program 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 is properly assessed. Currently, the NEA is soliciting comments concerning the proposed information collection of: Blanket Justification for NEA Funding Application Guidelines and Reporting Requirements. A copy of the current information collection request can be obtained by contacting the office listed below in the address section of this notice.

National Foundation on the Arts and the Humanities

The National Endowment for the Arts (NEA), as part of its continuing effort to reduce paperwork and respondent burden, conducts a preclearance consultation program to provide the general public and federal agencies with an opportunity to comment on proposed and/or continuing collections of information in accordance with the Paperwork Reduction Act of 1995. This program 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 is properly assessed. Currently, the NEA is soliciting comments concerning the proposed information collection of: Blanket Justification for NEA Funding Application Guidelines and Reporting Requirements. A copy of the current information collection request can be obtained by contacting the office listed below in the address section of this notice.

Rainier Arts Center

In the second edition of the 98118 Fest, we propose to center community partnership while building on our over forty years of experience in live outdoor events. 98118 Fest will take place on August 22, 2026, 12pm-6pm at Columbia Park, located at 3515 S Alaska St, Seattle WA, our community’s “living room,” and at Rainier Arts Center. The festival will showcase performances from a mix of world music and local artists. A pop-up gallery will create opportunities for local artists to sell their work. We will provide soccer- and art-themed activities for kids and families, including face painting, art making, and games. The event will be free and open to the public.

NIAID - National Institute of Allergy and Infectious Diseases

Infants are especially susceptible to intracellular pathogens because their immune system is not fully equipped to fight against these microorganisms. As a result, infant infections are a leading cause of mortality, with >1.5 million children dying of infections before 5 years of age in 2022 alone. The current consensus is that before birth, conventional T cells are skewed in favor of T regulatory or T helper (Th) 2 responses, leaving neonates and infants more vulnerable to pathogens cleared by Th1 immunity. Therefore, Vγ9Vδ2 (or simply Vδ 2) T cells, are particularly important in early life, because they are poised to secrete Th1 cytokines even before birth and acquire potent cytotoxic function shortly after birth. Despite their protective role against pathogens, human Vδ2 cells, which are absent in mice, are not well studied in neonates and infants. Our long-term goal is to elucidate their functional heterogeneity because understanding their features in the first few months of life will allow us to harness their properties to protect infants from infections. This task is challenging for many reasons, including the difficulty in obtaining samples from the infants at highest risk of early infections, such as premature babies. Our recent observations, obtained using spectral flow cytometry (SFC) and single cell RNA-seq, converge to show phenotypic and functional heterogeneity of cord blood (CB) Vδ2 cells, with heightened stemness compared to their adult counterpart and a cluster of PD1-hi cells (absent in adults) that may follow a distinct functional program specific for the early life stage. We posit that differences in Vδ2 cell cluster composition at birth have functional consequences and result in improved or decreased antimicrobial activity depending on the composition. The resulting overarching hypothesis is that human neonatal V δ2 lymphocytes exist in heterogenous functional/differentiation states impacting host immune competence in the critical early life window. As a multidisciplinary team of immunologists and computational biologists, we propose to characterize cord blood Vδ2 cells in existing specimens, including samples of premature babies, using state of the art techniques –Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE- seq) and SFC- with the following aims. Aim 1. Evaluate the phenotypic and functional heterogeneity of Vδ2 T cells at birth and in early life in relation to age, with a focus on a unique subset of PD1-hi cells present in cord blood. Aim 2: Assess how the composition of Vδ2 T cells at birth impacts function of these cells at the population level, combining CITE-seq analysis with depletion and transduction experiments. The goal of this proposal is to develop a robust molecular and functional map of a critical subset of innate-like T cells, which will provide a valuable reference for the cellular heterogeneity in the neonatal human immune system and a foundation for future proposals aimed at understanding Vδ2 cell biology in early life.

NIA - National Institute on Aging

ABSTRACT IdenƟfying Alzheimer’s disease (AD) in its presymptomaƟc stage can allow early intervenƟon and improve paƟent care. Crucially, the AD-induced amyloid/tau pathology is not limited to hippocampal insult or memory loss, but also impairs /disrupts funcƟonal connecƟons that integrate sensory inputs in the cortex. As these sensory deficits often precede the decline of cogniƟve funcƟon in AD paƟents, understanding their characterisƟc altered funcƟonal connecƟvity and neural hyperacƟvity patterns early in the AD cascade has the potenƟal to yield new diagnosƟc biomarkers or therapies. Similarly, blood flow decline and endothelial dysfuncƟon posited by the vascular hypothesis of AD remains underexplored. While the availability of transgenic AD mouse models has created a unique platiorm for invesƟgaƟng how AD pathogenesis can disturb the neurovascular unit (NVU), design limitaƟons of imaging hardware, e.g. bulky PET, MR or SPECT, that are not developed/opƟmized to probe AD onset, make it unfeasible to image AD pathogenesis at the spaƟal scale of the NVU. Specifically, AD insults the NVU on mulƟple fronts including neural, vascular/blood flow change that span from neurons to cortex-wide brain acƟvity changes, which are modulated with uneven sleep cycle fragmentaƟon/disrupted circadian rhythms. In contrast, preclinical imaging methods are restricted to short duraƟons (< 2 h) due to anesthesia use when imaging a small animal AD model with a device >1000× in size (e.g. PET), and even the state-of-the-art AD studies assess AD-inflicted NVU change only once in every 1-2 months, which substanƟally under-samples the Ɵme course of AD onset. Moreover, since no two brains age the same, subject-specificity can also mask AD-related NVU changes when imaged intermittently. Therefore, new imaging technologies that can generate large neuroimaging datasets and covering mulƟple temporal (days-months), spaƟal (neurons-whole cortex), and modal (neural-vascular) scales are needed to characterize the “funcƟonal fingerprints” of cortex-wide NVU disrupƟon during AD onset. Therefore, we are proposing the development of NeuroCube, which is a miniaturized microscope that will enable mulƟmodal, cortex-wide in vivo imaging >30 days during AD onset in mice. Unlike extant microscopes that lack capacity for long-term operaƟon (<3 h), we will use 3D-prinƟng and fabricate NeuroCube as a robust unit for longitudinal imaging amidst the harsh, jolty condiƟons in an animal enclosure (Aim 1A). To avoid photobleaching, we will use low-light levels, obtain images at low-signal-to-noise raƟos (SNR)/resoluƟon (50 µm), and recover high-SNR/resoluƟon (10 µm) images via a deep learning (DL) backed generaƟve adversarial network (GAN) (Aim 1B). To limit oversized data volumes, we will image in 1-min bursts (0.75 GB) per hour, and curate an imaging dataset that characterize cortex-wide changes of AD, together with gender/age-matched controls (Aim 2). We believe that The NeuroCube and publicly shared in vivo AD datasets will become a vital new tool for the broad AD research community. Moreover, NeuroCubes could be widely useful for interrogaƟng cortex-bound dysfuncƟon in aging and other brain disease.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT Pathogen transmission via indirect routes such as fomite, waterborne, and airborne transmission are hallmarks of both endemic and pandemic spread. Viruses such as Influenza, SARS-CoV-2, and measles are notable examples, in addition to deadly microbes such as Bordetella pertussis, Mycobacterium tuberculosis, and Coccidioides species. However, the rapid detection and analysis of airstreams as part of biosurveillance, public health monitoring, or epidemiological research remains challenging. Current state-of-the-art methods rely on bulky apparatuses for both the collection and detection of airborne agents; most of these methods are ill suited to rapid response point-of-testing within medical facilities, workplace locals, or public spaces. Further, these technologies are based on bulk Polymerase Chain Reaction (PCR) and Loop-mediated isothermal amplification (LAMP) methods that have limited quantitative accuracy. Thus, more portable and accurate platforms are needed to address the types of rapid response and ubiquitous monitoring that is required to minimize outbreaks in the 21st century. Towards this objective, this grant will address the need for an improved method of airborne pathogen detection through the development of the digital droplet Aerosol Capture & Quantification (ddACQ) system. The ddACQ system consists of two novel technologies, a filter particle array and a droplet buoyancy counter. The filter particle array allows for the capture of airborne pathogens or biological agents and generation of microfluidic droplets when mixed with an oil and water reagent solution. A phone-powered heat block then drives a one-step isothermal digital droplet reaction. Digital techniques have several key advantages over classical quantitative PCR and LAMP techniques, namely single molecule detection and direct quantification without a standard curve. Finally, the droplet buoyancy counter allows for smartphone based read out of the reaction immediately at the testing site in under an hour. Together, the innovations within and implementation of the ddACQ system represents a novel application of microfluidic principles and an enabling technology for both pathogen transmission research and public health monitoring applications.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Broadly neutralizing antibodies (bnAbs) and the antibody-like biologic eCD4-Ig (eCD4) can suppress established HIV-1 and SHIV infections when they are present at sufficient concentrations. BnAbs and eCD4 can be delivered passively or expressed from a recombinant adeno-associated virus (rAAV) vector. rAAV expression bypasses cost and compliance concerns associated with periodic antibody infusions, as well as side-effects associated with a life-time of use of conventional or long-acting antiretroviral therapy (ART). Moreover, unlike ART, long- term antibody-mediated control engages multiple effector arms of the immune system, potentially accelerating the rate of decay of the proviral reservoir. eCD4, a potency and half-life enhanced CD4-Ig fused to a coreceptor-mimetic sulfopeptide, has several advantages over bnAbs. It is exceptionally broad, neutralizing all 200-plus HIV-1 and SIV isolates assayed. rAAV-expressed eCD4 (rAAV-eCD4) can protect from multiple high-dose challenges of both SHIV and SIV. eCD4 can combine with non-neutralizing CD4-inducible antibodies common in the sera of infected persons to mediate very potent antibody-dependent cell-mediated cytotoxicity (ADCC). More recently, we have shown that more potent and bioavailable forms of eCD4, combined with the bnAb 10-1074, can fully suppress established SHIV infections in both infant and adult macaques. We are therefore close to robust functional cures in rhesus macaques. The current application seeks to bring us across the finish line and identify antibodies and eCD4-Ig variants that would best function in a human clinical trial. To do so, we will therefore in Aim 1 compare new eCD4 sulfopeptide variants, determine the Fc-domain that best limits anti-drug antibodies and enhances expression, and ensure in vivo that eCD4 poses no risk of immune interference. Aim 2 presumes that a bnAb partner of eCD4 will be useful in maintaining long term viral suppression and asks what class of antibodies works with eCD4 most effectively. Several properties are considered: their inherent bioavailablity, potency, and breadth, and how they complement eCD4 to limit potential viral escape. Aim 3 then seeks to improve the former properties by employing a novel system whereby human antibodies affinity mature in wild-type mice, starting with bnAbs modified with largely germline framework regions, and selecting in vivo those with greater potencies and longer half-lives. Aim 4 applies knowledge that we have accumulated from the previous decades and insights from the previous aims to establish and compare functional cures mediated by eCD4 paired with optimized forms of CD4-binding site bnAbs and V3-glycan antibodies. Collectively, these aims will directly inform human clinical trials designed to suppress established HIV-1 infections without ART.

NIH

Significance to VA: Treatment-resistant depression (TRD) is a serious mental health problem in Veterans, frequently comorbid with post-traumatic stress disorder (PTSD), and in need of novel and effective treatments. Also, TRD in Veterans is associated with a high risk of suicide, addiction, unemployment and medical morbidity. Innovation and Impact: Clinical studies have revealed antidepressant effects of psilocybin for depression and TRD in civilians, but less is known about its efficacy and safety in Veterans. Very limited data is available on the effects of psilocybin in the treatment of comorbid PTSD and when used in combination with serotonin reuptake inhibitor antidepressants. This state-of-art clinical trial will evaluate the safety and efficacy of psilocybin in the treatment of TRD with and without PTSD to advance knowledge in psychedelic therapy in Veterans. Methodology: This multi-site, double-blind, randomized controlled trial will evaluate the efficacy and risks of psilocybin for the treatment of TRD in U.S. military Veterans with and without (±) concurrent PTSD. Eligible and consenting Veterans will be randomized (N=240) and undergo two psilocybin dosing sessions along with preparation, administration, and integration psychological support. For the 1st psilocybin administration, participants will receive either a 1mg dose (control condition) or a 25mg dose (active) under blinded conditions. At their 2nd psilocybin dosing visit 4 weeks later, all participants will receive a 25mg dose. Outcomes will be measured by a centralized independent evaluator masked from all treatments at 2 and 4 weeks after each dosing session and over 6 months follow-up. Both expected and unanticipated adverse events will be collected by type, severity and relatedness to the study drug after each dosing session and at follow-up. Assessments of subjective experiences of psilocybin, expectancy and blinding are included in the protocol. Specific Aim 1 (Efficacy): Evaluate the short-term antidepressant effects of 25mg psilocybin compared to 1mg psilocybin for TRD under blinded conditions by centralized evaluator. Primary Hypothesis: Participants treated with the 25mg psilocybin dose (n=120) will show a significantly greater decrease on the Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to week-4 post-dose compared to the 1mg psilocybin dose control group (n=120). The Hamilton Depression scale is also collected as a common data element. Specific Aim 2 (Safety): Evaluate risks in participants who took ≥ one psilocybin dose with the Swiss Psychedelic Side Effects Inventory and other reported adverse events. Exploratory Aims (E): E1 PTSD: For the subgroup with TRD+PTSD (~50% of the sample), estimate the change from baseline to week 4 on Clinician-Administered PTSD Scale-Revised (CAPS- 5-R) by group. E2 2nd Dose: Examine the antidepressant effects of one vs two 25mg dosing sessions by comparing change in MADRS from baseline to week 8 (i.e., ~4 weeks after the 2nd dose) between the group receiving the 1mg dose followed by the 25mg dose versus the group treated with two 25mg doses. E3 Response & Remission: Explore rates of response (ΔMADRS ≥50% reduction) and remission (MADRS score ≤10) at week 4, week 8 and month 6, within group and between groups. E4 Other Relevant Outcomes: Explore potential effects of treatment on patient-reported and other outcomes over time, including expectancy, depression, PTSD, suicidality, psychological flexibility, and functional outcomes. Measure altered experience during psilocybin dosing sessions and explore impact on outcomes and functional unblinding. Qualitative Aim: Participants (~10 per site; n=50) will be interviewed on topics of acceptance, satisfaction, and facilitators/barriers of treatment with psilocybin to gain a better understanding of Veteran preferences on the treatment itself, the composition/structure of the psychological support model and future implementation of clinical psychedelic treatment programs in VA. Path to Translation/Implementation: Industry-sponsored studies seeking FDA approval are already underway. The timing of FDA-approval of psilocybin should align with the conclusion of this study. VA can use these results to make decisions on offering psilocybin treatment and to guide implementation within VA mental health systems.

NIMH - National Institute of Mental Health

Project Summary/Abstract The overarching aim of the proposed project is to develop and validate novel, multimodal, scalable, time- and cost-efficient assessment protocol for comprehensive characterization of key subdomains of restricted and repetitive behaviors (RRB) that can assist in the diagnostic process, facilitating etiologically oriented research, the treatment selection, and monitoring symptomatology over time. Although RRB are a core, clinically impactful feature of autism spectrum disorder (ASD), existing measures are limited by poor ability to comprehensively capture all relevant RRB subdomains and currently, there are no dedicated clinician interviews nor protocols to capture and quantify daily variations of distinct RRBs in ASD or in neurogenetic disorders. In the proposed project, we will build on the Dimensional Assessment of Restricted and Repetitive Behaviors (DARB), an informant-report questionnaire developed and validated by our group following the NIH Patient-Reported Outcome Measurement Information System framework. DARB has a comprehensive item bank developed to assess eight distinct RRB subdomains and has been shown to have a stable and replicable 8-factor structure, strong model and conditional reliability, invariance across age, sex and diagnostic status, and excellent test-retest replicability. In the current proposal, we will aim to: develop and validate the computerized adaptive test (CAT) version of the DARB (DARB-CAT) to maximize precision and reduce patient burden by individually tailored item selection and administration (Specific Aim 1), refine and validate a clinician interview version of the DARB (DARB-I) (Specific Aim 2) and develop an ecological momentary assessment (EMA) RRB protocol (DARB-EMA) to capture daily and weekly changes in specific RRB and contexts in which they occur (Specific Aim 3). We will also develop and pilot a platform that will integrate the administration, scoring and reporting of the DARB-CAT, DARB-I and DARB-EMA components (Exploratory Aim 4). Finally, we will explore mechanisms underlying RRB subdomains (Exploratory Aim 5). This project will generate the world’s first comprehensive, multimodal RRB assessment ecosystem incorporating state-of-the-art psychometric principles that will have a significant potential to enhance the pathway from screening to clinical and neurobiological characterization to treatment tailoring and tracking.

NIDA - National Institute on Drug Abuse

Project Summary: HIV infection and cocaine use are comorbid conditions that can exacerbate each other's harmful effects, as ART is not sufficient to fully suppress HIV transcription or prevent latency reactivation. HIV gene products (RNA and proteins) greatly contribute to perpetual immune activation and inflammation throughout the system, primarily in the central nervous system (CNS) of people with HIV (PWH). Additionally, viral latency, the main cause of HIV persistence, is also largely regulated at the transcriptional level. Therefore, defining all the mechanisms that control HIV transcription is essential before utilizing them therapeutically to limit HIV persistence and associated comorbidities, such as neuroinflammation, which is prevalent even in well-controlled PWH. DNA breaks are a common occurrence during the transcription of genes, which are required to be repaired via transcription-coupled repair (TCR). Without TCR, during transcription of a gene, breaks in the template DNA cause frequent RNAPII pausing or degradation, which halts transcription. Interestingly, upon cocaine exposure to microglia, we noted both the increased DNA-dependent protein kinase (DNA-PK) activity and corresponding enhanced HIV transcription and replication. Additionally, we found that DNA-PK knockdown results in the dissociation of TCR machinery from LTR, showing a direct role of DNA-PK. However, in microglia, the major HIV reservoir in the CNS, the impact of DNA-PK-mediated TCR during HIV transcription in the context of ART and cocaine, and the potential therapeutic reversal using clinically tested DNA-PK inhibitors (DNA-PKi), remains largely unexplored. This study aims to address this critical knowledge gap, using brain organoids harboring microglia. Together, these facts offer a strong premise for the hypothesis that DNA-PK plays a crucial role during TCR and neutralization of negative factors in relieving RNAPII pausing during HIV transcription, and cocaine further supports these effects by stimulating both the level and activity of DNA-PK; however, clinically tested DNA-PKi can reverse this process, limiting viral load and rebound after ART interruption. Aim 1 will investigate the role of cocaine-induced DNA-PK in relieving RNAPII pausing via TCR in brain organoids and iPSC-derived microglia +/- ART. Aim 2 will define the impact of DNA-PK mediated regulation of negative transcription factors (NFs) during RNAPII pause-release. Aim 3 will test the efficacy of clinically tested DNA-PKi in blocking HIV transcription and viral rebound upon ART interruption in the context of cocaine +/- ART in brain organoids. The proposed high-risk/high-payoff exploratory study with great translational potential is closely aligned with the main objective of this FOA: 1) we propose to develop new tools and techniques in our lab - DNA curtain methodology/assay and human brain organoids harboring microglia; 2) define a novel mechanism, DNA-PK- mediated TCR, in regulating HIV transcription, latency, and rebound in the context of cocaine+/- ART.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Description/Summary Reticulocyte maturation, the final stage of erythropoiesis, is critical for blood formation. Despite its importance in disease pathology, including inherited and acquired disorders of the erythrocyte, it is an understudied area. A major aspect of reticulocyte maturation is gradual loss of salt and water over time. Maintenance of water and solute homeostasis is critical to survival of both the reticulocyte and the mature erythrocyte. We have identified a novel regulator of erythrocyte hydration in erythropoiesis. In conjunction with the kinase WNK1, this TGF beta- stimulated clone (TSC) 22 family member controls potassium-chloride cotransport in reticulocytes and mature erythrocytes, shrinking reticulocytes to their normal volume in mature red blood cells. The goal of specific aim one is the identification of interacting proteins and characterization of regulator-WNK1 interactions and their influence on cellular hydration. The goal of specific aim two is elucidation of the influence of genetic variants on erythrocyte phenotype in humans and murine in vivo models of perturbed erythrocyte hydration. The overall goal of this proposal, which combines state of the art cellular, molecular, and genetic technologies in an innovative, multidisciplinary manner, is to characterize the structure and function of regulatory complexes in erythroid cells to better understand the mechanisms regulating erythrocyte volume homeostasis. These studies will extend our knowledge of normal erythropoiesis, particularly reticulocyte maturation. They will also provide a better understanding of the contribution of regulatory proteins to erythroid cell traits and its contribution to erythroid cell phenotype in inherited and acquired disorders of the erythrocyte.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY/ABSTRACT Ischemic stroke represents the second leading cause of death worldwide, and the direct costs of stroke are approximately $71.6 billion. These costs are disproportionately driven by patients with large vessel occlusions (LVO). Recent advances in urgent thrombectomy (clot removal) have led to improved outcomes, yet more than 50% of patients fail to achieve good functional outcomes even in the most recent trials. Developing neuroprotectants in order to mitigate neuronal injury immediately following the ischemic event is now a primary focus for researchers in this area. Among numerous proposed neuroprotectant strategies, hypothermia, or brain cooling, remains the most promising. Numerous previous investigators have proposed selective brain cooling of the brain only rather than full-body cooling, especially in conjunction with thrombectomy procedures since the access catheters to the carotid arteries are already in place and could be utilized to selectively cool the brain immediately after clot removal. These selective cooling approaches use the indwelling procedural catheters either for infusion of cold saline directly into the intracranial blood flow or cold saline to cool flowing blood as it passes along an indwelling catheter wall. Both of these approaches are limited by the cold saline's inherent warming as it travels to the target location. Also, saline will cause both fluid overload as well as dilution of oxygen- rich blood. Further, the devices being developed are not similar to the modern, high- performance catheters currently in use in thrombectomy procedures, which likely will limit their use. The long-term goal of this research and development proposal is to enable an advanced cooling system that targets the practitioners---neurointerventionalists, neurointensive care physicians, and perfusionists--- to provide them with a state-of-the-art cooling catheter system that focuses on ease of use rather than engineering principles, yet enables speed, depth, and duration of cooling superior to any other device. The first Specific Aim of this R21 proposal involves the design, construction, and bench-testing of a coaxial infusion catheter. Milestones for this Aim will include both heat transfer and mechanical design metrics as well as in vitro tests assessing the efficacy and safety of our catheter on the bench. Aim 2 will assess efficacy and safety in leading preclinical in vivo models. The research plan will include placement of the device in the carotid arteries in swine and measuring the speed, depth, and duration of parenchymal cooling. If successful, this research program will improve the neurological function of patients suffering from large vessel occlusion acute ischemic stroke by protecting brain tissue that would otherwise not be salvaged.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY HIV-1 establishes life-long infection that requires continual antiretroviral therapy (ART) to suppress virus replication. Although long-acting ART promises to improve treatment adherence, a therapeutic countermeasure for suppressing HIV-1 infection without lifelong treatment is needed. This type of HIV cure strategy is called a functional cure. In preliminary studies, we designed a series of immunogens that elicit serum nAbs against heterologous viruses in macaques. The nAbs target the second variable region (V2) Apex on HIV-1 envelope, with binding orientations similar to known human V2 Apex broadly nAbs (bnAbs). This B cell targeting countermeasure is the main innovation of our study. Furthermore, we developed an integrase-deficient lentiviral vector (IDLV) that delivers the viral gag gene to elicit specific CD8 T cells. Induction of these CD8 T cells suppressed viremia to undetectable levels in macaques. Our conceptual innovation is to combine both successful countermeasures together to potently and durably control viremia. The objective of this study is to sustainably suppress HIV viremia by combining a CD8 T cell countermeasure that controls viremia with a B cell countermeasure that elicits neutralizing antibodies (nAb) that are active against many heterologous viruses. The proposal has three specific aims. First, to determine the immunogenicity of the combination T cell and V2 Apex nAb-inducing countermeasure in ART-suppressed, SHIV-infected macaques by comparing the neutralization breadth of serum and monoclonal Abs, as well as CD8 T cell cytokine production and inhibition of virus-infected cells among a mock-treated group, the countermeasure treated group, and previous groups of uninfected macaques. Second, to demonstrate sustained viral suppression without ART by the administration of the therapeutic countermeasure in chronically SHIV-infected macaques by assessing changes in CD4 T cells and virus nucleic acid over time following ART cessation. Mechanistic studies will be done in macaques to show CD8 T cell and V2 apex nAb contributions to viral suppression. Third, to determine the impact of ART on the frequency of V2 Apex-specific B cells in people living with HIV-1 (PLWH) using a 10X Genomics BEAM-seq sequencing and AI/ML approach to identify V2 Apex B cells in PLWH before and during ART. The impact of this study is that it will define a therapeutic countermeasure that can permanently suppress viremia, taking the first steps toward a functional cure for the nearly 40 million people currently living with HIV-1.

NIAID - National Institute of Allergy and Infectious Diseases

Project summary Herpes simplex virus (HSV) establishes latency in ganglionic neurons of the peripheral nervous system. Latent HSV can later reactivate, causing recurrent disease and possible transmission to new hosts. Current anti-HSV therapy is inadequate, in that it does not eliminate latent HSV, and thus is only suppressive rather than curative. We developed a therapeutic approach based on gene editing using HSV-specific meganucleases. We showed that intravenous (IV) administration of adeno-associated virus (AAV) encoding anti-HSV-1 meganucleases can eliminate up to 97% of latent HSV DNA from dorsal root ganglia in mouse models of latent HSV-1 genital infection. We also demonstrated that this reduction in ganglionic viral load led to a corresponding reduction of viral shedding from treated vs. control mice. This approach offers the potential for a durable means of controlling latent HSV infection and subsequent reactivations, or even achieving a functional cure. In the R21 phase, we propose to extend our work to target HSV-2, and to determine whether IV or localized intrathecal (IT) administration is the optimal route. In the specific aims of the R33 phase we plan to address simultaneously several outstanding issues regarding both HSV biology and the safety and efficacy of in vivo gene therapy that are critical for clinical translation of our work. R21 Phase: Specific Aim 1. Evaluate IT vs. IV delivery of AAV/meganuclease therapy as a means to reduce AAV dose, minimize systemic exposure, and avoid pre-existing/induced anti-AAV immunity. We will evaluate the AAV biodistribution, antiviral efficacy, and dose response after IT vs. IV administration, and the doses at which toxicity occurs. We will also evaluate the ability of IT-delivered AAV to avoid neutralizing antibody present in serum, and whether IT administration will allow re-dosing of AAV. R33 Phase: Specific Aim 2. Compare the natural history of ganglionic HSV load and peripheral viral shedding in latently infected mice after IT or IV meganuclease therapy vs. untreated control animals. We will perform long-term studies of the ganglionic viral load and the frequency and quantity of peripheral shedding in control vs. AAV-meganuclease treated animals. These studies will shed light on the stability of reservoirs, the relationship of ganglionic viral load reductions with the frequency and quantity of viral shedding, and provide new insights into possible HSV re-seeding of ganglionic reservoirs after viral reactivations. R33 Phase: Specific Aim 3. Determine the host genomic consequences of AAV/meganuclease therapy, and compare to the effects after CRISPR/Cas9 exposure. We will perform an unbiased evaluation of genomic disruptions after our meganuclease therapy, and directly compare with CRISPR/Cas9 approaches, using the state-of-the-art techniques for the detection of off-target events, including GUIDE-seq, improved DISCOVER-Seq+, and analyses for the insertion of AAV vector (ITR-Seq) and HSV DNA (hybridization capture coupled with next generation sequencing) into the host genome.

OD - NIH Office of the Director

Project Summary/Abstract Nine NIH-funded investigators with similar but independent super-resolution microscopy needs are requesting funding to acquire an Abberior Mirava 3D STED microscope to enable imaging of molecular topographies in fixed or live tissues and cells at unprecedented resolution at the scale of tens of nanometers with fluorescent probes. This platform will be maintained in the Washington University Center for Cellular Imaging (WUCCI), an institution-wide shared technology resource. There is no instrument like this at WUCCI or anywhere else on campus. One huge advantage of this system is that it works just like a confocal microscope in terms of the field of view, imaging depth, and data acquisition interface. As such, many investigators will be ready to utilize it immediately. Sample preparation is nearly identical to conventional confocal microscopy, except for the use of specific fluorescent probes, and care taken to use mounting or immersion media and cover slips with matching refractive indexes to enable maximum resolution. STED technology breaks the traditional barrier of optical microscopy set by the diffraction-limited point spread function (PSF) by PSF engineering, achieving 40 nm resolution, exceeding the resolution of the already heavily subscribed Nikon NSPARC and Zeiss Airyscan. The major user group comprises nine investigators from 6 departments who will utilize this microscope to enable a wide range of basic and translational research studies. Scientific goals include understanding primary cilia, the role of actin cytoskeleton dynamics in intracellular networks, energy and lipid storage and lipid droplet or to resupply membranes with lipids, mechanobiological mechanisms underlying kidney glomerular filtration, glutamate receptor geography at cochlear synapses, receptor dynamics in pancreatic islet hormone secretion and neuroinflammation biomarkers for biological imaging and chemotherapeutics. Given its location in a busy core facility, we expect this microscope to be impactful to many research programs beyond the initial major user groups. The expertise and institutional support for this instrument are excellent. Dr. Mark Rutherford, Associate Professor of Otolaryngology, used STED microscopy extensively during the historical development of this technology. Dr. Rosa-Molinar and the WUCCI staff have a long-standing track record of training NIH- funded researchers to optimize their use of state-of-the-art microscopy methods. In support of this S10 grant application, the Washington University School of Medicine will commit $176,647 of matching funds for the acquisition of the instrumentation plus an additional $125,000 operational support ($25,000 per year for five years) to ensure the long-term success of this equipment.

Seniors Creating Art

Access to Art Expansion- West Seattle is a free weekly art workshops for one-year for the residents living in four Seattle Housing Authority (SHA) Senior Living Buildings in the West Seattle/High Point Neighborhoods. As well as weekly art programming, there will be monthly Intergenerational Creative Nights held at a selected SHA building and a Summer Community-wide ArtWalk taking place in High Point. The purpose of this project is to improve the physical and mental health of participants and provide jobs for artists within the Seattle region.

Shunpike

ACES is a BIPOC-led arts conference that fosters community, showcases talent, and facilitates professional development for BIPOC artists. It features performances, exhibits, workshops, films, presentations, artist talks, and info sessions. The conference will take place on April 2 & 3, 2022, at Langston Hughes Performing Arts Institute, located at 104 17th Ave S Seattle WA.

Shunpike

Shunpike will organize ACES: Artists of Color Expo and Symposium, a POC-centered and led art conference that fosters community, showcases talent, facilitates professional development, and provides resources, will be held on February 28th-29th, 2020 at Seattle Center, 305 Harrison Street.

OD - NIH Office of the Director

Project Summary/Abstract The Simons Electron Microscopy Center (SEMC) is requesting funds to purchase Gatan BioContinuum energy filters to extend the capability of our TFS Titan Krios G2 300-keV cryo- transmission electron microscopes (Krios#1, Krios#2 and Krios#3) for high resolution data collection supporting both single particle and tomography experiments. SEMC is housed at the New York Structural Biology Center, a consortium of nine (9) research institutions in New York State, and is one of the largest cryoEM facilities in the world that provides access to state-of-the-art equipment, including nine (9) 300-keV TFS Krios microscopes and four (4) 200-keV TFS Glacios microscopes with direct detectors, and all other ancillary equipment required to solve structures to the highest possible resolution using cryoEM. A highly qualified technical team provides direct support, guidance, and assistance, ensuring the highest quality structures are resolved quickly and efficiently. The long- term objectives of this application are: 1) to ensure access to state-of-the-art cryoEM instrumentation and expertise in cryoEM technologies for NIH funded researchers, in the region and nation, for the structural analysis of biological macromolecules and their interactions; and 2) to provide training in the most modern techniques of cryoEM approaches for the current and next generation of biomedical researchers. The requested instrumentation is essential to the core purpose of the Center to ensure continued access for NIH funded researchers to the instrumentation required for their research projects. All major and minor users have active research projects that would immediately benefit from the proposed equipment. The impact of this funding will extend beyond the projects of the major and minor users, since the microscopes will also be made available to the broader scientific community. To highlight the past 5 years, the center has provided cryoEM access to 36 states across the nation and directly supported over 750 active researchers. Taken together, this instrumentation will benefit all users of Center by increasing the capability and capacity of these instruments and provide outstanding training opportunities to the next generation of biomedical scientists. SEMC has a proven track record of maintaining various high-end imaging systems, strong institutional support and a large userbase, which guarantees that the instrumentation will be used to its maximum potential for years to come.

OD - NIH Office of the Director

PROJECT SUMMARY This proposal seeks to acquire a RH96 Octet – a next-generation, high-throughput bio-layer interferometer (BLI HTS) for biomolecular interaction studies. BLI HTS is a “96-channel” instrument that allows quantitative measurements of protein-protein and protein-small molecule interactions of up to 96 samples simultaneously. It uses small sample volumes, and the ease of use allows researchers with broad scientific expertise to use the instrument for high-throughput screening of interactors such as proteins, antibodies, and small molecules. There is an urgent unmet need for this instrument, as there is no high-throughput BLI instrument in the entire Midwest region. We have identified 14 NIH-funded researchers whose work and progress is severely limited due to the absence of this instrument. They often travel to out-of-state institutions or use the 2-channel BLI instrument currently available at Northwestern; clearly, neither option is a long term solution. The 2-channel instrument is not amenable to high-throughput data collection and requires large sample volumes, impeding drug discovery and screening efforts. Moreover, the data collection on the 2-channel is tedious even for single protein-protein interaction studies when testing multiple concentrations. The proposed instrument will address a significant gap in the instrumentation available at Northwestern University and will be beneficial not just to the Northwestern community but the entire Midwest area. We propose to add the BLI HTS to the Northwestern High-throughput Analysis Laboratory, which houses several instruments for high-throughput screening and has full-time staff with the technical expertise to manage and operate the instrument. We anticipate that at least 14 research groups from 6 departments across the College of Arts and Sciences, the Feinberg School of Medicine and the McCormik School of Engineering will utilize this equipment. The availability of this state-of-the-art instrument at Northwestern will be particularly important for drug development efforts and will advance a range of studies aimed at creating therapeutic and diagnostic tools for various human diseases, including cancer, metabolic disorders and neurodegeneration.

OD - NIH Office of the Director

Advanced mass spectrometry (MS) technologies unlock exceptional opportunities towards transformative applications and groundbreaking discoveries for life science research. We are requesting funding to purchase the latest Orbitrap Astral mass spectrometer interfaced with a Vanquish Neo ultra-high-performance liquid chromatography system from Thermo Fisher Scientific. This state-of-the-art system will be housed, operated and maintained in the Proteomics and Metabolomics Facility (PMF) at the Cornell University Biotechnology Resource Center (BRC). The BRC will provide administrative support to the PMF team with a proven track-record in managing shared resources for the biomedical and life science research community. Implementation of the instrument in the BRC as a university-wide shared research resource will enable cost-effective and flexible access to this vital technology for a broad range of NIH-funded research. There is a growing demand for proteomics and metabolomics applications at Cornell, as observed by the continuous growth in the number of facility users and processed samples by the facility over the past decade, and evidenced by the recently founded Center for Innovative Proteomics (CIP), which promotes campus-wide collaboration to develop cutting-edge proteomics methodologies for research. The proposed Orbitrap Astral system will replace the aging Orbitrap Fusion instrument, offering new capabilities as no such instrument is available across all Cornell campuses. It will also expand the capacity and capabilities of the facility on the existing instrumentation, which is currently utilized at near full capacity. The need for the increased performance and capacity is particularly critical with respect to applications involving analysis of complex samples with limited sample input (e.g. single-cell proteomics and affinity-enriched samples) for many NIH-funded projects, which require fast scan speed, ultra-high sensitivity and resolution, and highly accurate mass measurements. The requested instrument provides >5 orders of magnitude dynamic range, enabling confident identification of peptides from low abundance proteins and low stoichiometry modifications in complex samples. It will uniquely leverage the PMF’s and CIP’s expertise to support proteomics discovery studies at the single-cell level by developing and implementing high-throughput single-cell and spatial proteomics technologies, enabling Cornell PIs to propose and competitively undertake new research projects that are currently not feasible with our existing instrumentation. The BRC PMF has extensive experience in running LC-MS instruments and providing MS solutions to effectively advance research. The proposed instrument will be readily integrated into the facility’s established proteomics pipelines. Placement of the proposed system in the BRC will enable a large group of NIH-funded investigators to undertake research projects that would not otherwise be economically or technically feasible. This proposal describes 31 projects from 15 NIH-funded investigator groups that will utilize the proposed system. The requested instrument will benefit a wide range of current and future NIH-funded projects and other projects.

Community Dance Program

The Community Dance group will be hosting various " Fair Days" at the Centilia Cultural Center located at El Centro de la Raza 2524 16th Ave South. The Fair days will happen August 9 and September 13. The purpose of this project is to celebrate the rich diversity of the Beacon Hill neighborhood by highlighting various cultural activities and dance that reflect ethnic groups such as Latino, Asian, East African etc. The event is free and open to the public.