prevention

Research on End-user Acceptability.and Long-term Impacts of HIV Cure Strategies (REALISE)

ABSTRACT Despite remarkable advances in HIV cure science, emerging cure candidates will likely involve trade-offs (e.g., incomplete eradication, monitoring burdens) and must compete with increasingly convenient long-acting ART; without early implementation guidance, even efficacious products may see limited uptake, particularly among the ~30–40% of people with HIV (PWH) in the U.S. who are not durably suppressed. We propose REALISE, a multidisciplinary program to define plausible cure profiles, quantify end-user preferences, and project population-level impact to inform product design and policy before market entry. Aim 1 conducts qualitative interviews with ~30 researchers and developers to delineate credible 10–20-year cure and long-acting treatment scenarios (eradication vs functional control, safety, monitoring, durability), yielding bounded “target product profiles.” Aim 2 elicits patient-centered preferences through a two-stage study: formative interviews (n=60; ≥50% not virally suppressed) to identify salient attributes; best-worst scaling (n=360 across Missouri, Georgia, and San Francisco) to prioritize attributes; and a discrete choice experiment (n=360) to quantify trade-offs versus alternative therapies, with latent class analysis to identify preference segments and estimate potential reach. Aim 3 integrates preference-based uptake from Aim 2 with Aim 1 efficacy and cost inputs in a mathematical model to estimate health impact, QALYs, net QALYs, and incremental cost-effectiveness across heterogeneous populations and Ending the HIV Epidemic jurisdictions. Innovation lies in linking cure R&D horizons to end-user preferences and transmission-dynamic outcomes, an approach that anticipates real-world use rather than retrofitting after approval. Deliverables include ranked cure attributes for product optimization, uptake projections including among unsuppressed PWH, and jurisdiction-specific value assessments to guide public health investment. By aligning cure design with what patients will accept and systems can sustain, REALISE will accelerate effective deployment of future cure strategies and maximize their contribution to Ending the HIV Epidemic. In doing so, this study advances NIH's priorities by connecting implementation science with prevention, treatment, and cure research. Using a multidisciplinary strategy to refine and extend `target product profiles,' REALISE will ensure cure development reflects patient needs and accelerate translation into real-world benefit.

Eosinophils promote persistence and transmission during Bordetella spp. infections

ABSTRACT Despite widespread vaccination, Bordetella spp., the causative agents of whooping cough, continue to circulate globally. Resurgent outbreaks contribute to significant healthcare burdens and costs estimated up to $79 million annually. This persistence and reemergence highlight a critical need for new therapies and prevention methods. Our laboratory investigates bacterial and host drivers that enable Bordetella success, defined as enhanced persistence, reinfection, and transmission. We have identified the Bordetella sigma factor BtrS as a regulator of immunosuppressive pathways that modulate eosinophil function. Leveraging genetically tractable Bordetella strains, advanced murine models, and immunological tools, we are uniquely positioned to dissect how eosinophils contribute to respiratory bacterial infections. Our preliminary data reveal that eosinophils promote Bordetella persistence. Our results also show that the anti-inflammatory cytokine IL1 receptor antagonist (IL1Ra) also contribute to persistence. However, the contribution of eosinophil-derived immunosuppressors remains unclear and will be investigated in Specific Aim 1. Moreover, we have evidence that eosinophils are required for nasal shedding, through mucus enhancement, and paroxysmal coughing, via exacerbation of bronchoconstriction, during Bordetella spp. infection, two key metrics of transmission. The eosinophil-effectors that promote shedding, coughing, and transmission, will be investigated in Specific Aim 2. Based on our data, we hypothesize that eosinophils contribute to Bordetella pathogenesis by (1) promoting persistent infection and (2) enhancing transmission through mucus-driven shedding and cough reflex induction. This proposal will test this hypothesis through two specific aims: Aim 1: Delineate the immunosuppressive role of eosinophils in modulating host responses and enabling Bordetella persistence. Aim 2: Define the mechanisms by which eosinophils facilitate Bordetella spp. transmission. By reframing eosinophils as active modulators of bacterial pathogenesis, this research challenges traditional views of eosinophils as terminal effector cells and positions them as novel targets for therapeutic intervention, that might be applicable to other mucosal pathogens. The outcomes will contribute to our understanding of eosinophil biology in infection and may lead to innovative strategies to halt bacterial persistence and transmission.

Antibody-guided design of a human astrovirus vaccine

PROJECT SUMMARY Viral diarrheal diseases cause substantial global morbidity and mortality. Diarrheal disease is the second leading cause of childhood mortality in the world, accounting for over 10% of all deaths of children under 5 years old. Gobally, over 1 billion cases of diarrheal diseases occur every year, making prevention of these diseases a public health concern of the highest priority. Human astrovirus (HAstV) infection is a leading cause of viral diarrhea in children and has been shown to cause chronic gastrointestinal disease and fatal neurological disease in immunocompromised patients. There are nearly 4 million cases of HAstV infection each year in the United States alone, and there are no clinically approved HAstV-specific vaccines or therapeutics. Antibody-guided vaccine development leverages a deep understanding of productive antiviral antibody responses in order to design vaccine immunogens that deliberately focus the induced response toward highly conserved epitopes with the goal of reliably inducing broad, durable immunity. Using a cutting-edge monoclonal antibody (mAb) discovery approach based on next-generation antigen barcoding, single cell multi-omics, and sophisticated bioinformatics, we will exhaustively screen the HAstV- specific antibody repertoires of geographically distinct donor cohorts to uncover the structural and immunogenetic features that differentiate broad and potently neutralizing HAstV mAbs. A more complete understanding of these exceptional – and potentially very rare – mAbs will accelerate the development of HAstV vaccines and therapeutics. We have assembled a collaborative, multidisciplinary group of investigators with a long history of productive collaboration and with highly complementary areas of expertise. We expect our work will result in the discovery of thousands of novel anti-HAstV mAbs from cohorts of healthy adult and pediatric participants. Detailed genetic, functional, and structural characterization of these mAbs will reveal conserved sites of viral vulnerability, uncover the precise molecular mechanisms of viral neutralization, and inform our development of a broadly protective HAstV vaccine.

Factory-treated, long-lasting permethrin baby wraps for the prevention of malaria: A phase III randomized controlled trial

PROJECT SUMMARY/ABSTRACT Progress against malaria has stalled. Novel interventions – particularly those targeting outdoor and daytime biting – are needed. In a randomized, placebo-controlled trial of permethrin- vs. sham-treated baby wraps in Uganda, we found a significant reduction in clinical malaria incidence among children carried in permethrin- as compared to sham-treated wraps (Boyce et al, NEJM, 2025). Despite these promising results, our trial incorporated a monthly re-treatment strategy that would be difficult to operationalize at scale. Furthermore, we only followed participants for 6 months, which is shorter than the expected period of use. Therefore, implementation studies - and specifically trials of long-lasting, factory-treated textiles - are now needed. Factory-treated materials would not only eliminate the need for retreatment for up to 12 months, but because the chemicals are more tightly bound, result in less absorption across the skin. Therefore, we now propose to conduct a randomized, double-blind trial of factory-treated, long-lasting (FTLL) wraps. AIM 1: Determine the effectiveness of FTLL permethrin wraps in combination with existing interventions for the prevention of malaria in children. We will enroll 750 mother-infant pairs from routine immunization visits (~3 months of age) at 3 sites of varying transmission intensity across Uganda. All participants will receive new dual active ingredient (AI) bed nets and be randomized (1:1) to either FTLL or untreated wraps. The primary outcome will be clinical malaria incidence during the period of wrap use, defined as fever a positive malaria rapid diagnostic test (RDT) between the FTLL and untreated arms. AIM 2: Confirm the safety of extended exposure to FTLL permethrin wraps for use in young children. Although a review of factory-treated clothing by the US Environmental Protection Agency, including clothing for children and toddlers, did not identify scenarios of concern, the frequency of use envisioned here may be beyond that modeled. To accomplish this, we will perform semi-annual assessments of growth (e.g., height-for-weight) and neurodevelopment (ND) during the period of use and 12-months after discontinuation. AIM 3: Assess the effect of FTLL permethrin wraps on Anopheles mosquito indices and blood-meal seeking behaviors. We will conduct longitudinal entomological surveillance, including CDC-light trap and aspirator collections, supplemented by human landing catches at sentinel households (~10-15%) from both the FTLL and untreated arms. This work tests a novel intervention, which leverages technology developed by the US military, to reduce the burden of malaria in endemic countries. Addressing malaria in these countries minimizes the risk of importation into the US. If successful, the project will provide additional evidence for treated textiles, which may be used to protect American travelers and deployed military servicemembers. The project will be conducted in Uganda, where malaria is highly endemic and it will be possible to enroll at-risk women-infant pairs.

Defining Microbial and Host Pathways Driving Asymptomatic C. difficile Colonization Associated with Aging and High-Sugar Diets

SUMMARY Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated diarrhea, with rising incidence in community settings and a growing burden of asymptomatic colonization. Asymptomatic car- riers, particularly among the elderly and individuals consuming high-sugar diets, represent a critical but underexplored reservoir for transmission and disease progression. This proposal introduces novel, anti- biotic-independent mouse models demonstrating that both dietary sugar and aging independently pro- mote asymptomatic C. difficile colonization. We hypothesize that these factors disrupt colonization re- sistance (CR) through distinct but overlapping microbial, metabolic, and immune pathways. In Aim 1, we will define how traditional and emerging dietary sugars alter the gut environment to permit C. difficile colonization using in vitro bioreactors and in vivo models. Aim 2 will identify age-associated changes in microbiota and mucosal immunity that impair CR, using longitudinal studies and fecal micro- biota transfer. Aim 3 will functionally validate C. difficile genes upregulated during asymptomatic carriage using CRISPR-Cas9 mutants in both sugar- and age-induced models. This integrative, multi-omics approach will uncover the mechanisms enabling asymptomatic colonization and identify microbial and host targets for intervention. The findings will inform microbiome-based strat- egies to prevent CDI in vulnerable populations and shift current paradigms in CDI risk assessment and prevention.

The Role of the Intestinal Microbiota in Sepsis Mortality

Project Summary/Abstract Sepsis is a life-threatening condition characterized by a dysregulated host response to infection that can cause multi-organ damage and death. As the leading cause of in-hospital mortality, sepsis mortality rates reach up to 50%, and account for approximately 270,000 deaths and $38 billion annually in health care costs in the United States. Notably, patients with similar medical backgrounds can have vastly different sepsis outcomes— some survive with medical treatment while others die. The reasons for this dichotomy are unknown but is seen across all forms of bacterial bloodstream infections, is not specific to any strain-level differences in the infecting pathogen and cannot be explained by human genetic differences. Human microbiota studies suggest that gut microbial dysbiosis is associated with sepsis mortality and that these alterations influence gut barrier breakdown, leading to gram-negative bacteremia—one of the most common causes of sepsis and mortality. However, there are a lack of studies that investigate the causal role of the intestinal microbiota in sepsis mortality. This K08 proposal will elucidate the role of the intestinal microbiota in sepsis mortality. Utilizing the well- established murine model of sepsis by intraperitoneal injection of lipopolysaccharide (LPS), we combine microbiota taxonomic sequencing and metagenomics, advanced bioinformatic techniques and prediction modeling, with knowledge of mucosal immunity and germ-free mouse systems to characterize the microbiota features and members that correlate with, predict, and cause sepsis mortality. This proposal is organized into two specific aims: (1) identify baseline stool microbial features associated with and predictive of sepsis outcomes and (2) determine how colonization with immunostimulatory microbes heightens sepsis mortality. In this work, I will holistically characterize the host immunologic and microbiota features that are associated with and predictive of mortality and experimentally identify microbes and microbial pathways that cause death in our model. These findings will reveal new microbial and host biomarkers of sepsis mortality and identify novel targets for sepsis prevention and treatment to reduce the overall mortality rate of this deadly disease. My long-term goal is to become an independent physician-scientist who integrates cutting-edge computational methods with experimental biology to identify predictive biomarkers of disease onset and outcomes, investigate how they influence disease processes, and develop novel therapeutic and preventive strategies to improve patient care. This proposal details specific research aims and a structured career development and training plan that will allow me to acquire focused, in-depth and multidisciplinary training under the guidance of an internationally recognized team of experts in clinical infectious diseases, host-microbiota interactions, immunology, immunometabolism, and computational biology. The knowledge generated will address the fundamental role of the microbiota in sepsis outcomes and inform future preventative and therapeutic strategies that will lower the sepsis mortality rate worldwide.

Mentoring investigators in patient-oriented research on HIV and public health

PROJECT SUMMARY/ABSTRACT Despite marked progress in treatment and prevention, HIV remains a significant public health threat in the US and globally. Innovative strategies are needed to effectively deploy interventions and reduce HIV incidence, which requires a sustained and committed workforce. Dr. Dennis is an infectious disease physician and researcher at the University of North Carolina (UNC) at Chapel Hill, Division of Infectious Diseases. She seeks the protected time of the K24 award to ensure adequate time and effort to provide mentorship in patient- oriented HIV research focused on applied public health strategies. Dr. Dennis has a track record of performing high-quality patient-oriented research supported by independent funding. Her research bridges basic, clinical, and epidemiologic science by using HIV-1 molecular epidemiology and phylogenetics to understand HIV transmission at the population level and to use this information to direct prevention. She has expanded this work to optimize strategies to detect and respond to HIV networks using mixed-methods approaches. The overall goal of this work is to uncover the links between these sub-epidemics - which are overlapping sub- epidemics defined by risk groups, geography, social interaction - to facilitate the design of timely, effective interventions. The research specific aims are 1) Investigate HIV transmission networks using molecular epidemiology and phylodynamics (R01AI135970), 2) Evaluate uptake of HIV treatment and prevention services in public health with social network approaches (supported by R01AI169602), and 3) Pilot a network-based characterization of early syphilis infections to inform strategies to increase the uptake of injectable antiretrovirals for HIV treatment and prevention (supported by K24). With the support of the K24, she will leverage resources at UNC to support mentorship and professional development to strengthen new directions (implementation science, community-engaged research). Dr. Dennis is deeply committed to expanding her mentorship and dedicated to fostering diverse mentees with lived experiences that are critical for sustaining the HIV workforce. Dr. Dennis is Co-Director of the UNC Center for AIDS Research (CFAR) Scientific Working Group which focuses on Ending the HIV Epidemic efforts in North and South Carolina. She has strong institutional support and a multidisciplinary team of advisors, including the UNC CFAR, and is an advisor on the UNC T32 HIV/STI institutional training program. She has collaborated for the past 10 years with NC Division of Public Health and with multiple investigators and trainees at the UNC Gillings School of Public Health. She is active in the UNC Infectious Diseases Fellowship program, providing clinical and research mentorship to numerous ID fellows. Her clinical activity provides practical grounding and relevance in patient-oriented research. The K24 will provide 50% of Dr. Dennis’ salary and additional funds to support mentees’ research. The proposed research is timely and aligned with the National HIV/AIDS Strategy and will support the protected time needed to mentor the next-generation of investigators in HIV patient-oriented research.

Urothelial Resurfacing with Irreversible Electroporation for Adjuvant Therapy of Bladder Cancer

PROJECT SUMMARY Over 70% of bladder cancer (BCa) patients are diagnosed with early-stage and localized non-muscle invasive disease (NMIBC), yet achieving durable cancer-free survival remains a significant challenge. Most of these patients will experience local tumor recurrence within five years following standard of care (SoC) transurethral resection of bladder tumor (TURBT) and intravesical adjuvant chemo- or immunotherapy. Recurrence is driven by microscopic tumors and premalignant lesions dispersed within the urothelial layer that survive and escape these treatments. As TURBT effectively treats tumors visible on imaging, current research has predominantly focused on drugs and biologics for improving intravesical adjuvant therapy. In this proposal we pose the provocative question whether a TURBT-like ablative technique can be extended to debulk malignancy in the entire bladder and investigate the synergy with intravesical adjuvant therapy in improving outcomes. Our objective is to address this technology and knowledge gap by developing and validating whole bladder urothelial resurfacing (WBUR) using irreversible electroporation (IRE). During IRE, microsecond-long pulsed electric fields (PEF) are used to induce rapid cell death by catastrophic permeabilization of the cell membrane, without affecting the extracellular matrix (ECM) within the treated tissue. In prior work, we designed devices that utilized this unique mechanism of IRE for performing penetrative ablation in the ureter, bile duct and bronchus of swine while preserving lumen function. Our findings provided strong rationale for IRE being an ideal candidate for WBUR as alternate techniques such as thermal ablation or ionizing radiation must be performed with extreme care in the bladder to avoid perforation or fistula formation. In subsequent preliminary work we developed technology to demonstrate the feasibility and safety of WBUR with IRE in a rat model of BCa and scalability in human-sized swine bladder. In Aim 1, we will investigate the cancer treatment efficacy of combination WBUR and intravesical adjuvant therapy. In Aim 2, validate WBUR derived liquid biopsy for monitoring cancer status. In Aim 3, engineer PEF delivery strategy to enhance the safety and specificity of WBUR. The innovation of our proposed work is defined by developing whole bladder ablation as a debulking strategy and examining its synergy with SOC adjuvant therapy (Aim 1), enabled by new electrode paradigm and PEF delivery strategy (Aim 3), monitoring by an unconventional liquid biopsy approach (Aim 2). Our work can immediately aid the management of NMIBC patients who cannot undergo radical cystectomy, with future application as a cancer prevention strategy in high-risk patients. Success of individual aims will result in major contributions to the topics of IRE, BCa treatment and diagnosis.

Systems Biology of Early Atopy: Role of Human Milk (SunBEAm-Milk)

Surprisingly little is known about the effect of breastfeeding (BF) on infant immune system development besides an effect on the gut microbiome, but its impact on metabolites and Tregs could support protection against food allergy (FA). BF is currently recommended to prevent the development of allergic diseases, especially asthma/recurrent wheezing and AD in early childhood, but firm conclusions could not be drawn regarding FA due to high heterogeneity and low quality of studies. Reverse causation, recall bias and the poor accuracy of outcome assessment are significant limitations. Most are inadequately powered to specific FA; however, a recent study showed that exclusively BF infants had lower odds of egg, sesame, and peanut allergies. Importantly, immunomodulatory composition of HM varies between mothers, which has not been taken into consideration. For over two decades we have been developing methods to assess immunomodulatory factors in the complex matrix of HM and their association with infant FA. We have shown that high levels of HM total and specific IgA are associated with protection against cow’s milk allergy, but it is unclear whether HM IgA is responsible for or is a biomarker of the vertical transfer of protection. Infant fecal and systemic IgA levels during breastfeeding and after weaning are also elevated in infants at low risk for atopic disease raising the question of whether HM factors such as cytokines can promote IgA production in infants. Consistent with this, we showed that HM cytokines, such as APRIL, induce IgA production in naïve infant B cells, and infants receiving HM with higher levels of APRIL had lower incidence of allergic disease. Finally, lower levels of several HM fatty acids including short-chain fatty acids and DHA were associated with FA. While some these factors were are associated with maternal atopic disease, several of them are not and suggest a role for diet instead. The System Biology of Early Atopy (SunBEAm) population-based cohort of 2500 mother-infant pairs is >50% recruited and provides an unprecedented opportunity to assess association of HM feeding and immune factors in HM with development of infant immune system and FA/AD. The Common Sample comprises a subset of 100 dyads with FA, 100 with FA+AD, 100 with AD, 100 with no FA or AD and more extensively profiled biological data. Utilizing all 2-month HM samples available in the Common Sample, we will assess levels of immune factors in HM and their association with maternal/infant characteristics (Aim 1). Utilizing data from the whole cohort, we will assess the association between HM vs formula feeding on well-defined FA/AD further adjusted based on high vs low levels of HM immune components in the Common Sample (Aim 2b). Finally, we will examine the immune cell and epithelial effects of HM on infant immune markers and intestinal organoids (Aim 3). Key findings will be validated in an independent birth cohort. The ultimate goal is to uncover protective properties of BF and HM in FA and subsequent design of policies and prevention strategies to address the increasing rates of FA.

Behavioral, Implementation & Community Sciences Core

PROJECT SUMMARY: BEHAVIORAL, IMPLEMENTATION, AND COMMUNITY SCIENCES (BICS) CORE Like many US jurisdictions, New York City (NYC) is not on track to achieve 2030 End the Epidemic (EHE) 95- 95-95 goals. By the end of 2023, 95% of people with HIV (PWH) in NYC had been diagnosed with HIV, but only 88% of those were in HIV care, and of those, only 80% were virally suppressed. Further, in 2022, only 40% of individuals estimated to need PrEP were prescribed it. Highly efficacious biomedical HIV treatment and prevention interventions have the potential to end the HIV epidemic, but only if they are accessed and used. Yet, behavioral, social, and structural determinants of real-world adoption as well as population-level impact of HIV prevention, care, and treatment innovations have not been addressed adequately for individuals or communities. Meeting EHE goals will depend on behavioral, implementation, and community sciences research that identifies factors contributing to these outcomes, informs interventions to address them, and ensures that communities affected by HIV are engaged throughout the research process. The Behavioral, Implementation, and Community Sciences (BICS) Core will facilitate such rigorous, innovative research by Columbia University (CU) and Weill Cornell Medicine (WCM) investigators – particularly early career investigators (ECIs) and those new to HIV research – to help achieve EHE 2030 goals. The BICS Core will support the use of relevant theories, methods, and analytic approaches to advance the integration of context-specific behavioral, implementation, and community sciences perspectives across the research continuum – from basic research through scale-up and sustainment of evidence-based interventions. The Core has three Aims: (1) Behavioral science: To support CFAR users in developing, selecting, and integrating behavioral science methodologies across the research continuum; (2) Implementation science: To support CFAR users in designing and conducting implementation studies and related health services research and (3) Community science: To facilitate rigorous community-based participatory research across the research continuum to strengthen and sustain stakeholder engagement that will optimize research translation and impact. Led by Core Co-Directors Robert Remien and Bruce Schackman and Core Associate Directors Delivette Castor, Shashi Kapadia, and Justin Knox, the BICS Core will use multiple approaches to achieve each of these aims, including substantive scientific consultations on proposed or ongoing research; access to resources and tools; and seminars and educational activities that promote integration of these methods into EHE research. The Core, thus, will support CU-WCM CFAR investigators and outside collaborators – including ECIs and investigators new to HIV research – to advance local and national EHE goals.

Tbx4-Driven Pulmonary Hypertension: Mechanisms and Therapeutic Targets

Project Summary: Heterozygous rare variants in TBX4 are the second most common cause of heritable pulmonary arterial hypertension (PAH). Presentation of this form is commonly in children. Patients with mutations in TBX4 generally have alveolar simplification or hypoplasia in addition to elevated pulmonary vascular resistance. We have developed a set of three tools to help determine the molecular etiology of TBX4-induced PAH; (1) we identified the direct binding targets using a combination of ChIP-seq and RNA-seq; (2) we developed a mouse model with Tbx4 knockout after birth, that substantially phenocopies human disease; (3) we performed single-cell RNA-seq on these mice. By combining these three tools, we can develop a complete model for how loss of a transcription factor leads to the molecular and physiologic changes we see in our mice. The phenotype in mice appears to be dominated by defects in pericytes, resulting in impaired angiogenesis. Pericytes, which strongly express Tbx4, are cells located on the outside of capillaries and precapillary arterioles, and can either stabilize vessels (mesh pericytes), or drive angiogenesis (angiogenic pericytes). The pericytes in Tbx4 mutant mice are heavily skewed towards mesh and away from the angiogenic phenotype. Loss of Tbx4 results in derepression of Tbx4 binding target Rgs5 (10x induction), which directly results in inhibition of Pi3K, and the phenotypic switch in pericytes. We will test this hypothesis through pericyte-specific Tbx4 knockout (Aim 1) and pharmacologic induction of Pi3K in vivo in prevention and rescue models, as well as by siRNA to Rgs5 in precision-cut lung slices from Tbx4 KO mice (Aim 3). We will also test the role of Tbx4 in fibroblasts and smooth muscle using cell-specific knockouts – based on our mouse and single cell data, we expect they contribute somewhat, but primarily through increased stiffness (Aim 2). Finally, we will confirm relevance to human disease through spatial transcriptomics in lung sections explanted from patients with TBX4 mutation or rearrangement (Aim 1), and through determining whether defects in human patient iPSC-derived pericytes can be corrected through Rgs5 or Pi3K interventions (Aim 3). In combination, these aims determine the cellular and molecular mechanisms leading from mutation to physiology with loss of TBX4, and establish therapeutic targets.

Response and defense mechanisms of extraintestinal Escherichia coli to reactive oxygen and chlorine species

Members of the Escherichia coli species are remarkably diverse and comprise commensal, probiotic and pathogenic strains. While some pathogenic E. coli cause intestinal diseases, extraintestinal E. coli (ExPEC) can colonize and infect environments outside the gut. For instance, members of this pathotype can inhabit the urinary tract where they are confronted with a multitude of bactericidal host defense strategies, which requires specialized genetic adaption for survival. ExPEC must defend highly toxic antimicrobials such as hypochlorous acid (HOCl), a potent reactive oxygen and chlorine species (RO/CS) generated during neutrophil-mediated phagocytosis and by enzymes in uroepithelial cells to control bacterial colonization. The increasing rate of ExPEC infections in humans due to changing infection dynamics demonstrate the critical need for a better understanding of ExPEC pathogenesis, which is desperately needed to improve approaches for infection prevention and treatment given the rise in antibiotic resistance spreading among E. coli. Our lab has reported that members of the ExPEC pathotype are more resistant to RCS in vitro and to neutrophil-mediated phagocytosis when compared to non-pathogenic and enteropathogenic E. coli. We identified the defense system responsible for these phenotypes and characterized its regulation during RCS stress: the RcrR regulon consisting of the rcrARB genes is controlled by the RCS-sensing transcriptional repressor RcrR, which reversibly loses its repressor activity upon oxidation by RCS, resulting in de-repression of its downstream targets. Induced expression of rcrB contributes significantly to ExPEC’s increased RCS resistance, however, the precise mechanism of RcrB and the role of RcrA (and potentially other defense players) during RCS stress remain enigmatic. Our long-term goal is to increase the efficacy of existing antimicrobial therapies by purposefully and selectively sensitizing ExPEC to clearance by innate immune cells. The overall objective of this application is a comprehensive analysis of ExPEC’s RCS defense with particular focus on the mechanism of the RcrR regulon. We hypothesize that RcrB directly protects cells from HOCl, while RcrA, another member of the RcrR regulon, mediates evasion from HOCl and invasion into host cells. In Aim 1, we will use phenotypic, biochemical, and imaging approaches to investigate the mechanism by which RcrB contributes to ExPEC’s increased RCS resistance. In Aim 2, we will study the role of RcrA for ExPEC motility, biofilm formation, and host cell invasion. In Aim 3, we will use independent unbiased and targeted approaches, including phenotypic characterization of transposon mutants, to fully comprehend ExPEC-specific responses to and defenses against RCS. Identifying, characterizing and targeting ExPEC-specific defense systems has the potential to increase the body’s own capacity to fight UTIs. Overall, we will involve at least four undergraduate students in our research projects, which we believe will provide an excellent training opportunity for the next generation of scientists.

From Evidence to Scale: Implementation Science and Simulation Modeling to Transform HIV-Hypertension Care Integration

Project Summary As HIV programs mature, cardiovascular disease (CVD) is becoming a leading contributor to morbidity and mortality. Integration of HIV and CVD prevention, with a focus on hypertension–the most prevalent and impactful modifiable CVD risk factor, presents an opportunity to build more robust primary health systems that improve health outcomes and advance health system sustainability–a key priority for the U.S. PEPFAR program. Using an expanded version of the HIV Synthesis microsimulation model—which incorporates hypertension and CVD outcomes—and data from the NHLBI-funded HLB-SIMPLe consortium’s cluster randomized trials in six African countries, we will evaluate the health effects, cost-effectiveness, and scalability of implementation strategies to promote HIV-hypertension integration to improve health outcomes for people with and without HIV under a range of health system constraints. Our first aim is to develop and validate an additional layer to HIV Synthesis model that accounts for health system constraints and implementation strategies for integration of HIV and hypertension care. This will include parameterization using data from the WHO Health System Building Blocks framework and empiric data from trials in the HLB-SIMPLe consortium. Our second aim is to evaluate the health effects and cost-effectiveness of implementation strategies for HIV-hypertension integration to identify the most effective and scalable approaches for settings with varying health system constraints representative of conditions in west, east, and southern Africa. Analyses will include scenarios targeting people with HIV and scaling up to the broader population. Our third aim focuses on engaging policymakers and program managers to promote uptake of findings through dissemination workshops and interactive modeling tools, with tailored model outputs to specific health system contexts. Using qualitative interviews with policymakers, we will use the Weiss schema for conceptualizing research utilization to assess model impact on decision-making. We will use the Translational Science Benefits Model, to capture, classify and conceptualize the clinical, policy, economic, and operational impacts and identify barriers and facilitators to use in country programs focused on HIV, hypertension, and related NCDs. The overarching project goal is to inform evidence-based, cost-effective implementation strategies for integrating NCD care into HIV platforms, improving population health outcomes in Africa and advancing implementation science through generalizable knowledge about the intersection of implementation strategies, health system strength, and service integration.

SUPPORT SERVICES FOR THE PREVENTION AND TREATMENT THROUGH A COMPREHENSIVE CARE CONTINUUM FOR HIV-AFFECTED ADOLESCENTS IN RESOURCE CONSTRAINED SETTINGS IMPLEMENTATION SCIENCE NETWORK

Support Services for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) requires support for logistical and operational coordination, website and communication management, analytic and data management, infrastructure for emerging research, regulatory, and monitoring of research activities for the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings Implementation Science Network (PATC3H-IN) (UG1/UM2) Program. The NICHD and partner NIH Institutes anticipate funding 8 PATC3H-IN UG1 awards in Asia and throughout sub-Saharan Africa in 2023 through a cooperative agreement mechanism for interventions of high public health significance: The prevention of new HIV infections among adolescents at risk, and the identification of, linkage to and retention in care of, and long-term viral suppression among youth living with HIV in low-to-middle income countries with high HIV burden. The PATC3H-IN network will expand and/or improve on successes achieved by its predecessor, PATC3H, to new geographic settings and/or risk populations and stimulate much needed implementation science (IS) research in the prevention of new HIV infections among adolescents at risk and the identification of, and linkage and retention to care of and long-term viral suppression among youth living with HIV in low-to-middle income countries (LMICs). PATC3H-IN will establish a network of investigators with multidisciplinary expertise on the youth-specific PHCC and in IS research, whose mission will be to evaluate promising prevention innovations contextually and developmentally tailored for HIV uninfected at-risk youth, and treatment and care interventions for youth living with HIV which have demonstrated efficacy and/or effectiveness in adolescent or adult populations and to translate them into public health practices. The structure of PATC3H-IN will consist of multiple interdependent functional components: (1) Five Clinical Research Centers (CRC) awarded through the UG1 grant mechanism; (2) one Implementation Science Coordinating Center (ISCC) to be awarded through a UM2 grant mechanism in 2024; and (3) a Scientific Leadership Committee (SLC). The CRCs will conduct clinical research and clinical trials, including implementation, effectiveness, and hybrid implementation-effectiveness studies at their 8-or more participating Clinical Research Performance Sites (CRPS). The ISCC will establish infrastructure to support research education and capacity building across PATC3H-IN, as well as infrastructure for stakeholder engagement in and dissemination of findings from PATC3H-IN and advanced statistical modeling support across PATC3H-IN. The ISCC will also provide infrastructure for conducting foundational research to support the work of clinical sites, including possible modeling studies and translation projects, as well as national surveys, and/or systematic collection and analysis of relevant policies and laws. Lastly, the SLC will be responsible for PATC3H-IN governance, oversight, and coordination, and will develop and implement the network research agenda, convening working groups as needed, prioritizing emerging research projects, efficiently managing the development of clinical protocols, implementing and completing clinical trials, and ensuring timely publication and communication of results.

Avian influenza virus prevention in the domestic host by a deactivated vaccine

Abstract Influenza viruses, which affect both birds and mammals, pose a substantial public health concern. An estimated 10% of the global population annually becomes infected, resulting in 300,000 to 600,000 deaths worldwide. Our research objectives are to develop a Hemagglutinin (HA) and Neuraminidase (NA) based rabies-vectored vaccine against highly pathogenic Avian Influenza (HPAI) A virus H5N1. We have already demonstrated the vaccine’s immunogenicity and protective efficacy against HPAI H5N1 Vietnam 1203. To advance this research, we propose to utilize a novel RAVB-based deactivated vaccine that harbors the H5 antigens of the current homologous circulation (clade 2.3.4.4b) and a construct expressing N1. Our first aim will involve comparing the H5 or H5/N1 RABV-based vaccines against challenges by PR8 recombinants carrying H5N1 proteins in mice. We will employ a single immunization and a prime/boost approach, either with or without an adjuvant approved for use in animals and humans (SEPIVAC SWE™). We will assess the role of T cells in the vaccine-induced protection by performing CD4/CD8 depletion before challenge Our second aim will utilize the vaccine approach identified to protect our mouse system in dairy cows. Subsequently, we will assess the vaccine’s efficacy against challenges administered intranasally and intramammary. We will verify the role of the vaccine-induced antibodies in protection against H5N1 by performing passive transfer studies of purified IgG from vaccinated cows before challenge. In summary, this study will evaluate the efficacy and delineate the mechanism of protection of a safe and well- established vaccine platform to protect against HPAI H5 and explore its potential as an animal and human vaccine.

2-Deoxyglucose Therapy for Organophosphate Intoxication

Project Summary The main goal of this project is to determine the therapeutic potential of glycolysis inhibition as an adjunct to midazolam therapy in mitigating the long-term neurological effects from acute organophosphate pesticide and nerve agent (OPNA) exposure. Novel countermeasures are desperately needed for effective mitigation of morbidity and long-term effects of OPNAs. A variety of agents targeting glutamate, GABA and oxidative stress have been proposed, but glycolysis inhibitors have not been widely studied in OPNA intoxication. Dysregulated glucose metabolism plays a key role in seizures and neuronal injury following OPNA exposure. 2-Deoxyglucose (2-DG), a selective glycolysis inhibitor, has anticonvulsant and neuroprotection effects and hence can effectively mitigate acute and long-term OPNA neurotoxicity. In this project, we seek to identify the glycolysis inhibition as novel adjunct neuroprotection to midazolam therapy for OPNA exposure, with the goal of identifying 2-DG or related drugs as medical countermeasures. The glycolytic pathway represents a logical target for such intervention because glycolysis controls seizures and neuronal injury by regulating glucose utilization and activity in neurons and astrocytes in the brain. The proposed therapy is based on the hypothesis that acute OPNA neurotoxicity imparts sustained activation of the glycolysis pathway in the brain and therefore, 2- DG and selective glycolysis inhibitors prevents long-term neuronal damage neurological dysfunction. This hypothesis will be tested by using the FDA-approved (2-DG) or clinical-stage glycolytic inhibitors in two distinct OPNA models in rats: (Aim 1) To investigate the protective efficacy of 2-DG and novel glycolysis inhibitors against DFP-induced acute and long-term neuronal damage and neurological dysfunction. (Aim 2) Aim 2 (Year 2). To determine brain penetration, pilot toxicity and pharmacokinetic of 2-DG or other lead drug in naïve and DFP-exposed animals. Test drugs will be evaluated as per the NIH rigor criteria in a dose-related design in male and female rats and behavior/neuropathology will be checked for 3 months post-exposure. 2-DG and test drugs will be given starting 40-min after exposure to ONAs. Three primary outcome measures will be addressed for therapy effectiveness: (i) acute adjunct neuroprotection; (ii) chronic neuroprotectant efficacy; and (iii) prevention of neurological and behavioral deficits. The primary measures of neuroprotection include longitudinal MRI scanning, and extent of neurodegeneration, neuroinflammation, aberrant neurogenesis, and mossy fiber sprouting. Key neurological outcomes include memory deficits, depression, anxiety behavior, and neurological/motor deficits. The outcome of this project will provide “proof-of-efficacy” of a novel glycolytic therapy with FDA-approvable, repurposed drugs with promising potential to limit long-term effects of OPNAs in humans. Thus, the overall impact of the outcome is enormous for civilians, especially in developing a highly effective and safe post-exposure medical countermeasure for chemical nerve agents.

Understanding antiretroviral phosphorylation and dephosphorylation using mass spectrometry imaging-based enzyme histochemistry

PROJECT SUMMARY Our overall goal is to understand the mechanistic differences in the activation and deactivation of two widely used first-line antiretroviral drugs: tenofovir (TFV) and emtricitabine (FTC) in colonic tissues. HIV is a global health problem and roughly 1.3 million people became newly infected with HIV globally in 2022. Pre-exposure prophylaxis (PrEP) is an HIV prevention strategy where HIV-negative individuals use antiretrovirals to reduce the risk of HIV infection. Specifically, oral fixed-dose combinations of two antiretrovirals, namely, TFV (TFV; prescribed as TFV disoproxil fumarate or TFV alafenamide prodrugs) and FTC are FDA-approved for HIV PrEP. The pharmacologically active forms of TFV and FTC are TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP), respectively, and these phosphorylated metabolites are found in cells. Unfortunately, high variability in the responses of TFV and FTC can lead to poor clinical outcomes, including therapeutic failure. However, the molecular mechanisms responsible for the observed variability in TFV and FTC responses are poorly understood. Although the observed variability in TFV and FTC drug responses is likely to be multifactorial, alterations in drug activation and deactivation can contribute to the observed variability in drug responses. Phosphorylation of TFV is known and recent studies suggest that nucleotidases may involve in the dephosphorylation of TFV metabolites. Although the kinases that phosphorylate FTC in peripheral blood mononuclear cells are known, the kinases that are responsible for the phosphorylation of FTC in putative sites of HIV infection such as colonic tissues are yet to be determined. Notably, unprotected receptive anal intercourse has a 20-fold higher risk of HIV transmission than vaginal intercourse. Thus, understanding the biotransformation of TFV and FTC in colonic tissue is important since it is a susceptible tissue to HIV infection. Recently, we have reported the enzymatic activities of nucleotidases toward the pharmacologically active metabolites of TFV and FTC in vitro. However, the mechanistic details of the biotransformation of the above drugs in HIV susceptible tissues such as colonic tissues are yet to be elucidated. Gaining a mechanistic understanding of the biotransformation of TFV and FTC in putative sites of HIV infection is important to improve their therapeutic efficacy. As such, in this application, we propose an innovative mass spectrometry imaging-based interdisciplinary approach to understand the biotransformation of TFV and FTC in the colon. Aim 1 will establish the role of nucleotide kinases and nucleotidases in regulating TFV and FTC metabolites in colonic cells mechanistically. Aim 2 will characterize the region- and cell-type-specific expression patterns, as well as enzymatic activities of nucleotide kinases and nucleotidases in situ. The proposed project will provide novel understandings of TFV and FTC activating and deactivating mechanisms that can be leveraged to optimize the therapeutic efficacy of the above drugs.

Programming Offspring Metabolism: The Role of Milk Extracellular Vesicles in Fat Development

SUMMARY Obesity is a global health crisis, contributing significantly to the prevalence of metabolic disorders, cardiovascular diseases, and various chronic conditions. A growing body of evidence suggests that maternal obesity during pregnancy and lactation can predispose offspring to obesity and metabolic dysfunction later in life. However, the mechanisms by which maternal obesity programs these adverse outcomes in offspring remain poorly understood. Breast milk is not only a source of essential nutrients but also contains bioactive components, including extracellular vesicles (EVs), which play crucial roles in cellular communication and development. Recent studies have shown that EVs can survive digestion and enter the infant’s circulation, influencing immune and metabolic development. Despite the established link between maternal obesity and altered breast milk composition, no study has investigated the role of milk-derived EVs (mEVs) in programming offspring fat development and metabolism. Understanding this novel pathway could revolutionize our approach to preventing intergenerational transmission of obesity. Our preliminary studies using a mouse model of maternal high-fat diet-induced obesity revealed significant alterations in mEV biogenesis and cargo composition, including changes in specific miRNAs. Oral administration of mEVs from obese dams to neonatal mice increased adiposity and impaired lipid metabolism, indicating that mEVs are crucial in modulating fat development and metabolic pathways in offspring. Several key miRNAs found in mouse mEVs are conserved in human milk EVs, highlighting the potential translational relevance of our findings to human health. We hypothesize that mEVs are critical mediators of maternal obesity’s programming effects on offspring metabolism and adiposity. In specific aim 1, we will use mouse models and advanced molecular techniques (miRNA sequencing, proteomics, and lipidomics) to characterize how maternal obesity affects mEV biogenesis and the composition of their bioactive cargo. We will also evaluate how maternal dietary intake, independent of obesity, influences mEV composition. Specific aim 2 will define the programming effects of mEVs on offspring energy metabolism and obesity. In addition, we will explore whether human milk EVs from lean and obese mothers exert similar programming effects on fat development and metabolism in a mouse model. This R21 application embodies a high-risk, high-reward approach to obesity research. It ventures into uncharted territory by proposing that mEVs are novel regulators of metabolic programming, a concept that has not been explored in prior studies. The potential reward is substantial: discovering a new mechanism by which maternal obesity influences offspring health could fundamentally shift our understanding of early-life metabolic programming and lead to innovative strategies for obesity prevention. If successful, this research could open a new field of study with broad implications for maternal and child health.

A PROTAC Strategy to Combat Botulinum Neurotoxicity

PROJECT SUMMARY/ABSTRACT Botulinum neurotoxin (BoNT), the causative agent of botulism, is the most potent toxin known to humans. While BoNTs are widely recognized for their therapeutic and cosmetic applications, such as Botox™, their increasing use has raised concerns about iatrogenic botulism. Due to their extreme lethality, ease of production, and history of weaponization, the Centers for Disease Control and Prevention (CDC) classifies BoNTs as a Category A bioterrorism threat. Among the seven major serotypes (A-G), BoNT/A, BoNT/B, and BoNT/E account for over 95% of human botulism cases with A being the most prevalent. Despite the severity of botulism, no approved therapeutic exists to rescue intoxicated neurons. The current treatment, a heptavalent antitoxin, can only slow disease progression and requires early administration and prolonged hospitalization due to the inability of antibodies to penetrate infected cells. In the field of small- molecule inhibitors (SMIs), promising scaffolds targeting BoNT/A have been discovered, offering opportunities for further derivatization to incorporate bifunctional approaches. Developing a clinically viable therapeutic requires inhibiting the zinc (Zn2+) metalloprotease light chain (LC) as well as addressing toxin persistence. Through extensive inhibitor screening, we have identified two classes of small molecules that inhibit BoNT/A with submicromolar affinity and demonstrate efficacy in both cellular and animal models. However, the transient nature of these inhibitors necessitates the need of a sustained clearance approach. To achieve this, we propose integrating our previously identified BoNT/A LC SMIs with a targeted protein degradation (TPD) technology for toxin elimination. Based upon the background outlined, vide supra, our research strategy for the ablation of BoNT/A will be focused upon the following three specific objectives: 1) Structural Optimization – Utilize molecular docking, and structure-activity relationship (SAR) analysis to modify inhibitors for TPD ligand attachment. 2) Degrader Design – Development of ubiquitin-protease system (UPS)-based proteolysis-targeting chimeras (PROTACs) and autophagy-targeting chimeras to enhance degradation efficiency. 3) Cellular Evaluation – Assess enzyme inhibition, toxin clearance, degradation kinetics in cells.

Stability in disrupted maternal representations over the perinatal period: Contributors and consequences

Abstract High-quality mother-infant relationships promote social, emotional, and cognitive development while protecting against poor child behavioral, health, and psychological adaptation that create risk for long- term negative outcomes. As mothers transition to parenthood, their own experiences of being cared for influence their emerging views of parenting and representations of their developing child. Evidence suggests that ‘disrupted’ maternal representations of the child, i.e., representations characterized by mixed communication, role merging, extreme withdrawal, and other unusual psychological processes, are tied to both poor child socioemotional adjustment and both insecure and disorganized attachment. However, it is unclear whether disrupted representations that emerge during pregnancy remain stable across the first several years of the child’s life. In addition, to date, research has not examined how change/stability in these representations may affect maternal caregiving and subsequent child adaptation. Using data from a longitudinal, multi-method study, this proposed project will examine the stability of maternal representations of the child for 99 women living in high risk contexts using the Working Model of the Child Interview during the third trimester and again when the child is two years of age. Mothers’ demographic characteristics (i.e. SES and relationship status), interpersonal violence experiences (i.e. child maltreatment or intimate violence exposure), psychological health (i.e. depressive, anxious, and PTSD symptoms), and parenting stress (i.e. perceptions of the child as difficult and parent-child interactions as dysfunctional) are measured as well to examine influences on representation stability. Finally, the observed quality of maternal caregiving and child adaptation are measured and examined in relation to stability in maternal representations of the child. Findings from this study have the potential to identify which mother-child dyads are at greatest risk for poor adaptation across the perinatal period and to delineate the contributors and consequences of maternal representational stability. These findings will serve as an important step towards informing the development or modification of existing prevention/intervention approaches that are targeted specifically towards mother-child dyads who are most at need.

2026 Thiol-Based Redox Regulation and Signaling Gordon Research Conference and Gordon Research Seminar

PROJECT SUMMARY This proposal requests support for the 10th meeting of the biennial Gordon Research Conference (GRC) and associated Gordon Research Seminar (GRS) on Thiol-Based Redox Regulation and Signaling to be held at the Rey Don Jaime Grand Hotel, Castelldefels, Spain on July 11-12 (GRS) and July 12-17 (GRC), 2026. Regulation of protein function through the post-translational modification of specific cysteine residues (thiol oxidation) plays an important role in cellular adaptation to local and global changes to endogenous and environmental oxidants. A key challenge for the redox-signaling field is to understand how thiol-based signaling mechanisms are integrated into cellular redox homeostasis and how these events facilitate communication between molecules, organelles, cells, and tissues to initiate and coordinate a specialized biological outcome. Significant emphasis for the 2026 meeting will be placed on an exploration of a wider range of cysteine thiol chemistry placed within a cellular context of other, often competing, oxidative or acyl modifications, some of which derive from environmental exposures, and contribute to cancer, aging and the progression of disease. In addition, we will discuss new insights into how cellular redox status impacts metabolic disease and new mathematical and analytical approaches to understand how redox gradients or “waves” impact the spatial and temporal aspects of signaling. A long-term objective is to use this new information to develop diagnostics and therapeutics for a wide range of redox-associated diseases that impact public health. This meeting provides a unique forum for extensive and immersive interaction among chemists, biologists, structural biologists and redox tool-builders, interested in a range of animal and cellular model systems, with clinical researchers and physicians focused on disease processes. While the thematic area of the conference is intentionally broad, its relevance to specialized NIH institutes is highly significant. Not only is redox toxicity proposed as a primary driver of chemically-induced pathology in humans, notably in aging and age-associated diseases, protection from these pathologies by “supersulfides” holds considerable promise. In keeping with the GRC tradition, the 2026 meeting will highlight presentations that emphasize unpublished work, creating a distinctive intellectual experience that enhances the excitement of the meeting. Investigators new to the meeting, junior investigators and graduate and post-graduate trainees will be welcomed. The associated GRS will provide a more intimate forum where graduate and postdoctoral trainees present their research to their peers, while receiving constructive comments from a few senior investigators who serve as mentors. We intend that the GRS/GRC meetings will attract and increase retention of junior scientists in the field of redox biology. We anticipate that the GRC will enhance the education of researchers at all career levels, generate new ideas and collaborations aimed at understanding thiol-based redox regulation and dysfunction, and enable future progress in the prevention, detection, and treatment of a wide-range of human diseases associated with perturbations in redox homeostasis.

From the guts to the brain through adaptive immunity in the prevention of Alzheimer’ disease

Dr. Pasinetti is the Saunders Family Chair and Professor of Neurology at Icahn School of medicine at Mount Sinai, New York. His studies allowed him to develop novel therapeutic approaches through investigation of preventable risk factors including mood disorders in the promotion of resilience against neurodegenerative disorder. In his presentation Dr. Pasinetti will discuss novel concepts about the gut-brain axis in mechanisms associated to peripheral adaptive immunity as therapeutic targets to mitigate the onset and the progression of Alzheimer’s disease and other form of dementia.

Programmed axon death: from animal models into human disease

Programmed axon death is a widespread and completely preventable mechanism in injury and disease. Mouse and Drosophila studies define a molecular pathway involving activation of SARM1 NA Dase and its prevention by NAD synthesising enzyme NMNAT2 . Loss of axonal NMNAT2 causes its substrate, NMN , to accumulate and activate SARM1 , driving loss of NAD and changes in ATP , ROS and calcium. Animal models caused by genetic mutation, toxins, viruses or metabolic defects can be alleviated by blocking programmed axon death, for example models of CMT1B , chemotherapy-induced peripheral neuropathy (CIPN), rabies and diabetic peripheral neuropathy (DPN). The perinatal lethality of NMNAT2 null mice is completely rescued, restoring a normal, healthy lifespan. Animal models lack the genetic and environmental diversity present in human populations and this is problematic for modelling gene-environment combinations, for example in CIPN and DPN , and identifying rare, pathogenic mutations. Instead, by testing human gene variants in WGS datasets for loss- and gain-of-function, we identified enrichment of rare SARM1 gain-of-function variants in sporadic ALS , despite previous negative findings in SOD1 transgenic mice. We have shown in mice that heterozygous SARM1 loss-of-function is protective from a range of axonal stresses and that naturally-occurring SARM1 loss-of-function alleles are present in human populations. This enables new approaches to identify disorders where blocking SARM1 may be therapeutically useful, and the existence of two dominant negative human variants in healthy adults is some of the best evidence available that drugs blocking SARM1 are likely to be safe. Further loss- and gain-of-function variants in SARM1 and NMNAT2 are being identified and used to extend and strengthen the evidence of association with neurological disorders. We aim to identify diseases, and specific patients, in whom SARM1 -blocking drugs are most likely to be effective.

Post-traumatic headache

Concussion (mild traumatic brain injury) affects approximately 50 million people annually. Headache is the most common symptom after concussion and persists in up to 50% of those affected for at least one-year. The biological underpinnings of and the efficacy and tolerability of treatments for post-traumatic headache has historically received little attention. While treatment in clinical practice is mostly directly at the underlying phenotype of the headache, persistent post-traumatic headache is considered to be less responsive to treatments used to treat migraine or tension-type headache. Over the past several years, significant pre-clinical research has begun to elucidate the mechanism(s) involved in the development of post-traumatic headache, and a concerted effort to evaluate the efficacy of selected treatments for persistent post-traumatic headache has begun. This presentation will review the epidemiology, pathophysiology, and emerging data on the prevention and treatment of post-traumatic headache.

The Role of Cerebrovascular Pathology in Aging and Neurodegenerative Disease Populations

Late-life cognitive impairment and dementia are heterogeneous and multifactorial conditions driven by a combination of genetic, vascular, and lifestyle-related factors. More than 75% of patients with dementia have evidence of cerebrovascular pathology at autopsy. Cerebrovascular disease lesions can be detected on structural MRI and used as biomarkers to determine the extent of cerebrovascular pathology. These biomarkers are associated with cognitive difficulties and increase the risk of dementia for the same level of neurodegenerative pathology. Given that some of the risk factors for cerebrovascular disease are potentially modifiable, identifying the role of cerebrovascular pathology in aging and neurodegenerative disease populations opens a window for prevention of cognitive decline and dementia.

Multimodal imaging in Dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a synucleinopathy but more than half of patients with DLB also have varying degrees of tau and amyloid-β co-pathology. Identifying and tracking the pathologic heterogeneity of DLB with multi-modal biomarkers is critical for the design of clinical trials that target each pathology early in the disease at a time when prevention or delaying the transition to dementia is possible. Furthermore, longitudinal evaluation of multi-modal biomarkers contributes to our understanding of the type and extent of the pathologic progression and serves to characterize the temporal emergence of the associated phenotypic expression. This talk will focus on the utility of multi-modal imaging in DLB.

Common elements: An innovative methodology for identifying effective interventions in early childhood education

Evidence-based education programmes, like many clinical interventions, are multi-faceted and can be expensive to implement. In this talk I will describe an alternative: distilling the common elements across many evidence-based programmes. Published programme manuals are selected through systematic review, then extensively coded and cross-referenced. Finally, the common elements that emerge are shared with practitioners as part of a ‘library’ of practices (rather than a holistic programme manual). Although the common elements methodology has been used in the prevention and intervention sciences, this project reflects the first attempt at applying this approach to early childhood education. I will describe the common elements methods and preliminary findings from our Nuffield-funded project, in collaboration with the Early Intervention Foundation. I will discuss the challenges and opportunities we have encountered, alongside our strategies for sharing evidence with practitioners in a digestible way.

​Improving the identification of cardiometabolic risk in early psychosis

People with chronic schizophrenia die on average 10-15 years sooner than the general population, mostly due to physical comorbidity. While sociodemographic, chronic lifestyle and iatrogenic factors are important contributors to this comorbidity, a growing body of research is beginning to suggest that early signs of cardiometabolic dysfunction may be present from the onset of psychosis in some young adults, and may even be detectable before the onset of psychosis. Given that primary prevention is the best means to prevent the onset of more chronic and severe cardiometabolic phenotypes such as CVD, there is clear need to be able to identify young adults with psychosis who are most at risk of future adverse cardiometabolic outcomes, such that the most intensive interventions can be directed in an informed way to attenuate the risk or even prevent those adverse outcomes from occurring.In this talk, Ben will first outline some recent advances in our understanding of the association between cardiometabolic and schizophrenia spectrum disorders. He will then introduce the field of cardiometabolic risk prediction, and highlight how existing tools developed for older general population adults are unlikely to be suitable for young people with psychosis. Finally, he will discuss the current state of play and the future of the Psychosis Metabolic Risk Calculator (PsyMetRiC), a novel clinically useful cardiometabolic risk prediction algorithm tailored for young people with psychosis, which has been developed and externally validated using data from three psychosis early intervention services in the UK.

Worms use their brain to regulate their behavior and physiology to deal with the lethal threat of hydrogen peroxide

In this talk I will discuss our recent findings that sensory signals from the brain adjust the physiology and behavior of the nematode C. elegans, enabling this animal to deal with the lethal threat of hydrogen peroxide. Hydrogen peroxide (H2O2) is the most common chemical threat in the microbial battlefield. Prevention and repair of the damage that hydrogen peroxide inflicts on macromolecules are critical for health and survival. In the first part of the talk, I will discuss our findings that C. elegans represses their own H2O2 defenses in response to sensory perception of Escherichia coli, the nematode’s food source, because E. coli can deplete H2O2 from the local environment and thereby protect the nematodes. Thus, the E. coli self-defense mechanisms create a public good, an environment safe from the threat of H2O2, that benefits C. elegans. In the second part of the talk, I will discuss how the modulation of C. elegans’ sensory perception by the interplay of hydrogen peroxide and bacteria adjusts the nematode’s behavior to improve the nematode’s chances of finding a niche that provides both food and protection from hydrogen peroxide.

Neural stem cells as biomarkers of cognitive aging and dementia

Adult hippocampal neurogenesis is implicated in memory formation and mood regulation. The Thuret lab investigates environmental and molecular mechanisms controlling the production of these adult-born neurons and how they impact mental health. We study neurogenesis in healthy ageing as well as in the context of diseases such as Alzheimer’s and depression. By approaching neurogenesis in health and disease, the strategy is two folds: (i) Validating the neurogenic process as a target for prevention and pharmacological interventions. (ii) Developing neurogenesis as a biomarker of disease prediction and progression. In this talk, I will focus on presenting some recent human studies demonstrating how hippocampal neural stem cells fate can be used as biomarkers of cognitive aging and dementia.

Unpacking Nature from Nurture: Understanding how Family Processes Affect Child and Adolescent Mental Health

Mental Health problems among youth constitutes an area of significant social, educational, clinical, policy and public health concern. Understanding processes and mechanisms that underlie the development of mental health problems during childhood and adolescence requires theoretical and methodological integration across multiple scientific domains, including developmental science, neuroscience, genetics, education and prevention science. The primary focus of this presentation is to examine the relative role of genetic and family environmental influences on children’s emotional and behavioural development. Specifically, a complementary array of genetically sensitive and longitudinal research designs will be employed to examine the role of early environmental adversity (e.g. inter-parental conflict, negative parenting practices) relative to inherited factors in accounting for individual differences in children’s symptoms of psychopathology (e.g. depression, aggression, ADHD ). Examples of recent applications of this research to the development of evidence-based intervention programmes aimed at reducing psychopathology in the context of high-risk family settings will also be presented.

Harnessing Mindset in 21st Century Healthcare

Mindsets are core assumptions about the nature and workings of things in the world that orient us to a particular set of attributions, expectations, and goals. Our study of mindsets is, in part, inspired by research on the placebo effect, a robust demonstration of the ability of mindsets, conscious or subconscious, to elicit physiological changes in the body. This talk will explore the role of mindsets in three stages of chronic disease progression: genetic predisposition, behavioral prevention, and clinical treatment. I will discuss the mechanisms through which mindsets influence health as well as the myriad ways that mindsets can be more effectively leveraged to motivate healthy behaviors and improve 21st century healthcare.

European University for Brain and Technology Virtual Opening

The European University for Brain and Technology, NeurotechEU, is opening its doors on the 16th of December. From health & healthcare to learning & education, Neuroscience has a key role in addressing some of the most pressing challenges that we face in Europe today. Whether the challenge is the translation of fundamental research to advance the state of the art in prevention, diagnosis or treatment of brain disorders or explaining the complex interactions between the brain, individuals and their environments to design novel practices in cities, schools, hospitals, or companies, brain research is already providing solutions for society at large. There has never been a branch of study that is as inter- and multi-disciplinary as Neuroscience. From the humanities, social sciences and law to natural sciences, engineering and mathematics all traditional disciplines in modern universities have an interest in brain and behaviour as a subject matter. Neuroscience has a great promise to become an applied science, to provide brain-centred or brain-inspired solutions that could benefit the society and kindle a new economy in Europe. The European University of Brain and Technology (NeurotechEU) aims to be the backbone of this new vision by bringing together eight leading universities, 250+ partner research institutions, companies, societal stakeholders, cities, and non-governmental organizations to shape education and training for all segments of society and in all regions of Europe. We will educate students across all levels (bachelor’s, master’s, doctoral as well as life-long learners) and train the next generation multidisciplinary scientists, scholars and graduates, provide them direct access to cutting-edge infrastructure for fundamental, translational and applied research to help Europe address this unmet challenge.

Population studies and ageing brains, in a time of COVID

This presentation will include a brief resume of research in older populations led from Cambridge that have informed current clinical understanding and policy regarding services and prevention for and of dementia. These population studies have more recently been ‘re-purposed’ with enthusiasm from participants into a trial platform, and this also has enabled ongoing follow-up by telephone during the COVID pandemic. Although there are no formal outputs from these latter developments general impressions will be shared.

Targeting the Endocannabinoid System for Management of Chemotherapy, HIV and Antiretroviral-Induced Neuropathic Pain

Chemotherapeutic drugs (used for treating cancer), HIV infection and antiretroviral therapy (ART) can independently cause difficult-to-manage painful neuropathy. Paclitaxel, a chemotherapeutic drug, for example is associated with high incidence of peripheral neuropathy, around 71% of the patients of which 27% of these develop neuropathic pain. Use of cannabis or phytocannabinoids has been reported to improve pain measures in patients with neuropathic pain, including painful HIV-associated sensory neuropathy and cancer pain. Phytocannabinoids and endocannabinoids, such as anandamide and 2-arachidonoylglycerol (2-AG), produce their effects via cannabinoid (CB) receptors, which are present both in the periphery and central nervous system. Endocannabinoids are synthesized in an “on demand” fashion and are degraded by various enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Various studies, including those from our group, suggest that there are changes in gene and protein expression of endocannabinoid molecules during chemotherapy-induced neuropathic pain (CINP), HIV and antiretroviral-induced neuropathic pain. Analysis of endocannabinoid molecule expression in the brain, spinal cord and paw skin using LC-MS/MS show that there is a specific deficiency of the endocannabinoids 2-AG and/or anandamide in the periphery during CINP. Various drugs including endocannabinoids, cannabidiol, inhibitors of FAAH and MGL, CB receptor agonists, desipramine and coadministered indomethacin plus minocycline have been found to either prevent the development and/or attenuate established CINP, HIV and antiretroviral-induced neuropathic pain in a CB receptor-dependent manner. The results available suggest that targeting the endocannabinoid system for prevention and treatment of CINP, HIV-associated neuropathic pain and antiretroviral-induced neuropathic pain is a plausible therapeutic option.

Meditation: A potential therapy targeting amygdala for the prevention & reversal of Alzheimer's Disease

Mild liver damage induces spatial learning and memory impairment in rats. Underlying mechanisms and prevention by rifaximin

Study on the efficacy and mechanism of ginsenoside in the prevention of cerebral ischemic stroke

FENS Forum 2024

Prediction and prevention of compulsive behaviors by closed-loop optogenetic recruitment of striatal interneurons

Prevention of Amyloidogenesis by Neuronal Aquaporin 1 Inhibiting the Interaction Between Amyloid Precursor Protein and BACE 1 in Alzheimer's disease

Cannabidiol prevention of cognitive deficits in a rat model for Alzheimer’s disease is associated with neuroinflammation

FENS Forum 2024

Prediction and prevention of compulsive behaviors by closed-loop optogenetic recruitment of striatal interneurons

FENS Forum 2024