Bulletin of Computer Science and Electrical Engineering (BCSEE)
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Mechanisms of Impaired Immunity in Aging and SIV-Infected Rhesus Macaques
No full textNatural aging and human immunodeficiency virus (HIV) infection are associated with chronic low-grade systemic inflammation, immune senescence and impaired antibody (Ab) responses to vaccines such as influenza (flu). We investigated the role of Interleukin (IL)-21, a CD4 T follicular helper cells (Tfh) regulator, on flu vaccine Ab response in non-human primates (NHPs) in the context of age and controlled simian immunodeficiency virus (SIV) mac239 infection. Three doses of the flu vaccine with or without IL-21-IgFc were administered at 3-month intervals in aged SIV+ NHPs following viral suppression with anti-retroviral therapy. IL-21 treated animals demonstrated enhanced day 14 post-boost vaccine-induced Ab responses. In peripheral blood we demonstrate IL-21-induced expansion of CD4+ T central memory cells, T cell immunoreceptor with Ig and ITIM domains (TIGIT) expressing peripheral Tfh, activated memory B cells and contraction of CD11b+ monocytes. Histocytometry analysis of draining lymph nodes (dLN) tissues from IL-21 treated animals revealed direct association between LN follicle Tfh density and frequency of circulating TIGIT+ pTfh cells. Investigation of dLN cell suspensions revealed IL-21-induced proliferation of flu-specific LN CD4 memory T cells, expansion of B cells expressing IL-21 receptor (IL-21R), and expansion of Tfh cells co-expressing TIGIT and DNAX accessory molecule (DNAM-1). Single cell RNA sequencing of dLN cells revealed IL-21-induced enhancement of B cell development and antigen presentation alongside significant inhibition of germinal center (GC) Tfh and B cell interferon signaling. We conclude that IL-21 enhances flu vaccine-induced Ab responses in aged SIV+ rhesus macaques, acting as an adjuvant modulating LN germinal center activity and potentially reversing SIV associated LN Tfh and B cell dysfunction. Strategies to supplement IL-21 in aging could be a valuable addition in the toolbox for improving vaccine responses in an aging HIV+ population.</p
The Design and Optimization of a First-in-Class Inhibitor of NACK: Illuminating a Druggable Target in Notch
No full textNotch Activation Complex Kinase (NACK) is a key player in Notch-mediated tumorigenesis and an attractive novel target for the treatment of esophageal adenocarcinoma, and other Notch-rich cancers. NACK, annotated in the kinome as SgK223, is an atypical pseudokinase and an established Notch transcriptional co-activator. However, there is no known endogenous or exogenous ligand, no existing co-crystal structure, and no reported biological data. To identify a scaffold for NACK inhibition, a machine learning approach was utilized. Over six million commercially available compounds were screened against established kinase machine learning classifiers, and nearly 8000 were prioritized based on the predicted probability of being active. A homology structure model of the NACK kinase domain was generated and further optimized by all-atom explicit water molecular dynamics (MD) simulations, followed by virtual screening of prioritized compounds. Top-scoring compounds were purchased and screened in in vitro and in vivo assays. Commercially available compound Z271-0326 displayed low micromolar inhibitory activity across several Notch-rich cancer cell-lines and was further validated in rodent models. A robust novel chemical synthesis for Z271-0326 was accomplished in six steps with an overall yield of 26%. Efforts were then aimed towards optimizing Z271-0326 into the first NACK molecular probe. I optimized our virtual NACK kinase domain structure model via MD simulations and performed a structure-guided optimization approach to elucidate putative binding interactions. Analogues were designed and synthesized with the goal of improving inhibitory activity while retaining selectivity. Assay results demonstrate that the hit compound is optimizable as analogue UM-323 demonstrates an EC50 of 20 nM in OE33 cells and displays NACK target engagement via thermal shift assay. In vivo DMPK studies reveal UM-323 half-life was increased six-fold and potency was increased 150-fold. However, I arrived at a molecular probe and a First-in-Class NACK inhibitor.</p
The Neurovasculome: Key Roles in Brain Health and Cognitive Impairment: A Scientific Statement From the American Heart Association/American Stroke Association
No full textBACKGROUNDPreservation of brain health has emerged as a leading public health priority for the aging world population. Advances in neurovascular biology have revealed an intricate relationship among brain cells, meninges, and the hematic and lymphatic vasculature (the neurovasculome) that is highly relevant to the maintenance of cognitive function. In this scientific statement, a multidisciplinary team of experts examines these advances, assesses their relevance to brain health and disease, identifies knowledge gaps, and provides future directions. METHODSAuthors with relevant expertise were selected in accordance with the American Heart Association conflict-of-interest management policy. They were assigned topics pertaining to their areas of expertise, reviewed the literature, and summarized the available data. RESULTSThe neurovasculome, composed of extracranial, intracranial, and meningeal vessels, as well as lymphatics and associated cells, subserves critical homeostatic functions vital for brain health. These include delivering O2 and nutrients through blood flow and regulating immune trafficking, as well as clearing pathogenic proteins through perivascular spaces and dural lymphatics. Single-cell omics technologies have unveiled an unprecedented molecular heterogeneity in the cellular components of the neurovasculome and have identified novel reciprocal interactions with brain cells. The evidence suggests a previously unappreciated diversity of the pathogenic mechanisms by which disruption of the neurovasculome contributes to cognitive dysfunction in neurovascular and neurodegenerative diseases, providing new opportunities for the prevention, recognition, and treatment of these conditions. CONCLUSIONSThese advances shed new light on the symbiotic relationship between the brain and its vessels and promise to provide new diagnostic and therapeutic approaches for brain disorders associated with cognitive dysfunction
Sex Differences in the Inflammatory Profile in the Brain of Young and Aged Mice
No full textNeurodegenerative diseases are a leading cause of death worldwide with no cures identified. Thus, there is a critical need for preventative measures and treatments as the number of patients is expected to increase. Many neurodegenerative diseases have sex-biased prevalence, indicating a need to examine sex differences when investigating prevention and treatment strategies. Inflammation is a key contributor to many neurodegenerative diseases and is a promising target for prevention since inflammation increases with age, which is known as inflammaging. Here, we analyzed the protein expression levels of cytokines, chemokines, and inflammasome signaling proteins in the cortex of young and aged male and female mice. Our results show an increase in caspase-1, interleukin (IL)-1β, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and ASC specks in females compared to males. Additionally, there was an increase in IL-1α, VEGF-A, CCL3, CXCL1, CCL4, CCL17, and CCL22 in aging females and an increase in IL-8, IL-17a, IL-7, LT-α, and CCL22 in aging males. IL-12/IL-23p40, CCL13, and IL-10 were increased in females compared to males but not with age. These results indicate that there are sex differences in cortical inflammaging and provide potential targets to attenuate inflammation to prevent the development of neurodegenerative disease
Abstract A44: The influence of dietary one-carbon metabolites on gut dysbiosis during pre-malignant hematopoiesis
No full textAbstract TET2 loss-of-function mutations induce a pre-malignant state known as clonal hematopoiesis of indeterminate potential (CHIP). CHIP occurs in approximately 10% of people over 65 years of age and confers a 10-fold greater risk of developing hematological malignancy. Several environmental factors, including radiation, sleep deprivation, atherosclerosis, and diet, have been associated with the expansion of pre-malignant clones in CHIP patients. Tet2-deficiency in mice has also been shown to trigger a pro-inflammatory state with increased intestinal permeability and accelerated myeloid expansion. Gut microbes exert an influence on host disease progression through the synthesis of many compounds including short-chain fatty acids (SCFAs), which promote gut barrier integrity. Dietary levels of one-carbon metabolites and cofactors, including methionine and folate, have been found to alter gut microbial composition in disease-free adults and influence SCFA production in the gut in murine models. Given the connection between diet, SCFAs and gut permeability, we sought to determine the impact of dietary one-carbon metabolites on gut microbial composition and function in a murine model of pre-malignant hematopoiesis. We performed competitive bone marrow transplantation assays in mice fed diets with altered one-carbon metabolite supplementation, such as high and low folate or methionine. We found that differential supplementation with these one-carbon metabolites did not influence the competitiveness of Tet2-deficient hematopoietic cells, however, increased dietary methionine promoted a myeloid lineage differentiation bias and an elevation in circulating pro-inflammatory cytokines. After 8 months of dietary treatment, fecal samples were collected, and shotgun sequencing was performed to examine the role of one-carbon metabolite levels on gut microbial diversity. Alterations in dietary methionine and folate caused significant changes to gut microbial composition in Tet2-deficient mice. High folate or methionine supplementation led to a decrease in the ratio of Firmicutes to Bacteroidetes and high folate supplementation was also associated with decreased alpha diversity and a decrease in SCFA-producing bacteria in the gut. These studies highlight the potential influence of dietary one-carbon metabolites on the microbiome and inflammatory microenvironment of pre-malignant hematopoiesis. Citation Format: Peter Lyon, Praveen Singh, Byron Fang, Victoria Strippoli, Sabita Roy, Luisa Cimmino. The influence of dietary one-carbon metabolites on gut dysbiosis during pre-malignant hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A44
Understanding speech and language in tuberous sclerosis complex
No full textTuberous Sclerosis Complex (TSC), is a neurocutaneous disorder, associated with a high prevalence of autism spectrum disorder (ASD; ~50%). Understanding language development in TSC would not only be important for individuals with TSC but may also have implications for other causes of syndromic and idiopathic ASD. In this mini review, we consider what is known about language development in TSC and how speech and language are related to ASD. Although up to 70% with TSC report language difficulties, much of the research to date has been based on summary scores from standardized assessments. Missing is a detailed understanding of the mechanisms driving speech and language and how they relate to ASD. Here, we review recent work suggesting that canonical babbling and volubility—two precursors of language development that predict the emergence of speech and are delayed in infants with idiopathic ASD—are also delayed in infants with TSC. We then look to the literature on language development to identify other early precursors of language development that tend to be delayed in children with autism as a guide for future research in TSC. We argue that vocal turn-taking, shared attention, and fast mapping are skills that can provide important information about how speech and language develop in TSC and where potential delays come from. The overall goal of this research is to not only illuminate the trajectory of language in TSC with and without ASD, but to ultimately find strategies for earlier recognition and treatment of the pervasive language difficulties in this population
Long term aortic arch plaque progression in older adults
No full textThe presence of aortic arch plaques (AAP) is significantly associated with increased cardiovascular morbidity and mortality. Few studies have examined the incidence of AAP progression and factors which may contribute to it using transthoracic echocardiography (TTE). The objective of this study was to utilize sequential imaging of the aortic arch using TTE to examine the rate of AAP progression and its risk factors in a cohort of older adults.
Participants enrolled in both the Cardiovascular Abnormalities and Brain Lesion study (years 2005–2010) and the Subclinical Atrial Fibrillation and Risk of Ischemic Stroke study (2014–2019) who underwent TTE with assessment of aortic arch plaques at both time points represent the study cohort.
300 participants were included in the study. Mean age was 67.8 ± 7.5 years at baseline, and 76.7 ± 6.8 years at follow-up; 197 (65.7%) were women. At baseline, 87 (29%) had no significant AAP, 182 (60.7%) had evidence of small AAP (2.0–3.9 mm) and 31 (10.3%) had evidence of large (≥4 mm) AAP. At the time of follow-up assessment, 157 (52.3%) of participants exhibited progression of AAP with 70 (23.3%) having mild progression and 87 (29%) having severe progression. There were no significant demographic or clinical predictors of AAP progression except baseline plaque thickness itself which was significantly lower in the group with AAP progression.
Our study demonstrates a high prevalence of AAP on TTE exam in a population-based cohort of older adults with a high incidence of AAP progression. TTE is a useful test for baseline and follow up imaging of AAP, even in subjects with no or little AAP at baseline.
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•Aortic arch plaques (AAP) are associated with increased cardiovascular morbidity and mortality.•71% of subjects in a population based cohort of older adults had evidence of AAP on transthoracic echo.•About 50% had progression of AAP at mean follow up of 9 years.•The only factor predictive of progression was lower AAP thickness at baseline
Glycerophospholipid Analysis of Optic Nerve Regeneration Models Indicate Potential Membrane Order Changes Associated with the Lipidomic Shifts
No full textOptic nerve (ON) injury causes irreversible degeneration, leading to vision loss that cannot be restored with available therapeutics. Current therapies slow further degeneration but do not promote regeneration. New regenerative factors have been discovered that are successful
. However, the mechanisms of efficient long-distance regeneration are still unknown. Membrane expansion by lipid insertion is an essential regenerative process, so lipid profiles for regenerating axons can provide insight into growth mechanisms. This article's analysis aims to add to the increasingly available ON regeneration lipid profiles and relate it to membrane order/properties.
In this study, we present an analysis of glycerophospholipids, one of the largest axonal lipid groups, from three mammalian ON regeneration lipid profiles: Wnt3a, Zymosan + CPT-cAMP, and Phosphatase/Tensin homolog knockout (PTENKO) at 7 and 14 days post crush (dpc). Significant lipid classes, species, and ontological properties were crossreferenced between treatments and analyzed using Metaboanalyst 5.0 and Lipid Ontology (LION). Membrane order changes associated with significant lipid classes were evaluated by C-Laurdan dye and exogenous lipids provided to a neuroblastoma cell line.
At 7 dpc, ONs show increased lysoglycerophospholipids and decreased phosphatidylethanolamines (PEs)/negative intrinsic curvature lipids. At 14 dpc, regenerative treatments show divergence: Wnt3a displays higher lysoglycerophospholipid content, while Zymosan and PTENKO decrease lysoglycerophospholipids and increase phosphatidylcholine (PC)-related species. Membrane order imaging indicates lysoglycerophospholipids decreases membrane order while PE and PC had no significant membrane order effects. Understanding these changes will allow therapeutic development targeting lipid metabolic pathways that can be used for vision loss treatments