Modulation of antigen delivery and lymph node activation in nonhuman primates by saponin adjuvant saponin/monophosphoryl lipid A nanoparticle.

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in nonhuman primates (NHPs) comparing the most common clinical adjuvant aluminum hydroxide (alum) with saponin/monophosphoryl lipid A nanoparticles (SMNP), an immune-stimulating complex-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B-cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells.

Deep learning reveals pathology-confirmed neuroimaging signatures in Alzheimer's, vascular and Lewy body dementias.

Concurrent neurodegenerative and vascular pathologies pose a diagnostic challenge in the clinical setting, with histopathology remaining the definitive modality for dementia-type diagnosis. To address this clinical challenge, we introduce a neuropathology-based, data-driven, multi-label deep learning framework to identify and quantify in-vivo biomarkers for Alzheimer's disease (AD), vascular dementia (VD), and Lewy body dementia (LBD) using antemortem T1-weighted MRI scans of 423 demented and 361 control participants from NACC and ADNI datasets. Based on the best-performing deep learning model, explainable heatmaps are extracted to visualize disease patterns, and the novel Deep Signature of Pathology Atrophy REcognition (DeepSPARE) indices are developed, where a higher DeepSPARE score indicates more brain alterations associated with that specific pathology.

Bias-accounting meta-analyses overcome cerebellar neglect to refine the cerebellar behavioral topography.

The cerebellum plays important roles in motor, cognitive, and emotional behaviors. Previous cerebellar coordinate-based meta-analyses and mappings have attributed different behaviors to cerebellar subareas, but an accurate behavioral topography is lacking. Here, we show overrepresentation of superior activation foci, which may be exacerbated by historical cerebellar neglect.

Effect of Hyperketonemia on Myocardial Function in Patients With Heart Failure and Type 2 Diabetes.

We examined the effect of increased levels of plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in patients with type 2 diabetes (T2DM) with heart failure. Three groups of patients with T2DM (n = 12 per group) with an LV ejection fraction (EF) ≤50% received incremental infusions of β-hydroxybutyrate (β-OH-B) for 3-6 h to increase the plasma β-OH-B concentration throughout the physiologic (groups I and II) and pharmacologic (group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function.

Convergent functional effects of antidepressants in major depressive disorder: a neuroimaging meta-analysis.

Background: Neuroimaging studies have provided valuable insights into the macroscale impacts of antidepressants on brain functions in patients with major depressive disorder. However, the findings of individual studies are inconsistent. Here, we aimed to provide a quantitative synthesis of the literature to identify convergence of the reported findings at both regional and network levels and to examine their associations with neurotransmitter systems.

Modulation of antigen delivery and lymph node activation in non-human primates by saponin adjuvant SMNP.

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in non-human primates (NHPs) comparing the most common clinical adjuvant alum with Saponin/MPLA Nanoparticles (SMNP), a novel ISCOMs-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells.

PET/CT Targeted Tissue Sampling Reveals Intravenously Administered HGN194 IgG1 Affects HIV Distribution after Rectal Exposure.

Neutralizing monoclonal antibodies hold great potential for prevention of human immunodeficiency virus (HIV) acquisition. IgG is the most abundant antibody in human serum, has a long half-life, and potent effector functions, making it a prime candidate for an HIV prevention therapeutic. We combined Positron Emission Tomography imaging and fluorescent microscopy of Cu-labeled, photoactivatable-green fluorescent protein HIV (PA-GFP-BaL) and fluorescently labeled HGN194 IgG1 to determine whether intravenously instilled IgG influences viral interaction with mucosal barriers and viral penetration in colorectal tissue 2 h after rectal viral challenge.

Activation Likelihood Estimation Neuroimaging Meta-Analysis: a Powerful Tool for Emotion Research.

Over the past two decades, functional magnetic resonance imaging (fMRI) has become the primary tool for exploring neural correlates of emotion. To enhance the reliability of results in understanding the complex nature of emotional experiences, researchers combine findings from multiple fMRI studies using coordinate-based meta-analysis (CBMA). As one of the most widely employed CBMA methods worldwide, activation likelihood estimation (ALE) is of great importance in affective neuroscience and neuropsychology.

Perinatal maternal undernutrition in baboons modulates hepatic mitochondrial function but not metabolites in aging offspring.

We previously demonstrated in baboons that maternal undernutrition (MUN), achieved by 70 % of control nutrition, impairs fetal liver function, but long-term changes associated with aging in this model remain unexplored. Here, we assessed clinical phenotypes of liver function, mitochondrial bioenergetics, and protein abundance in adult male and female baboons exposed to MUN during pregnancy and lactation and their control counterparts. Plasma liver enzymes were assessed enzymatically.

Metabolic Diaschisis in Mild Traumatic Brain Injury.

Neurophysiological diaschisis presents in traumatic brain injury (TBI) as functional impairment distant to the lesion site caused by axonal neuroexcitation and deafferentation. Diaschisis studies in TBI models have evaluated acute phase functional and microstructural changes. Here, biochemical changes and cerebral blood flow (CBF) dynamics following TBI are studied with magnetic resonance.

Reproducibility and Repeatability of Intravoxel Incoherent Motion MRI Acquisition Methods in Liver.

Background: Intravoxel incoherent motion (IVIM) diffusion weighted MRI (DWI) has potential for evaluating hepatic fibrosis but image acquisition technique influence on diffusion parameter estimation bears investigation.

Purpose: To minimize variability and maximize repeatably in abdominal DWI in terms of IVIM parameter estimates.

Study Type: Prospective test-retest and image quality comparison.

Long-Term Neurocognitive Outcomes in Pediatric Nonfatal Drowning: Results of a Family Caregiver Survey.

Background: Drowning is a leading cause of brain injury in children. Long-term outcome data for drowning survivors are sparse. This study reports neurocognitive outcomes for 154 children hospitalized following drowning.

Postmortem Brain Imaging in Alzheimer's Disease and Related Dementias: The South Texas Alzheimer's Disease Research Center Repository.

Background: Neuroimaging bears the promise of providing new biomarkers that could refine the diagnosis of dementia. Still, obtaining the pathology data required to validate the relationship between neuroimaging markers and neurological changes is challenging. Existing data repositories are focused on a single pathology, are too small, or do not precisely match neuroimaging and pathology findings.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

Background: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease.

Objective: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol.

ALE meta-analyses of voxel-based morphometry studies: Parameter validation via large-scale simulations.

Activation likelihood estimation (ALE) meta-analysis has been applied to structural neuroimaging data since long, but up to now, any systematic assessment of the algorithm's behavior, power and sensitivity has been based on simulations using functional neuroimaging databases as their foundation. Here, we aimed to determine whether the guidelines offered by previous evaluations can be generalized to ALE meta-analyses of voxel-based morphometry (VBM) studies. We ran 365000 distinct ALE analyses filled with simulated experiments, randomly sampling parameters from BrainMap's VBM experiment database.

Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial.

Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility and efficacy. Five participants (mean age = 76 + 5 years; 40% female) completed the 12-week pilot study.

Convergent abnormality in the subgenual anterior cingulate cortex in insomnia disorder: A revisited neuroimaging meta-analysis of 39 studies.

The neurobiological underpinnings of insomnia disorder (ID) are still poorly understood. A previous meta-analysis conducted by our research group in 2018 revealed no consistent regional alterations based on the limited number of eligible studies. Given the number of studies published during the last few years, we revisited the meta-analysis to provide an update to the field.

Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease.

Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy.

Structural equation modeling of treatment-related changes in neural connectivity for youth with PTSD.

Background: Previous studies suggest that improvement in symptoms of posttraumatic stress disorder (PTSD) is accompanied by changes in neural connectivity, however, few studies have investigated directional (effective) connectivity. The current study assesses treatment-related changes in effective connectivity in youth with PTSD undergoing Trauma-Focused Cognitive Behavioral Therapy (TF-CBT).

Methods: Functional MRI scans before and after 16 weeks of TF-CBT for 20 youth with PTSD, or the same time interval for 20 healthy controls (HC) were included in the analysis.

A Minimum Bayes Factor Based Threshold for Activation Likelihood Estimation.

Activation likelihood estimation (ALE) is among the most used algorithms to perform neuroimaging meta-analysis. Since its first implementation, several thresholding procedures had been proposed, all referred to the frequentist framework, returning a rejection criterion for the null hypothesis according to the critical p-value selected. However, this is not informative in terms of probabilities of the validity of the hypotheses.

Cocktail-party listening and cognitive abilities show strong pleiotropy.

Introduction: The cocktail-party problem refers to the difficulty listeners face when trying to attend to relevant sounds that are mixed with irrelevant ones. Previous studies have shown that solving these problems relies on perceptual as well as cognitive processes. Previously, we showed that speech-reception thresholds (SRTs) on a cocktail-party listening task were influenced by genetic factors.

Imaging ocular water inflow in the mouse with deuterium oxide MRI.

Abnormal intraocular fluid flow or clearance is involved with a variety of eye diseases such as glaucoma and diabetic retinopathy, but measurement of water exchange dynamics in the vitreous and aqueous remain challenging. H MRI can be used to image deuterium oxide (D₂O) as a tracer, but the signal-to-noise ratio for deuterium is low due to its low concentration, which has hampered its application to imaging the eye. To overcome this challenge, we investigated the feasibility of direct DO MRI to measure water dynamics in the mouse eye.

Deep neural network heatmaps capture Alzheimer's disease patterns reported in a large meta-analysis of neuroimaging studies.

Deep neural networks currently provide the most advanced and accurate machine learning models to distinguish between structural MRI scans of subjects with Alzheimer's disease and healthy controls. Unfortunately, the subtle brain alterations captured by these models are difficult to interpret because of the complexity of these multi-layer and non-linear models. Several heatmap methods have been proposed to address this issue and analyze the imaging patterns extracted from the deep neural networks, but no quantitative comparison between these methods has been carried out so far.