Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy.

Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer's disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. In this study, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old (aged 19 months) wildtype mice, and in rTg4510 tau pathology mice (aged 2 months). We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and rTg4510 mice. These effects of NF-κB/NLRP3-targeting Nanoligomers were also associated with reduced glial cell activation and pathology, favorable changes in transcriptome signatures of glia-associated inflammation (reduced) and neuronal health (increased), and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting both NF-κB and NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegeneration.

Inflammasome-Inhibiting Nanoligomers Are Neuroprotective against Space-Induced Pathology in Healthy and Diseased Three-Dimensional Human Motor and Prefrontal Cortex Brain Organoids.

The microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to astronauts and space tourists and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station. First, comparing 3D healthy and diseased prefrontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 that targeted NF-κB and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aß42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.

Development and first implementation of a novel multi-modality cardiac motion and dosimetry phantom for radiotherapy applications.

BACKGROUND: Cardiac applications in radiation therapy are rapidly expanding including magnetic resonance guided radiation therapy (MRgRT) for real-time gating for targeting and avoidance near the heart or treating ventricular tachycardia (VT). PURPOSE: This work describes the development and implementation of a novel multi-modality and magnetic resonance (MR)-compatible cardiac phantom. METHODS: The patient-informed 3D model was derived from manual contouring of a contrast-enhanced Coronary Computed Tomography Angiography scan, exported as a Stereolithography model, then post-processed to simulate female heart with an average volume. The model was 3D-printed using Elastic50A to provide MR contrast to water background. Two rigid acrylic modules containing cardiac structures were designed and assembled, retrofitting to an MR-safe programmable motor to supply cardiac and respiratory motion in superior-inferior directions. One module contained a cavity for an ion chamber (IC), and the other was equipped with multiple interchangeable cavities for plastic scintillation detectors (PSDs). Images were acquired on a 0.35 T MR-linac for validation of phantom geometry, motion, and simulated online treatment planning and delivery. Three motion profiles were prescribed: patient-derived cardiac (sine waveform, 4.3 mm peak-to-peak, 60 beats/min), respiratory (cos4 waveform, 30 mm peak-to-peak, 12 breaths/min), and a superposition of cardiac (sine waveform, 4 mm peak-to-peak, 70 beats/min) and respiratory (cos4 waveform, 24 mm peak-to-peak, 12 breaths/min). The amplitude of the motion profiles was evaluated from sagittal cine images at eight frames/s with a resolution of 2.4 mm × 2.4 mm. Gated dosimetry experiments were performed using the two module configurations for calculating dose relative to stationary. A CT-based VT treatment plan was delivered twice under cone-beam CT guidance and cumulative stationary doses to multi-point PSDs were evaluated. RESULTS: No artifacts were observed on any images acquired during phantom operation. Phantom excursions measured 49.3 ± 25.8%/66.9 ± 14.0%, 97.0 ± 2.2%/96.4 ± 1.7%, and 90.4 ± 4.8%/89.3 ± 3.5% of prescription for cardiac, respiratory, and cardio-respiratory motion profiles for the 2-chamber (PSD) and 12-substructure (IC) phantom modules respectively. In the gated experiments, the cumulative dose was <2% from expected using the IC module. Real-time dose measured for the PSDs at 10 Hz acquisition rate demonstrated the ability to detect the dosimetric consequences of cardiac, respiratory, and cardio-respiratory motion when sampling of different locations during a single delivery, and the stability of our phantom dosimetric results over repeated cycles for the high dose and high gradient regions. For the VT delivery, high dose PSD was <1% from expected (5-6 cGy deviation of 5.9 Gy/fraction) and high gradient/low dose regions had deviations <3.6% (6.3 cGy less than expected 1.73 Gy/fraction). CONCLUSIONS: A novel multi-modality modular heart phantom was designed, constructed, and used for gated radiotherapy experiments on a 0.35 T MR-linac. Our phantom was capable of mimicking cardiac, cardio-respiratory, and respiratory motion while performing dosimetric evaluations of gated procedures using IC and PSD configurations. Time-resolved PSDs with small sensitive volumes appear promising for low-amplitude/high-frequency motion and multi-point data acquisition for advanced dosimetric capabilities. Illustrating VT planning and delivery further expands our phantom to address the unmet needs of cardiac applications in radiotherapy.

ACR Appropriateness Criteria® Screening for abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a significant vascular disease found in 4% to 8% of the screening population. If ruptured, its mortality rate is between 75% and 90%, and it accounts for up to 5% of sudden deaths in the United States. Therefore, screening of AAA while asymptomatic has been a crucial portion of preventive health care worldwide. Ultrasound of the abdominal aorta is the primary imaging modality for screening of AAA recommended for asymptomatic adults regardless of their family history or smoking history. Alternatively, duplex ultrasound and CT abdomen and pelvis without contrast may be appropriate for screening. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation

ACR Appropriateness Criteria® Pulmonary arteriovenous malformation (PAVM): 2023 update

Pulmonary arteriovenous malformations (PAVMs) occur in 30% to 50% of patients with hereditary hemorrhagic telangiectasia. Clinical presentations vary from asymptomatic disease to complications resulting from the right to left shunting of blood through the PAVM such as paradoxical stroke, brain abscesses, hypoxemia, and cardiac failure. Radiology plays an important role both in the diagnosis and treatment of PAVM. Based on different clinical scenarios, the appropriate imaging study has been reviewed and is presented in this document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Screening for Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a significant vascular disease found in 4% to 8% of the screening population. If ruptured, its mortality rate is between 75% and 90%, and it accounts for up to 5% of sudden deaths in the United States. Therefore, screening of AAA while asymptomatic has been a crucial portion of preventive health care worldwide. Ultrasound of the abdominal aorta is the primary imaging modality for screening of AAA recommended for asymptomatic adults regardless of their family history or smoking history. Alternatively, duplex ultrasound and CT abdomen and pelvis without contrast may be appropriate for screening. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Pulmonary Arteriovenous Malformation (PAVM): 2023 Update.

Pulmonary arteriovenous malformations (PAVMs) occur in 30% to 50% of patients with hereditary hemorrhagic telangiectasia. Clinical presentations vary from asymptomatic disease to complications resulting from the right to left shunting of blood through the PAVM such as paradoxical stroke, brain abscesses, hypoxemia, and cardiac failure. Radiology plays an important role both in the diagnosis and treatment of PAVM. Based on different clinical scenarios, the appropriate imaging study has been reviewed and is presented in this document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Association of Ground Glass Opacities with Systemic Inflammation and Progression of Emphysema.

RATIONAL: Ground glass opacities (GGO) in the absence of interstitial lung disease are understudied. OBJECTIVE: To assess the association of GGO with white blood cells (WBCs) and progression of quantified chest CT emphysema. METHODS: We analyzed data of participants in the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). Chest radiologists and pulmonologists labeled regions of the lung as GGO and adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGO (%GGOAMFM). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGOAMFM with WBC, changes in %emphysema, and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Among 2,714 participants, 1,680 had COPD and 1,034 had normal spirometry. Among COPD participants, based on the multivariable analysis, current smoking and chronic productive cough was associated with higher %GGOAMFM. Higher %GGOAMFM was cross-sectionally associated with higher WBCs and neutrophils levels. Higher %GGOAMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at one-year follow visit by 11.7% (Relative increase; 95%CI 7.5-16.1%;P<0.001). We found no association between %GGOAMFM and one-year FEV1 decline but %GGOAMFM was associated with exacerbations and all-cause mortality during a median follow-up time of 1,544 days (Interquartile Interval=1,118-2,059). Among normal spirometry participants, we found similar results except that %GGOAMFM was associated with progression to COPD at one-year follow-up. CONCLUSIONS: Our findings suggest that GGOAMFM is associated with increased systemic inflammation and emphysema progression.

Spatial Resolution Fidelity Comparison Between Energy Integrating and Deep Silicon Photon Counting CT: Implications for Pulmonary Imaging.

PURPOSE: We investigated spatial resolution loss away from isocenter for a prototype deep silicon photon-counting detector (PCD) CT scanner and compare with a clinical energy-integrating detector (EID) CT scanner. MATERIALS AND METHODS: We performed three scans on a wire phantom at four positions (isocenter, 6.7, 11.8, and 17.1 cm off isocenter). The acquisition modes were 120 kV EID CT, 120 kV high-definition (HD) EID CT, and 120 kV PCD CT. HD mode used double the projection view angles per rotation as the "regular" EID scan mode. The diameter of the wire was calculated by taking the full width of half max (FWHM) of a profile drawn over the radial and azimuthal directions of the wire. Change in wire diameter appearance was assessed by calculating the ratio of the radial and azimuthal diameter relative to isocenter. t tests were used to make pairwise comparisons of the wire diameter ratio with each acquisition and mean ratios' difference from unity. RESULTS: Deep silicon PCD CT had statistically smaller (P<0.05) changes in diameter ratio for both radial and azimuthal directions compared with both regular and HD EID modes and was not statistically different from unity (P<0.05). Maximum increases in FWMH relative to isocenter were 36%, 12%, and 1% for regular EID, HD EID, and deep silicon PCD, respectively. CONCLUSION: Deep silicon PCD CT exhibits less change in spatial resolution in both the radial and azimuthal directions compared with EID CT.

Role of Radiology in Assessment of Postoperative Complications of Heart Transplantation.

Heart transplantation is a pivotal treatment of end-stage heart failure, and recent advancements have extended median posttransplant life expectancy. However, despite the progress in surgical techniques and medical treatment, heart transplant patients still face complications such as rejection, infections, and drug toxicity. CT is a reliable tool for detecting most of these complications, whereas MR imaging is particularly adept at identifying pericardial pathologies and signs of rejection. Awareness of these nuances by radiologists, cardiologists, and surgeons is desired to optimize care, reduce morbidities, and enhance survival.

Computed Tomography Angiography for Aortic Diseases.

Aortic pathologies encompass a heterogeneous group of disorders, including acute aortic syndrome, traumatic aortic injury , aneurysm, aortitis, and atherosclerosis. The clinical manifestations of these disorders can be varied and non-specific, ranging from acute presentations in the emergency department to chronic incidental findings in an outpatient setting. Given the non-specific nature of their clinical presentations, the reliance on non-invasive imaging for screening, definitive diagnosis, therapeutic strategy planning, and post-intervention surveillance has become paramount. Commonly used imaging modalities include ultrasound, computed tomography (CT), and MR imaging. Among these modalities, computed tomography angiography (CTA) has emerged as a first-line imaging modality owing to its excellent anatomic detail, widespread availability, established imaging protocols, evidence-proven indications, and rapid acquisition time.

Targeting Neuroinflammation by Pharmacologic Downregulation of Inflammatory Pathways Is Neuroprotective in Protein Misfolding Disorders.

Neuroinflammation plays a crucial role in the development of neurodegenerative protein misfolding disorders. This category of progressive diseases includes, but is not limited to, Alzheimer's disease, Parkinson's disease, and prion diseases. Shared pathogenesis involves the accumulation of misfolded proteins, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to irreversible neuronal loss, measurable cognitive deficits, and death. Presently, there are few to no effective treatments to halt the advancement of neurodegenerative diseases. We hypothesized that directly targeting neuroinflammation by downregulating the transcription factor, NF-κB, and the inflammasome protein, NLRP3, would be neuroprotective. To achieve this, we used a cocktail of RNA targeting therapeutics (SB_NI_112) shown to be brain-penetrant, nontoxic, and effective inhibitors of both NF-κB and NLRP3. We utilized a mouse-adapted prion strain as a model for neurodegenerative diseases to assess the aggregation of misfolded proteins, glial inflammation, neuronal loss, cognitive deficits, and lifespan. Prion-diseased mice were treated either intraperitoneally or intranasally with SB_NI_112. Behavioral and cognitive deficits were significantly protected by this combination of NF-κB and NLRP3 downregulators. Treatment reduced glial inflammation, protected against neuronal loss, prevented spongiotic change, rescued cognitive deficits, and significantly lengthened the lifespan of prion-diseased mice. We have identified a nontoxic, systemic pharmacologic that downregulates NF-κB and NLRP3, prevents neuronal death, and slows the progression of neurodegenerative diseases. Though mouse models do not always predict human patient success and the study was limited due to sample size and number of dosing methods utilized, these findings serve as a proof of principle for continued translation of the therapeutic SB_NI_112 for prion disease and other neurodegenerative diseases. Based on the success in a murine prion model, we will continue testing SB_NI_112 in a variety of neurodegenerative disease models, including Alzheimer's disease and Parkinson's disease.

Targeted-Neuroinflammation Mitigation Using Inflammasome-Inhibiting Nanoligomers is Therapeutic in an Experimental Autoimmune Encephalomyelitis Mouse Model.

Multiple sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages of life. This disease affects the spinal cord and brain and is characterized by severe neuroinflammation, demyelination, and subsequent neuronal damage, resulting in symptoms like loss of mobility. While untargeted and pan-immunosuppressive therapies have proven to be disease-modifying and manage (or prolong the time between) symptoms in many patients, a significant fraction are unable to achieve remission. Recent work has suggested that targeted neuroinflammation mitigation through selective inflammasome inhibition can offer relief to patients while preserving key components of immune function. Here, we show a screening of potential therapeutic targets using inflammasome-inhibiting Nanoligomers (NF-κB1, TNFR1, TNF-α, IL-6) that meet or far-exceed commercially available small-molecule counterparts like ruxolitinib, MCC950, and deucravacitinib. Using the human brain organoid model, top Nanoligomer combinations (NF-κB1 + TNFR1: NI111, and NF-κB1 + NLRP3: NI112) were shown to significantly reduce neuroinflammation without any observable negative impact on organoid function. Further testing of these top Nanoligomer combinations in an aggressive experimental autoimmune encephalomyelitis (EAE) mouse model for MS using intraperitoneal (IP) injections showed that NF-κB1 and NLRP3 targeting Nanoligomer combination NI112 rescues mice without observable loss of mobility or disability, minimal inflammation in brain and spinal cord histology, and minimal to no immune cell infiltration of the spinal cord and no demyelination, similar to or at par with mice that received no EAE injections (negative control). Mice receiving NI111 (NF-κB1 + TNFR1) also showed reduced neuroinflammation compared to saline (sham)-treated EAE mice and at par/similar to other inflammasome-inhibiting small molecule treatments, although it was significantly higher than NI112 leading to subsequent worsening clinical outcomes. Furthermore, treatment with an oral formulation of NI112 at lower doses showed a significant reduction in EAE severity, albeit with higher variance owing to administration and formulation/fill-and-finish variability. Overall, these results point to the potential of further development and testing of these inflammasome-targeting Nanoliogmers as an effective neuroinflammation treatment for multiple neurodegenerative diseases and potentially benefit several patients suffering from such debilitating autoimmune diseases like MS.

Vessel and Airway Characteristics in One-Year Computed Tomography-defined Rapid Emphysema Progression: SPIROMICS.

Rationale: Rates of emphysema progression vary in chronic obstructive pulmonary disease (COPD), and the relationships with vascular and airway pathophysiology remain unclear. Objectives: We sought to determine if indices of peripheral (segmental and beyond) pulmonary arterial dilation measured on computed tomography (CT) are associated with a 1-year index of emphysema (EI; percentage of voxels <-950 Hounsfield units) progression. Methods: Five hundred ninety-nine former and never-smokers (Global Initiative for Chronic Obstructive Lung Disease stages 0-3) were evaluated from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort: rapid emphysema progressors (RPs; n = 188, 1-year ΔEI > 1%), nonprogressors (n = 301, 1-year ΔEI ± 0.5%), and never-smokers (n = 110). Segmental pulmonary arterial cross-sectional areas were standardized to associated airway luminal areas (segmental pulmonary artery-to-airway ratio [PAARseg]). Full-inspiratory CT scan-derived total (arteries and veins) pulmonary vascular volume (TPVV) was compared with small vessel volume (radius smaller than 0.75 mm). Ratios of airway to lung volume (an index of dysanapsis and COPD risk) were compared with ratios of TPVV to lung volume. Results: Compared with nonprogressors, RPs exhibited significantly larger PAARseg (0.73 ± 0.29 vs. 0.67 ± 0.23; P = 0.001), lower ratios of TPVV to lung volume (3.21 ± 0.42% vs. 3.48 ± 0.38%; P = 5.0 × 10-12), lower ratios of airway to lung volume (0.031 ± 0.003 vs. 0.034 ± 0.004; P = 6.1 × 10-13), and larger ratios of small vessel volume to TPVV (37.91 ± 4.26% vs. 35.53 ± 4.89%; P = 1.9 × 10-7). In adjusted analyses, an increment of 1 standard deviation in PAARseg was associated with a 98.4% higher rate of severe exacerbations (95% confidence interval, 29-206%; P = 0.002) and 79.3% higher odds of being in the RP group (95% confidence interval, 24-157%; P = 0.001). At 2-year follow-up, the CT-defined RP group demonstrated a significant decline in postbronchodilator percentage predicted forced expiratory volume in 1 second. Conclusions: Rapid one-year progression of emphysema was associated with indices indicative of higher peripheral pulmonary vascular resistance and a possible role played by pulmonary vascular-airway dysanapsis.

NF-κB/NLRP3 Translational Inhibition by Nanoligomer Therapy Mitigates Ethanol and Advanced Age-Related Neuroinflammation.

Binge alcohol use is increasing among aged adults (>65 years). Alcohol-related toxicity in aged adults is associated with neurodegeneration, yet the molecular underpinnings of age-related sensitivity to alcohol are not well described. Studies utilizing rodent models of neurodegenerative disease reveal heightened activation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Nod like receptor 3 (NLRP3) mediate microglia activation and associated neuronal injury. Our group, and others, have implicated hippocampal-resident microglia as key producers of inflammatory mediators, yet the link between inflammation and neurodegeneration has not been established in models of binge ethanol exposure and advanced age. Here, we report binge ethanol increased the proportion of NLRP3+ microglia in the hippocampus of aged (18-20 months) female C57BL/6N mice compared to young (3-4 months). In primary microglia, ethanol-induced expression of reactivity markers and NLRP3 inflammasome activation were more pronounced in microglia from aged mice compared to young. Making use of an NLRP3-specific inhibitor (OLT1177) and a novel brain-penetrant Nanoligomer that inhibits NF-κB and NLRP3 translation (SB_NI_112), we find ethanol-induced microglial reactivity can be attenuated by OLT1177 and SB_NI_112 in microglia from aged mice. In a model of intermittent binge ethanol exposure, SB_NI_112 prevented ethanol-mediated microglia reactivity, IL-1ß production, and tau hyperphosphorylation in the hippocampus of aged mice. These data suggest early indicators of neurodegeneration occurring with advanced age and binge ethanol exposure are NF-κB- and NLRP3-dependent. Further investigation is warranted to explore the use of targeted immunosuppression via Nanoligomers to attenuate neuroinflammation after alcohol consumption in the aged.

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy.

Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer's disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. In this study, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old (aged 19 months) wildtype mice, and in rTg4510 tau pathology mice (aged 2 months). We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and rTg4510 mice. These effects of NF-κB/NLRP3-targeting Nanoligomers were also associated with reduced glial cell activation and pathology, favorable changes in transcriptome signatures of glia-associated inflammation (reduced) and neuronal health (increased), and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting both NF-κB and NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegeneration.

Utilizing Artificial Intelligence-Based Deformable Registration for Global and Layer-Specific Cardiac MRI Strain Analysis in Healthy Children and Young Adults.

RATIONALE AND OBJECTIVES: The absence of published reference values for multilayer-specific strain measurement using cardiac magnetic resonance (CMR) in young healthy individuals limits its use. This study aimed to establish normal global and layer-specific strain values in healthy children and young adults using a deformable registration algorithm (DRA). MATERIALS AND METHODS: A retrospective study included 131 healthy children and young adults (62 males and 69 females) with a mean age of 16.6 ± 3.9 years. CMR examinations were conducted using 1.5T scanners, and strain analysis was performed using TrufiStrain research prototype software (Siemens Healthineers, Erlangen, Germany). Global and layer-specific strain parameters were extracted from balanced Steady-state free precession cine images. Statistical analyses were conducted to evaluate the impact of demographic variables on strain measurements. RESULTS: The peak global longitudinal strain (LS) was -16.0 ± 3.0%, peak global radial strain (RS) was 29.9 ± 6.3%, and peak global circumferential strain (CS) was -17.0 ± 1.8%. Global LS differed significantly between males and females. Transmural strain analysis showed a consistent pattern of decreasing LS and CS from endocardium to epicardium, while radial strain increased. Basal-to-apical strain distribution exhibited decreasing LS and increasing CS in both global and layer-specific analysis. CONCLUSION: This study uses DRA to provide reference values for global and layer-specific strain in healthy children and young adults. The study highlights the impact of sex and age on LS and body mass index on RS. These insights are vital for future cardiac assessments in children, particularly for early detection of heart diseases.

"From Vision to Reality: Virtual Reality's Impact on Baffle Planning in Congenital Heart Disease".

This study aims to evaluate the feasibility and utility of virtual reality (VR) for baffle planning in congenital heart disease (CHD), specifically by creating patient-specific 3D heart models and assessing a user-friendly VR interface. Patient-specific 3D heart models were created using high-resolution imaging data and a VR interface was developed for baffle planning. The process of model creation and the VR interface were assessed for their feasibility, usability, and clinical relevance. Collaborative and interactive planning within the VR space were also explored. The study findings demonstrate the feasibility and usefulness of VR in baffle planning for CHD. Patient-specific 3D heart models generated from imaging data provided valuable insights into complex spatial relationships. The developed VR interface allowed clinicians to interact with the models, simulate different baffle configurations, and assess their impact on blood flow. The VR space's collaborative and interactive planning enhanced the baffle planning process. This study highlights the potential of VR as a valuable tool in baffle planning for CHD. The findings demonstrate the feasibility of using patient-specific 3D heart models and a user-friendly VR interface to enhance surgical planning and patient outcomes. Further research and development in this field are warranted to harness the full benefits of VR technology in CHD surgical management.

Light-Driven Metabolic Pathways in Non-Photosynthetic Biohybrid Bacteria.

Biomanufacturing via microorganisms relies on carbon substrates for molecular feedstocks and a source of energy to carry out enzymatic reactions. This creates metabolic bottlenecks and lowers the efficiency for substrate conversion. Nanoparticle biohybridization with proteins and whole cell surfaces can bypass the need for redox cofactor regeneration for improved secondary metabolite production in a non-specific manner. Here we propose using nanobiohybrid organisms (Nanorgs), intracellular protein-nanoparticle hybrids formed through the spontaneous coupling of core-shell quantum dots (QDs) with histidine-tagged enzymes in non-photosynthetic bacteria, for light-mediated control of bacterial metabolism. This proved to eliminate metabolic constrictions and replace glucose with light as the source of energy in Escherichia coli, with an increase in growth by 1.7-fold in 75 % reduced nutrient media. Metabolomic tracking through carbon isotope labeling confirmed flux shunting through targeted pathways, with accumulation of metabolites downstream of respective targets. Finally, application of Nanorgs with the Ehrlich pathway improved isobutanol titers/yield by 3.9-fold in 75 % less sugar from E. coli strains with no genetic alterations. These results demonstrate the promise of Nanorgs for metabolic engineering and low-cost biomanufacturing.