Altered Cortical Activity during a Finger Tap in People with Stroke.

This study describes electroencephalography (EEG) measurements during a simple finger movement in people with stroke to understand how temporal patterns of cortical activation and network connectivity align with prolonged muscle contraction at the end of a task. We investigated changes in the EEG temporal patterns in the beta band (13-26 Hz) of people with chronic stroke (N = 10, 7 F/3 M) and controls (N = 10, 7 F/3 M), during and after a cued movement of the index finger. We quantified the change in beta band EEG power relative to baseline as activation at each electrode and the change in task-based phase-locking value (tbPLV) and beta band task-based coherence (tbCoh) relative to baseline coherence as connectivity between EEG electrodes. Finger movements were associated with a decrease in beta power (event related desynchronization (ERD)) followed by an increase in beta power (event related resynchronization (ERS)). The ERS in the post task period was lower in the stroke group (7%), compared to controls (44%) (p < 0.001) and the transition from ERD to ERS was delayed in the stroke group (1.43 s) compared to controls (0.90 s) in the C3 electrode (p = 0.007). In the same post movement period, the stroke group maintained a heightened tbPLV (p = 0.030 for time to baseline of the C3:Fz electrode pair) and did not show the decrease in connectivity in electrode pair C3:Fz that was observed in controls (tbPLV: p = 0.006; tbCoh: p = 0.023). Our results suggest that delays in cortical deactivation patterns following movement coupled with changes in the time course of connectivity between the sensorimotor and frontal cortices in the stroke group might explain clinical observations of prolonged muscle activation in people with stroke. This prolonged activation might be attributed to the combination of cortical reorganization and changes to sensory feedback post-stroke.

Accelerated Aging Induced by an Unhealthy High-Fat Diet: Initial Evidence for the Role of Nrf2 Deficiency and Impaired Stress Resilience in Cellular Senescence.

High-fat diets (HFDs) have pervaded modern dietary habits, characterized by their excessive saturated fat content and low nutritional value. Epidemiological studies have compellingly linked HFD consumption to obesity and the development of type 2 diabetes mellitus. Moreover, the synergistic interplay of HFD, obesity, and diabetes expedites the aging process and prematurely fosters age-related diseases. However, the underlying mechanisms driving these associations remain enigmatic. One of the most conspicuous hallmarks of aging is the accumulation of highly inflammatory senescent cells, with mounting evidence implicating increased cellular senescence in the pathogenesis of age-related diseases. Our hypothesis posits that HFD consumption amplifies senescence burden across multiple organs. To scrutinize this hypothesis, we subjected mice to a 6-month HFD regimen, assessing senescence biomarker expression in the liver, white adipose tissue, and the brain. Aging is intrinsically linked to impaired cellular stress resilience, driven by dysfunction in Nrf2-mediated cytoprotective pathways that safeguard cells against oxidative stress-induced senescence. To ascertain whether Nrf2-mediated pathways shield against senescence induction in response to HFD consumption, we explored senescence burden in a novel model of aging: Nrf2-deficient (Nrf2+/-) mice, emulating the aging phenotype. Our initial findings unveiled significant Nrf2 dysfunction in Nrf2+/- mice, mirroring aging-related alterations. HFD led to substantial obesity, hyperglycemia, and impaired insulin sensitivity in both Nrf2+/- and Nrf2+/+ mice. In control mice, HFD primarily heightened senescence burden in white adipose tissue, evidenced by increased Cdkn2a senescence biomarker expression. In Nrf2+/- mice, HFD elicited a significant surge in senescence burden across the liver, white adipose tissue, and the brain. We postulate that HFD-induced augmentation of senescence burden may be a pivotal contributor to accelerated organismal aging and the premature onset of age-related diseases.

Normal or improved cardiovascular risk factors in IGF-I-deficient adults with growth hormone receptor deficiency.

BACKGROUND: Human subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. METHODS: We measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD = 16, control relatives = 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD = 21, control relatives = 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio-economic circumstances. RESULTS: Compared to controls, GHRD subjects displayed lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity, lower carotid artery intima-media thickness, lower creatinine, and a non-significant but major reduction in the portion of subjects with carotid atherosclerotic plaques (7% GHRDs vs. 36%, Controls p = 0.1333) despite elevated low-density lipoprotein cholesterol levels. CONCLUSION: The current study indicates that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors as compared to their relatives. FUNDING: This study was funded in part by NIH/NIA grant P01 AG034906 to V.D.L.

Comprehensive integrated analysis of MR and DCE-MR radiomics models for prognostic prediction in nasopharyngeal carcinoma.

Although prognostic prediction of nasopharyngeal carcinoma (NPC) remains a pivotal research area, the role of dynamic contrast-enhanced magnetic resonance (DCE-MR) has been less explored. This study aimed to investigate the role of DCR-MR in predicting progression-free survival (PFS) in patients with NPC using magnetic resonance (MR)- and DCE-MR-based radiomic models. A total of 434 patients with two MR scanning sequences were included. The MR- and DCE-MR-based radiomics models were developed based on 289 patients with only MR scanning sequences and 145 patients with four additional pharmacokinetic parameters (volume fraction of extravascular extracellular space (ve), volume fraction of plasma space (vp), volume transfer constant (Ktrans), and reverse reflux rate constant (kep) of DCE-MR. A combined model integrating MR and DCE-MR was constructed. Utilizing methods such as correlation analysis, least absolute shrinkage and selection operator regression, and multivariate Cox proportional hazards regression, we built the radiomics models. Finally, we calculated the net reclassification index and C-index to evaluate and compare the prognostic performance of the radiomics models. Kaplan-Meier survival curve analysis was performed to investigate the model's ability to stratify risk in patients with NPC. The integration of MR and DCE-MR radiomic features significantly enhanced prognostic prediction performance compared to MR- and DCE-MR-based models, evidenced by a test set C-index of 0.808 vs 0.729 and 0.731, respectively. The combined radiomics model improved net reclassification by 22.9%-52.6% and could significantly stratify the risk levels of patients with NPC (p = 0.036). Furthermore, the MR-based radiomic feature maps achieved similar results to the DCE-MR pharmacokinetic parameters in terms of reflecting the underlying angiogenesis information in NPC. Compared to conventional MR-based radiomics models, the combined radiomics model integrating MR and DCE-MR showed promising results in delivering more accurate prognostic predictions and provided more clinical benefits in quantifying and monitoring phenotypic changes associated with NPC prognosis.

Mass Spectrometry-Based Multiomics Identifies Metabolic Signatures of Sarcopenia in Rhesus Monkey Skeletal Muscle.

Sarcopenia is a progressive disorder characterized by age-related loss of skeletal muscle mass and function. Although significant progress has been made over the years to identify the molecular determinants of sarcopenia, the precise mechanisms underlying the age-related loss of contractile function remains unclear. Advances in "omics" technologies, including mass spectrometry-based proteomic and metabolomic analyses, offer great opportunities to better understand sarcopenia. Herein, we performed mass spectrometry-based analyses of the vastus lateralis from young, middle-aged, and older rhesus monkeys to identify molecular signatures of sarcopenia. In our proteomic analysis, we identified proteins that change with age, including those involved in adenosine triphosphate and adenosine monophosphate metabolism as well as fatty acid beta oxidation. In our untargeted metabolomic analysis, we identified metabolites that changed with age largely related to energy metabolism including fatty acid beta oxidation. Pathway analysis of age-responsive proteins and metabolites revealed changes in muscle structure and contraction as well as lipid, carbohydrate, and purine metabolism. Together, this study discovers new metabolic signatures and offers new insights into the molecular mechanisms underlying sarcopenia for the evaluation and monitoring of a therapeutic treatment of sarcopenia.

Mass spectrometry-based multi-omics identifies metabolic signatures of sarcopenia in rhesus monkey skeletal muscle.

Sarcopenia is a progressive disorder characterized by age-related loss of skeletal muscle mass and function. Although significant progress has been made over the years to identify the molecular determinants of sarcopenia, the precise mechanisms underlying the age-related loss of contractile function remains unclear. Advances in omics technologies, including mass spectrometry-based proteomic and metabolomic analyses, offer great opportunities to better understand sarcopenia. Herein, we performed mass spectrometry-based analyses of the vastus lateralis from young, middle-aged, and older rhesus monkeys to identify molecular signatures of sarcopenia. In our proteomic analysis, we identified numerous proteins that change with age, including those involved in adenosine triphosphate and adenosine monophosphate metabolism as well as fatty acid beta oxidation. In our untargeted metabolomic analysis, we identified multiple metabolites that changed with age largely related to energy metabolism including fatty acid beta oxidation. Pathway analysis of age-responsive proteins and metabolites revealed changes in muscle structure and contraction as well as lipid, carbohydrate, and purine metabolism. Together, this study discovers new metabolic signatures and offer new insights into the molecular mechanism underlying sarcopenia for the evaluation and monitoring of therapeutic treatment of sarcopenia.

Vascular mechanisms leading to progression of mild cognitive impairment to dementia after COVID-19: Protocol and methodology of a prospective longitudinal observational study.

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage to dementia, affecting up to 20% of the aging population worldwide. Patients with MCI have an annual conversion rate to dementia of 15-20%. Thus, conditions that increase the conversion from MCI to dementia are of the utmost public health concern. The COVID-19 pandemic poses a significant impact on our aging population with cognitive decline as one of the leading complications following recovery from acute infection. Recent findings suggest that COVID-19 increases the conversion rate from MCI to dementia in older adults. Hence, we aim to uncover a mechanism for COVID-19 induced cognitive impairment and progression to dementia to pave the way for future therapeutic targets that may mitigate COVID-19 induced cognitive decline. METHODOLOGY: A prospective longitudinal study is conducted at the University of Oklahoma Health Sciences Center. Patients are screened in the Department of Neurology and must have a formal diagnosis of MCI, and MRI imaging prior to study enrollment. Patients who meet the inclusion criteria are enrolled and followed-up at 18-months after their first visit. Visit one and 18-month follow-up will include an integrated and cohesive battery of vascular and cognitive measurements, including peripheral endothelial function (flow-mediated dilation, laser speckle contrast imaging), retinal and cerebrovascular hemodynamics (dynamic vessel retinal analysis, functional near-infrared spectroscopy), and fluid and crystalized intelligence (NIH-Toolbox, n-back). Multiple logistic regression will be used for primary longitudinal data analysis to determine whether COVID-19 related impairment in neurovascular coupling and increases in white matter hyperintensity burden contribute to progression to dementia.

Elimination of senescent cells by treatment with Navitoclax/ABT263 reverses whole brain irradiation-induced blood-brain barrier disruption in the mouse brain.

Whole brain irradiation (WBI), a commonly employed therapy for multiple brain metastases and as a prophylactic measure after cerebral metastasis resection, is associated with a progressive decline in neurocognitive function, significantly impacting the quality of life for approximately half of the surviving patients. Recent preclinical investigations have shed light on the multifaceted cerebrovascular injury mechanisms underlying this side effect of WBI. In this study, we aimed to test the hypothesis that WBI induces endothelial senescence, contributing to chronic disruption of the blood-brain barrier (BBB) and microvascular rarefaction. To accomplish this, we utilized transgenic p16-3MR mice, which enable the identification and selective elimination of senescent cells. These mice were subjected to a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks), and cranial windows were applied to both WBI-treated and control mice. Quantitative assessment of BBB permeability and capillary density was performed using two-photon microscopy at the 6-month post-irradiation time point. The presence of senescent microvascular endothelial cells was assessed by imaging flow cytometry, immunolabeling, and single-cell RNA-sequencing (scRNA-seq). WBI induced endothelial senescence, which associated with chronic BBB disruption and a trend for decreased microvascular density in the mouse cortex. In order to investigate the cause-and-effect relationship between WBI-induced senescence and microvascular injury, senescent cells were selectively removed from animals subjected to WBI treatment using Navitoclax/ABT263, a well-known senolytic drug. This intervention was carried out at the 3-month post-WBI time point. In WBI-treated mice, Navitoclax/ABT263 effectively eliminated senescent endothelial cells, which was associated with decreased BBB permeability and a trend for increased cortical capillarization. Our findings provide additional preclinical evidence that senolytic treatment approaches may be developed for prevention of the side effects of WBI.

GHz ultrasonic sensor for ionic content with high sensitivity and localization.

Sensing the ionic content of a solution at high spatial and temporal resolution and sensitivity is a challenge in nanosensing. This paper describes a comprehensive investigation of the possibility of GHz ultrasound acoustic impedance sensors to sense the content of an ionic aqueous medium. At the 1.55 GHz ultrasonic frequency used in this study, the micron-scale wavelength and the decay lengths in liquid result in a highly localized sense volume with the added potential for high temporal resolution and sensitivity. The amplitude of the back reflected pulse is related to the acoustic impedance of the medium and a function of ionic species concentration of the KCl, NaCl, and CaCl2 solutions used in this study. A concentration sensitivity as high as 1 mM and concentration detection range of 0 to 3 M was achieved. These bulk acoustic wave pulse-echo acoustic impedance sensors can also be used to record dynamic ionic flux.

Accelerated cerebromicrovascular senescence contributes to cognitive decline in a mouse model of paclitaxel (Taxol)-induced chemobrain.

Chemotherapy-induced cognitive impairment ("chemobrain") is a frequent side-effect in cancer survivors treated with paclitaxel (PTX). The mechanisms responsible for PTX-induced cognitive impairment remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that PTX induces endothelial senescence, which impairs microvascular function and contributes to the genesis of cognitive decline. We treated transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells, with PTX (5 mg/kg/day, 2 cycles; 5 days/cycle). PTX-treated and control mice were tested for spatial memory performance, neurovascular coupling (NVC) responses (whisker-stimulation-induced increases in cerebral blood flow), microvascular density, blood-brain barrier (BBB) permeability and the presence of senescent endothelial cells (by flow cytometry and single-cell transcriptomics) at 6 months post-treatment. PTX induced senescence in endothelial cells, which associated with microvascular rarefaction, NVC dysfunction, BBB disruption, neuroinflammation, and impaired performance on cognitive tasks. To establish a causal relationship between PTX-induced senescence and impaired microvascular functions, senescent cells were depleted from PTX-treated animals (at 3 months post-treatment) by genetic (ganciclovir) or pharmacological (treatment with the senolytic drug ABT263/Navitoclax) means. In PTX treated mice, both treatments effectively eliminated senescent endothelial cells, rescued endothelium-mediated NVC responses and BBB integrity, increased capillarization and improved cognitive performance. Our findings suggest that senolytic treatments can be a promising strategy for preventing chemotherapy-induced cognitive impairment.

Revisiting adipose thermogenesis for delaying aging and age-related diseases: Opportunities and challenges.

Adipose tissue undergoes significant changes in structure, composition, and function with age including altered adipokine secretion, decreased adipogenesis, altered immune cell profile and increased inflammation. Considering the role of adipose tissue in whole-body energy homeostasis, age-related dysfunction in adipose metabolism could potentially contribute to an increased risk for metabolic diseases and accelerate the onset of other age-related diseases. Increasing cellular energy expenditure in adipose tissue, also referred to as thermogenesis, has emerged as a promising strategy to improve adipose metabolism and treat obesity-related metabolic disorders. However, translating this strategy to the aged population comes with several challenges such as decreased thermogenic response and the paucity of safe pharmacological agents to activate thermogenesis. This mini-review aims to discuss the current body of knowledge on aging and thermogenesis and highlight the unexplored opportunities (cellular mechanisms and secreted factors) to target thermogenic mechanisms for delaying aging and age-related diseases. Finally, we also discuss the emerging role of thermogenic adipocytes in healthspan and lifespan extension.

Mapping white matter structural and network alterations in betel quid-dependent chewers using high angular resolution diffusion imaging.

Background: To evaluate brain white matter diffusion characteristics and anatomical network alterations in betel quid dependence (BQD) chewers using high angular resolution diffusion imaging (HARDI). Methods: The current study recruited 53 BQD chewers and 37 healthy controls (HC) in two groups. We explored regional diffusion metrics alternations in the BQD group compared with the HC group using automated fiber quantification (AFQ). We further employed the white matter (WM) anatomical network of HARDI to explore connectivity alterations in BQD chewers using graph theory. Results: BQD chewers presented significantly lower FA values in the left and right cingulum cingulate, the left and right thalamic radiation, and the right uncinate. The BQD has a significantly higher RD value in the right uncinate fasciculus than the HC group. At the global WM anatomical network level, global network efficiency (p = 0.008) was poorer and Lp (p = 0.016) was greater in the BQD group. At the nodal WM anatomical network level, nodal efficiency (p < 0.05) was lower in the BQD group. Conclusion: Our findings provide novel morphometric evidence that brain structural changes in BQD are characterized by white matter diffusivity and anatomical network connectivity among regions of the brain, potentially leading to the enhanced reward system and impaired inhibitory control.

Gait variability predicts cognitive impairment in older adults with subclinical cerebral small vessel disease.

Introduction: Advanced methods of gait research, including approaches to quantify variability, and orderliness/regularity/predictability, are increasingly used to identify patients at risk for the development of cognitive impairment. Cerebral small vessel disease (CSVD) is highly prevalent in older adults and is known to contribute to the development of vascular cognitive impairment and dementia (VCID). Studies in preclinical models demonstrate that subclinical alterations precede CSVD-related cognitive impairment in gait coordination. In humans, CSVD also associates with gait abnormalities. The present study was designed to test the hypothesis that increased gait variability and gait asymmetry predict a decline in cognitive performance in older adults with CSVD. Methods: To test this hypothesis, we compared cognitive performance and gait function in patients with CSVD (age: 69.8 ± 5.3 years; n = 11) and age- and sex-matched control participants (age: 70.7 ± 5.8 years; n = 11). Based on imaging findings, patients with CSVD were identified [presence of white matter hyperintensities plus silent brain infarcts and/or microhemorrhages on magnetic resonance imaging (MRI) assessment]. Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Gait parameters were measured during the single and dual tasks, during which participants, in addition to the motor task, completed a series of mental arithmetic calculations. Spatial and temporal parameters of gait variability, symmetry, and permutation entropy were determined using a pressure-sensitive gait mat during single and dual cognitive task conditions. Results: Patients with CSVD exhibited lower performance in a visual learning test (p = 0.030) and in a sustained attention test (p = 0.007). CSVD also affected step time variability (p = 0.009) and step length variability (p = 0.017). Step lengths of CSVD participants were more asymmetric (p = 0.043) than that of controls, while the two groups were statistically similar regarding step time symmetry and entropy of step time and length. Gait variability was inversely associated with sustained attention, especially among CSVD patients, and this relationship was significantly different between the two groups. The association of sustained attention with gait symmetry was also significantly different between the two groups. Discussion: Our findings provide additional evidence in support of the concept that increased gait variability and asymmetry may predict cognitive impairment in older adults with CSVD.

Obesity as a premature aging phenotype - implications for sarcopenic obesity.

Obesity and aging have both seen dramatic increases in prevalence throughout society. This review seeks to highlight common pathologies that present with obesity, along with the underlying risk factors, that have remarkable similarity to what is observed in the aged. These include skeletal muscle dysfunction (loss of quantity and quality), significant increases in adiposity, systemic alterations to autonomic dysfunction, reduction in nitric oxide bioavailability, increases in oxidant stress and inflammation, dysregulation of glucose homeostasis, and mitochondrial dysfunction. This review is organized by the aforementioned indices and succinctly highlights literature that demonstrates similarities between the aged and obese phenotypes in both human and animal models. As aging is an inevitability and obesity prevalence is unlikely to significantly decrease in the near future, these two phenotypes will ultimately combine as a multidimensional syndrome (a pathology termed sarcopenic obesity). Whether the pre-mature aging indices accompanying obesity are additive or synergistic upon entering aging is not yet well defined, but the goal of this review is to illustrate the potential consequences of a double aged phenotype in sarcopenic obesity. Clinically, the modifiable risk factors could be targeted specifically in obesity to allow for increased health span in the aged and sarcopenic obese populations.

Microvascular dysfunction and neurovascular uncoupling are exacerbated in peripheral artery disease, increasing the risk of cognitive decline in older adults.

Peripheral artery disease (PAD) is a vascular pathology with high prevalence among the aging population. PAD is associated with decreased cognitive performance, but the underlying mechanisms remain obscure. Normal brain function critically depends on an adequate adjustment of cerebral blood supply to match the needs of active brain regions via neurovascular coupling (NVC). NVC responses depend on healthy microvascular endothelial function. PAD is associated with significant endothelial dysfunction in peripheral arteries, but its effect on NVC responses has not been investigated. This study was designed to test the hypothesis that NVC and peripheral microvascular endothelial function are impaired in PAD. We enrolled 11 symptomatic patients with PAD and 11 age- and sex-matched controls. Participants were evaluated for cognitive performance using the Cambridge Neuropsychological Test Automated Battery and functional near-infrared spectroscopy to assess NVC responses during the cognitive n-back task. Peripheral microvascular endothelial function was evaluated using laser speckle contrast imaging. We found that cognitive performance was compromised in patients with PAD, evidenced by reduced visual memory, short-term memory, and sustained attention. We found that NVC responses and peripheral microvascular endothelial function were significantly impaired in patients with PAD. A positive correlation was observed between microvascular endothelial function, NVC responses, and cognitive performance in the study participants. Our findings support the concept that microvascular endothelial dysfunction and neurovascular uncoupling contribute to the genesis of cognitive impairment in older PAD patients with claudication. Longitudinal studies are warranted to test whether the targeted improvement of NVC responses can prevent or delay the onset of PAD-associated cognitive decline.NEW & NOTEWORTHY Peripheral artery disease (PAD) was associated with significantly decreased cognitive performance, impaired neurovascular coupling (NVC) responses in the prefrontal cortex (PFC), left and right dorsolateral prefrontal cortices (LDLPFC and RDLPFC), and impaired peripheral microvascular endothelial function. A positive correlation between microvascular endothelial function, NVC responses, and cognitive performance may suggest that PAD-related cognitive decrement is mechanistically linked, at least in part, to generalized microvascular endothelial dysfunction and subsequent impairment of NVC responses.

Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice.

The loss of skeletal muscle function with age, known as sarcopenia, significantly reduces independence and quality of life and can have significant metabolic consequences. Although exercise is effective in treating sarcopenia it is not always a viable option clinically, and currently, there are no pharmacological therapeutic interventions for sarcopenia. Here, we show that chronic treatment with pan-adiponectin receptor agonist AdipoRon improved muscle function in male mice by a mechanism linked to skeletal muscle metabolism and tissue remodeling. In aged mice, 6 weeks of AdipoRon treatment improved skeletal muscle functional measures in vivo and ex vivo. Improvements were linked to changes in fiber type, including an enrichment of oxidative fibers, and an increase in mitochondrial activity. In young mice, 6 weeks of AdipoRon treatment improved contractile force and activated the energy-sensing kinase AMPK and the mitochondrial regulator PGC-1a (peroxisome proliferator-activated receptor gamma coactivator one alpha). In cultured cells, the AdipoRon induced stimulation of AMPK and PGC-1a was associated with increased mitochondrial membrane potential, reorganization of mitochondrial architecture, increased respiration, and increased ATP production. Furthermore, the ability of AdipoRon to stimulate AMPK and PGC1a was conserved in nonhuman primate cultured cells. These data show that AdipoRon is an effective agent for the prevention of sarcopenia in mice and indicate that its effects translate to primates, suggesting it may also be a suitable therapeutic for sarcopenia in clinical application.

GHz Ultrasound and Electrode Chip-Scale Arrays Stimulate and Influence Morphology of Human Neural Cells.

This study describes the effects of chip-scale gigahertz (GHz) ultrasound (US) and electrical stimulus on the morphology, functionality, and viability of neural cells in vitro. The GHz frequency stimulation is achieved using aluminum nitride piezoelectric transducers fabricated on a silicon wafer, operating at 1.47 GHz, corresponding to the film's thickness mode resonance. These devices are used to stimulate SH-SY5Y neural cells in vitro and observe effects on the morphology and viability of the stimulated cells. It is possible to use these devices to deliver either ultrasonic stimulus alone or US stimulus in conjunction with electrical stimulus. Viability tests demonstrated that the neurons retained structural integrity and viability across a wide range of GHz US stimulus intensities (0-1.2 W/cm2), validating that measurements occur at nontoxic doses of US. Neural stimulation is validated with these devices following the outputs of a previous study, with the normalized fluorescence intensity of activated cells between 1.9 and 2.4. The 300-s ultrasonic stimulation at 1.47 GHz and 0.05 W/cm2 peak intensity led to a decrease in nuclear elongation by 17.5% and a cross-sectional area decrease by 17.8% across three independent trials of over 150 cells per category ( ). The F-actin governed cellular elongation increased in length by up to 16.3% in cells exposed to an ultrasonic stimulus or costimulus ( ). Neurite length increased following ultrasonic stimulation compared with control by 75.8% ( ). This article demonstrates new GHz US and electrical chip-scale arrays with apparent effects in both neural excitation and cell morphology.

Old blood from heterochronic parabionts accelerates vascular aging in young mice: transcriptomic signature of pathologic smooth muscle remodeling.

Vascular aging has a central role in the pathogenesis of cardiovascular diseases contributing to increased mortality of older adults. There is increasing evidence that, in addition to the documented role of cell-autonomous mechanisms of aging, cell-nonautonomous mechanisms also play a critical role in the regulation of vascular aging processes. Our recent transcriptomic studies (Kiss T. et al. Geroscience. 2020;42(2):727-748) demonstrated that circulating anti-geronic factors from young blood promote vascular rejuvenation in aged mice. The present study was designed to expand upon the results of this study by testing the hypothesis that circulating pro-geronic factors also contribute to the genesis of vascular aging phenotypes. To test this hypothesis, through heterochronic parabiosis, we determined the extent to which shifts in the vascular transcriptome (RNA-seq) are modulated by the old systemic environment. We reanalyzed existing RNA-seq data, comparing the transcriptome in the aorta arch samples isolated from isochronic parabiont aged (20-month-old) C57BL/6 mice [A-(A); parabiosis for 8 weeks] and young isochronic parabiont (6-month-old) mice [Y-(Y)] and also assessing transcriptomic changes in the aortic arch in young (6-month-old) parabiont mice [Y-(A); heterochronic parabiosis for 8 weeks] induced by the presence of old blood derived from aged (20-month-old) parabionts. We identified 528 concordant genes whose expression levels differed in the aged phenotype and were shifted towards the aged phenotype by the presence of old blood in young Y-(A) animals. Among them, the expression of 221 concordant genes was unaffected by the presence of young blood in A-(Y) mice. GO enrichment analysis suggests that old blood-regulated genes may contribute to pathologic vascular remodeling. IPA Upstream Regulator analysis (performed to identify upstream transcriptional regulators that may contribute to the observed transcriptomic changes) suggests that the mechanism of action of pro-geronic factors present in old blood may include inhibition of pathways mediated by SRF (serum response factor), insulin-like growth factor-1 (IGF-1) and VEGF-A. In conclusion, relatively short-term exposure to old blood can accelerate vascular aging processes. Our findings provide additional evidence supporting the significant plasticity of vascular aging and the existence of circulating pro-geronic factors mediating pathological remodeling of the vascular smooth muscle cells and the extracellular matrix.

Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain.

There is strong evidence that aging is associated with an increased presence of senescent cells in the brain. The finding that treatment with senolytic drugs improves cognitive performance of aged laboratory mice suggests that increased cellular senescence is causally linked to age-related cognitive decline. The relationship between senescent cells and their relative locations within the brain is critical to understanding the pathology of age-related cognitive decline and dementia. To assess spatial distribution of cellular senescence in the aged mouse brain, spatially resolved whole transcriptome mRNA expression was analyzed in sections of brains derived from young (3 months old) and aged (28 months old) C57BL/6 mice while capturing histological information in the same tissue section. Using this spatial transcriptomics (ST)-based method, microdomains containing senescent cells were identified on the basis of their senescence-related gene expression profiles (i.e., expression of the senescence marker cyclin-dependent kinase inhibitor p16INK4A encoded by the Cdkn2a gene) and were mapped to different anatomical brain regions. We confirmed that brain aging is associated with increased cellular senescence in the white matter, the hippocampi and the cortical grey matter. Transcriptional analysis of the senescent cell-containing ST spots shows that presence of senescent cells is associated with a gene expression signature suggestive of neuroinflammation. GO enrichment analysis of differentially expressed genes in the outer region of senescent cell-containing ST spots ("neighboring ST spots") also identified functions related to microglia activation and neuroinflammation. In conclusion, senescent cells accumulate with age in the white matter, the hippocampi and cortical grey matter and likely contribute to the genesis of inflammatory foci in a paracrine manner.

Dynamic contrast-enhanced MRI predicts PTEN protein expression which can function as a prognostic measure of progression-free survival in NPC patients.

OBJECTIVES: The objective of our study was to investigate whether a phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression was associated with dynamic contrast-enhanced MRI (DCE-MRI) parameters and prognosis in nasopharyngeal carcinoma (NPC). METHODS: Two-hundred-and-forty-five (245) patients with NPC who underwent pretreatment biopsy, expression of PTEN detected by immunohistochemistry of biopsy, and radical intensity-modulated radiation therapy (IMRT) with or without chemotherapy were included. Tumor segmentations were delineated on pretreatment MRI manually. The pharmacokinetic parameters (Ktrans, Kep, Ve, and Vp) derived from dynamic contrast-enhanced MRI (DCE-MRI) using the extended Toft's model within the tumor segmentations were estimated. The following demographics and clinical features were assessed and correlated against each other: gender, age, TNM stage, clinical-stage, Epstein-Barr virus (EBV), pathological type, progression-free survival (PFS), and prognosis status. DCE parameter evaluation and clinical feature comparison between the PTEN positive and negative groups were performed and correlation between PTEN expression with the PFS and prognosis status using Cox regression for survival analysis were assessed. RESULTS: A significantly lower Ktrans and Kep were found in NPC tumors in PTEN negative patients than in PTEN positive patients. Ktrans performed better than Kep in detecting PTEN expression with the ROC AUC of 0.752. PTEN negative was associated with later TNM stage, later clinical-stage, shorter PFS, and worse prognosis. Moreover, N stage, pathological type, Kep, and prognostic status can be considered as independent variables in discrimination of PTEN negative expression in NPCs. CONCLUSIONS: PTEN negative indicated a shorter PFS and worse prognosis than PTEN positive in NPC patients. Ktrans and Kep derived from DCE-MRI, which yielded reliable capability, may be considered as potential imaging markers that are correlated with PTEN expression and could be used to predict PTEN expression noninvasively. Combined radiological and clinical features can improve the performance of the classification of PTEN expression.