Compensatory Response Research Articles

Tinnitus: Clinical Insights in Its Pathophysiology-A Perspective

Tinnitus, the perception of sound without a corresponding external sound source, and tinnitus disorder, which is tinnitus with associated suffering, present a multifaceted clinical challenge due to its heterogeneity and its incompletely understood pathophysiology and especially due to the limited therapeutic options. In this narrative review, we give an overview on various clinical aspects of tinnitus including its heterogeneity, contributing factors, comorbidities and therapeutic pathways with a specific emphasis on the implications for its pathophysiology and future research directions. Tinnitus exhibits high perceptual variability between affected individuals (heterogeneity) and within affected individuals (temporal variability). Hearing loss emerges as predominant risk factor and the perceived pitch corresponds to areas of hearing loss, supporting the compensatory response theory. Whereas most people who have tinnitus can live a normal life, in 10–20% tinnitus interferes severely with quality of life. These patients suffer frequently from comorbidities such as anxiety, depression or insomnia, acting as both risk factors and consequences. Accordingly, neuroimaging studies demonstrate shared brain networks between tinnitus and stress-related disorders shedding light on the intricate interplay of mental health and tinnitus. The challenge lies in deciphering causative relationships and shared pathophysiological mechanisms. Stress, external sounds, time of day, head movements, distraction, and sleep quality can impact tinnitus perception. Understanding these factors provides insights into the interplay with autonomic, sensory, motor, and cognitive processes. Counselling and cognitive-behavioural therapy demonstrate efficacy in reducing suffering, supporting the involvement of stress and anxiety-related networks. Hearing improvement, especially through cochlear implants, reduces tinnitus and thus indirectly validates the compensatory nature of tinnitus. Brain stimulation techniques can modulate the suffering of tinnitus, presumably by alteration of stress-related brain networks. Continued research is crucial for unravelling the complexities of tinnitus. Progress in management hinges on decoding diverse manifestations, identifying treatment-responsive subtypes, and advancing targeted therapeutic approaches.

The regulatory effects of serum catecholamines and endothelial cells in pig hemorrhagic shock and fluid resuscitation models

BackgroundAcute blood loss not only leads to systemic compensatory response, but also the induced changes in vascular endothelial function.These pathological changes may have potential compensatory significance for maintaining organ perfusion and fluid resuscitation. ObjectiveTo understand trauma-induced endotheliopathy and their compensatory roles in acute hemorrhage, a porcine model of hemorrhagic shock (HS) was used to evaluate changes in vascular endothelial factors and catecholamine levels at different time points from shock to fluid resuscitation. Methods: HS was induced in female pigs by rapid bleeding via the arterial sheath. Hemodynamic monitoring was performed using a pulse index continuous cardiac output (PiCCO) system in HS and fluid resuscitation. Femoral vein blood samples were collected at baseline and 40% mean arterial pressure (MAP, shock), MAP recovery, and 30 min, 1 h, and 2 h after recovery. Serum levels of catecholamine and Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Tie-2, Eselectin, intracellular adhesion molecule-1 (ICAM-1), soluble thrombomodulin (sTM), and Syndecan-1 (SDC-1) were evaluated using enzyme-linked immunosorbent assay (ELISA). ResultsSerum catecholamine levels were significantly higher in the shock than in the baseline state. Ang-1 and Ang-2 are endothelial growth factors secreted with distinct roles. Ang-1 stabilizes the endothelium and inhibits vascular leakage, and Ang-2 has the opposite effect. The ratio of Ang-2/Ang-1 was significantly higher in the shock state than in the baseline state; however, the Ang-1/Tie-2 ratio was comparable between the two states. This suggests that changes in vascular permeability may mainly depend on the upregulation of Ang-2 function. Serum levels of E-selectin, ICAM-1, sTM, and SDC-1 were significantly higher in the shock state than in the baseline state. After the MAP was restored to the baseline state, the levels of E-selectin, and SDC-1 remained higher compared with the baseline state until 1 h after MAP recovery. Conclusions: serum levels of catecholamines and vascular endothelial markers increased transiently under HS, promoting a compensatory response of the circulatory system to acute bleeding. This may be one of the potential theoretical basis for restrictive fluid resuscitation.

Abstract 7100: Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma

Abstract Glioblastoma (GBM) is a highly malignant brain tumor, and conventional treatments such as surgical resection and chemotherapy have limited effectiveness, with a high rate of recurrence and poor prognosis for patients. In 2011, the FDA approved a novel therapy for recurrent GBM known as Tumor Treating Fields (TTFields). TTFields use alternating intermediate-frequency (200 kHz) and low-intensity (1-3 V/cm) electric fields to interfere with tumor cells, inducing apoptosis and inhibiting tumor growth. This study aimed to explore the molecular mechanisms of TTFields therapy at the systems biology level using quantitative proteomics technology. We analyzed U87 cells before and after TTFields treatment using quantitative proteomics and identified a total of 7679 proteins. Among them, 804 proteins were significantly upregulated after TTFields treatment, and 1141 proteins were significantly downregulated. Pathway enrichment analysis of differentially expressed proteins showed that upregulated proteins were mainly associated with cell proliferation, cell cycle, and transcription, possibly representing compensatory responses to the TTFields treatment. Further analysis revealed a significant upregulation of the tumor proliferation key protein PARP1, which was validated by protein immunoblotting experiments. Based on this analysis, we hypothesized that combining TTFields with Olaparib (a PARP1 inhibitor) might enhance the sensitivity of TTFields. Subsequently, we performed cell proliferation experiments to evaluate the concomitant application strategy, and the results demonstrated that Olaparib in combination with TTFields treatment significantly reduced the survival rate of U87 cells compared to single-drug treatment. In conclusion, using quantitative proteomics, this study revealed the biological processes underlying the inhibitory effects of TTFields on GBM proliferation. Under TTFields intervention, the expression of PARP1 was upregulated, and the use of a PARP1 inhibitor in combination significantly increased the sensitivity of TTFields. Therefore, this study not only elucidated the molecular mechanisms of TTFields therapy for GBM treatment at the systems biology level, but also provided support for further enhancing the efficacy of TTFields. Citation Format: Qi Mei, Yanmei Gao, Rong Li, Chenxu Wang, Guangyuan Hu, He Huang. Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7100.

Abstract 2268: CREDAC: Copy number-based reference-free expression deconvolution analysis of cancers

Abstract Introduction: Analyses of bulk RNA sequencing data are central to most large-scale tumor sequencing studies. Bulk expression data represent population averages and its interpretation is confounded by both normal cell contamination and somatic copy number alterations. Several computational methods to deconvolve have been developed recently. However, these methods often rely on a set of cell-type-specific reference signatures and ignore the effect of copy number changes. Methods: To address these issues, we have developed a method that formalizes the relationship between allele-specific copy number, expression and sample purity to deconvolve the expression profiles of tumor and normal cells from bulk RNA-seq in an unbiased manner. Our method was applied to sequencing data produced by the TRACERx consortium, a longitudinal study with multi-region whole-exome and RNA-seq of non-small-cell lung cancers. A total of 414 primary tumor regions and 140 adjacent normal tissue samples from 140 patients with matched DNA and RNA-seq data were processed. Results: We were able to directly deconvolve a median of ~2,000 genes per sample and indirectly infer tumor and normal expression profiles of ~10,000 genes using an scaled and weighted mean approach. The accuracy of the deconvolution was validated using (1) in-silico mixtures of patient-derived tumor and normal cells, (2) pseudo-bulk scRNAseq and (3) in regions with loss of heterogeneity (LOH) directly on the bulk sequencing data, where the total fraction of expression attributed to tumor cells can be computed directly using somatic mutations. CREDAC allows for single sample bulk-level tumor-normal differential expression analysis and revealed a strong and constitutive genome-wide overexpression in cancer compared to admixed normal cells, with a more pronounced overexpression in lung squamous cell carcinoma than lung adenocarcinoma (p<0.001). CREDAC adjusts for variations in copy number, thus facilitating the investigation of cancer-specific dosage compensatory responses triggered by aneuploidy. We revealed that a majority of genes (~65%) exhibit proportionality to copy number alterations, while a substantial proportion (~35%) shows anti-scaling or dosage compensation strategies. We show an enrichment of genes involved in cell cycle and expression processes within the dosage compensated group and revealed methylation as a key mechanism driving this compensatory process. Conclusion: Overall, our results suggest that CREDAC is able to accurately disentangle the expression of tumor and normal cells from bulk RNA-seq without any previous knowledge. It has potential applications in many studies that include matched RNA-seq and copy number data and can provide new insights functional characterization, the taxonomy of cancer, and tumor evolution. Citation Format: Carla Castignani, Jonas Demeulemeester, Oriol Pich, Tom Lesluyes, Robert E. Hynds, David R. Pearce, Elizabeth Larose Cadieux, Stefan C. Dentro, TRACERx Consortium, Nnenna Kanu, Charles Swanton, Peter Van Loo. CREDAC: Copy number-based reference-free expression deconvolution analysis of cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2268.

Functional and metabolomic analysis of urinary extracellular vesicles from juvenile mice with renal compensatory hypertrophy

Unilateral nephrectomy, a procedure reducing kidney mass, triggers a compensatory response in the remaining kidney, increasing its size and function to maintain a normal glomerular filtration rate (GFR). Recent research has highlighted the role of extracellular vesicles (EVs) in renal physiology and disease, although their involvement in unilateral nephrectomy has been underexplored. In this study, unilateral nephrectomy was performed on young mice, and urinary extracellular vesicles (uEVs) characterization and cargo were analyzed. Kidney volume increased significantly post-nephrectomy, demonstrating compensatory hypertrophy. Serum creatinine, cystatin C, and urinary electrolytes concentrations were similar in both nephrectomized and control groups. Western blot analysis revealed upregulation of sodium-glucose cotransporter 2 (SGLT2) and sodium chloride cotransporter (NCC), and downregulation of sodium‑potassium-chloride co-transporter (NKCC2) and epithelial sodium channel (ENaC) in the nephrectomized group. Metabolomic analysis of uEVs showed an enrichment of certain metabolites, including citrate and stachydrine. Interestingly, uEVs from the nephrectomized group demonstrated a protective effect, downregulating signal transducer and activator of transcription 3 (STAT3) and reducing reactive oxygen species (ROS) in renal proximal cells, compared to uEVs from the control group. This study suggests that uEVs contain bioactive components capable of inducing protective, anti-inflammatory, anti-fibrinolytic, and antioxidative effects in renal cells. These findings contribute to our understanding of uEVs' role in renal compensatory mechanisms after unilateral nephrectomy and may hold promise for future therapeutic interventions in renal diseases.

Patch age alters seagrass response mechanisms to herbivory damage

Natural disturbances can produce a mosaic of seagrass patches of different ages, which may affect the response to herbivory. These pressures can have consequences for plant performance. To assess how seagrass patch age affects the response to herbivory, we simulated the effect of herbivory by clipping leaves of Halodule wrightii in patches of 2, 4 and 6 years. All clipped plants showed ability to compensate herbivory by increasing leaf growth rate (on average 4.5-fold). The oldest patches showed resistance response by increasing phenolic compounds (1.2-fold). Contrastingly, the concentration of phenolics decreased in the youngest patches (0.26-fold), although they had a similar leaf carbon content to controls. These results suggest that younger plants facing herbivory pressure reallocate their phenolic compounds towards primary metabolism. Results confirm the H. wrightii tolerance to herbivory damage and provides evidence of age-dependent compensatory responses, which may have consequences for seagrass colonization and growth in perturbed habitats.

How important is hidden phenotypic plasticity arising from alternative but converging developmental trajectories, and what limits it?

Developmental plasticity -- the capacity for a genotype to develop into different phenotypes, depending on the environment - is typically viewed from the perspective of the resulting phenotype. Thus, if development is viewed as a trajectory towards a target, then developmental plasticity allows environmentally induced alterations to the target. However, there can also be variations in the trajectory. This is seen with compensatory responses, for instance where growth accelerates after an earlier period of food shortage, or where investment in sexual ornaments is maintained even when resources are limiting. If the compensation is complete, the adult phenotype can appear 'normal' (i.e. the different developmental trajectories converge on the same target). However, alternative trajectories to a common target can have multiple long-term consequences, including altered physiological programming and rates of senescence, possibly owing to trade-offs between allocating resources to the prioritized trait versus to body maintenance. This suggests that plasticity in developmental trajectories towards a common target leads to variation in the resilience and robustness of the adult body. This form of developmental plasticity is far more hidden than plasticity in final adult target, but it may be more common. Here, I discuss the causes, consequences and limitations of these different kinds of plasticity, with a special focus on whether they are likely to be adaptive. I emphasize the need to study plasticity in developmental trajectories, and conclude with suggestions for future research to tease apart the different forms of developmental plasticity and the factors that influence their evolution and expression.

Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury.

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances. However, its contribution to the progression of liver damage remains unclear. To determine the role and mechanism of UGT1A1 in liver damage progression. We investigated the relationship between UGT1A1 expression and liver injury through clinical research. Additionally, the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study. Patients with UGT1A1 gene mutations showed varying degrees of liver damage, while patients with acute-on-chronic liver failure (ACLF) exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis. This suggests that low UGT1A1 levels may be associated with the progression of liver damage. In mouse models of liver injury induced by carbon tetrachloride (CCl4) and concanavalin A (ConA), the hepatic levels of UGT1A1 protein were found to be increased. In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression, the hepatic protein levels of UGT1A1 were decreased, which is consistent with the observations in patients with ACLF. UGT1A1 knockout exacerbated CCl4- and ConA-induced liver injury, hepatocyte apoptosis and necroptosis in mice, intensified hepatocyte endoplasmic reticulum (ER) stress and oxidative stress, and disrupted lipid metabolism. UGT1A1 is upregulated as a compensatory response during liver injury, and interference with this upregulation process may worsen liver injury. UGT1A1 reduces ER stress, oxidative stress, and lipid metabolism disorder, thereby mitigating hepatocyte apoptosis and necroptosis.

Changes in Endogenous Intoxication and Antioxidant Defense System Markers in Patients with Tumor-Induced Acute Colonic Obstruction

A comprehensive evaluation of clinical and biochemical markers defining the status of endotoxemia in patients diagnosed with acute colonic obstruction (ACO) was conducted. The findings revealed that advancing stages of ACO corresponded to an increase in serum levels of endogenous intoxication markers and a simultaneous decrease in antioxidant defense system (ADS) markers.
 The aim of the study was to analyze changes in endogenous intoxication and ADS markers in patients with tumor-induced ACO throughout the disease progression and evaluate the outcomes.
 Materials and Methods. The study is based on examining serum levels of endogenous intoxication markers, including middle weight molecules (MWM), products of lipid peroxidation (LPO) - conjugated dienes (CD), malonaldehyde (MA), protein oxidative modification (POM), and key ADS markers, specifically superoxide dismutase (SOD), catalase (CAT), and ceruloplasmin (CP), in 155 patients with ACO throughout the disease progression and 20 apparently healthy individuals.
 Results. Upon patient admission to the hospital, the duration of ACO was found to correlate with an increase in endogenous intoxication markers and a decrease in antioxidant defense markers. Depending on ACO stage, MWM levels were 0.42 (0.38; 0.43) IU, 0.56 (0.51; 0.58) IU, and 0.72 (0.69; 0.73) IU, respectively (р1<0.01, р2<0.01, р3<0.01), with a normal range of 0.23 (0.18; 0.25) IU. In the compensated stage of ACO, MA levels significantly increased compared to the control group, reaching 6.39 (6.25; 6.42) nmol/mL (р1<0.001, р2<0.01, р3<0.05). Additionally, with the progression of the disease, a gradual increase in MA levels up to 6.39 (6.25; 6.42) nmol/mL, 7.88 (7.62; 7.92) nmol/mL, and 8.11 (8.05; 8.15) nmol/mL, respectively, was noted (р1<0.001, р2<0.01, р3<0.05), with a normal range of 3.14 (2.58; 3.17) nmol/mL. Similar trend was observed in serum CD levels - 3.11 (3.02; 3.18) IU, 3.69 (3.52; 3.72) IU, and 4.69 (4.53; 4.82) IU, respectively, with a normal range of 1.41 (1.32; 1.46) IU (р1<0.01, р2<0.01, р3<0.01). The study of LPO intensity via the optical density of aldehyde and ketone derivatives of neutral and basic dinitrophenylhydrazones (POM 356, POM 370, POM 430, POM 530) revealed an increase in POM product levels with the disease progression compared to the control group (р1<0.001, р2<0.01, р3<0.01). The analysis of the ADS showed an opposite trend, characterized by a significant decrease in marker levels. In patients with different ACO stages, serum CAT levels were 8.08 (7.95; 8.12) Н2О2/mL, 6.32 (6.25;6.41) Н2О2/mL, and 5.67 (5.59; 5.75) Н2О2/mL, respectively, with a normal range of 12.36 (12.21; 12.55) Н2О2/ml (р1<0.001, р2<0.01, р3<0.01), while SOD concentration decreased with the disease progression as well - 42.43 (31.75; 51.84) IU, 35.65 (24.72; 45.53) IU, and 32.18 (18.72; 41.15) IU, respectively, with a normal range of 63.60 (54.41; 74.56) IU (р1<0.001, р2<0.01, р3<0.01). In the compensated stage of ACO, CP level exceeded the normal value - 39.21 (38.92; 39.41) IU, with a normal range of 28.9 (28.4; 29.1) IU, indicating a compensatory defensive response of the body to a dramatic increase in LPO products. CP reserves, however, were depleted with the disease progression and a consistent decrease in this marker was subsequently observed: 19.10 (18.91; 19.23) IU in the subcompensated stage and 16.12 (16.01; 16.15) IU in the decompensated stage (р1<0.001, р2<0.01, р3<0.01).
 Conclusions. As a systemic process that induces various metabolic homeostasis disorders, endogenous intoxication serves as the pathogenetic foundation for the development of multiple organ failure in ACO patients. With ACO progression, endogenous intoxication caused an increase in LPO and POM activity, resulting in elevation of highly toxic middle-molecular weight substances, concurrently accompanied by a decline in the AOS activity.

Modeling the spatial distribution of numbers of coral reef fish species and community types in the Western Indian Ocean faunal province

Predicting and mapping coral reef diversity at moderate scales can assist spatial planning and prioritizing conservation activities. We made coarse-scale (6.25 km2) predictive models for numbers of coral reef fish species and community composition starting with a spatially complete database of 70 environmental variables available for 7039 mapped reef cells in the Western Indian Ocean. An ensemble model was created from a process of variable elimination and selectivity to make the best predictions irrespective of human influences. This best model was compared to models using preselected variables commonly used to evaluate climate change and human fishing and water quality influences. Many variables (~27) contributed to the best number of species and community composition models, but local variables of biomass, depth, and retention connectivity were dominant predictors. The key human-influenced variables included fish biomass and distance to human populations, with weaker associations with sediments and nutrients. Climate-influenced variables were generally weaker and included median sea surface temperature (SST) with contributions in declining order from SST kurtosis, bimodality, excess summer heat, SST skewness, SST rate of rise, and coral cover. Community composition variability was best explained by 2 dominant community richness axes of damselfishes-angelfishes and butterflyfishes-parrotfishes. Numbers of damselfish-angelfish species were ecologically separated by depth, and damselfishes declined with increasing depth, median temperature, cumulative excess heat, rate of temperature rise, and chronic temperature stresses. Species of butterflyfish-parrotfish separated by median temperature, and butterflyfish numbers declined with increasing temperature, chronic and acute temperature variability, and the rate of temperature rise. Several fish diversity hotspots were found in the East African Coastal Current Ecoregion centered in Tanzania, followed by Mayotte, southern Kenya, and northern Mozambique. If biomass can be maintained, the broad distributions of species combined with compensatory community responses should maintain high diversity and ecological resilience to climate change and other human stressors.

Prevalence of Systemic Hypertension and the Effects of Cerebral Revascularization in Patients With Moyamoya Disease

Background Hypertension is often codiagnosed in patients with moyamoya disease (MMD), a progressive intracranial steno‐occlusive vasculopathy; this has principally been attributed to renal artery stenosis (up to 10%). Susceptibility MMD genes, including ring finger protein 213/mysterin and GUCY1A3 , have also been linked to extracranial vascular disease and increased systolic blood pressure. We aimed to define the prevalence of systemic hypertension in MMD patients and characterize its evolution after cerebral revascularization. Methods Patients with MMD treated with extracranial‐intracranial bypass from 2014 to 2018 were retrospectively enrolled. Blood pressure measurements and antihypertensive agent use were recorded pre‐ and postoperatively. Hypertension was defined according to the 2020 International Society of Hypertension Guidelines (adults) and 2017 American Academy of Pediatrics Guidelines (children). Multivariate logistic regression was performed for clinical and radiographic predictors of hypertension. Results A total of 242 adult and 51 pediatric patients underwent revascularization. Preoperatively, 146 adult and 20 pediatric patients met the diagnostic criteria for hypertension resulting in prevalences of 60.3% and 39.2% respectively. In adults, this was significantly associated with age (odds ratio [OR] 1.05 [95% CI, 1.02–1.09]), body mass index (OR, 1.08 [95% CI, 1.03–1.13]), hyperlipidemia (OR, 2.57 [95% CI, 1.09–6.04]), kidney disease (OR, 18.98 [95% CI, 1.80–200.47]), and symptomatic presentation (OR, 8.88 [95% CI, 1.16–68.06]). After a mean follow‐up of 34.3±18.1 months in adults (33.8±14.9 months – children), patients with hypertension decreased by 15.3% (1.9% – pediatrics) and 31.8% (17.7% – children) experienced improvement in hypertensive status with normalization of blood pressure or reduced need for antihypertensive agents. Posterior circulation involvement was a negative predictor for response of hypertensive status to revascularization (OR, 0.10 [95% CI, 0.01–0.79]). Conclusion Hypertension is prevalent among adult and pediatric patients with MMD with contributions from known vascular risk factors. Its association with symptomatic presentation and observed improvement following revascularization suggests blood pressure changes, in part, are a compensatory physiological response to increased intracranial vascular resistance.

Acute Aromatase Inhibition Impairs Neural and Behavioral Auditory Scene Analysis in Zebra Finches.

Auditory perception can be significantly disrupted by noise. To discriminate sounds from noise, auditory scene analysis (ASA) extracts the functionally relevant sounds from acoustic input. The zebra finch communicates in noisy environments. Neurons in their secondary auditory pallial cortex (caudomedial nidopallium, NCM) can encode song from background chorus, or scenes, and this capacity may aid behavioral ASA. Furthermore, song processing is modulated by the rapid synthesis of neuroestrogens when hearing conspecific song. To examine whether neuroestrogens support neural and behavioral ASA in both sexes, we retrodialyzed fadrozole (aromatase inhibitor, FAD) and recorded in vivo awake extracellular NCM responses to songs and scenes. We found that FAD affected neural encoding of songs by decreasing responsiveness and timing reliability in inhibitory (narrow-spiking), but not in excitatory (broad-spiking) neurons. Congruently, FAD decreased neural encoding of songs in scenes for both cell types, particularly in females. Behaviorally, we trained birds using operant conditioning and tested their ability to detect songs in scenes after administering FAD orally or injected bilaterally into NCM. Oral FAD increased response bias and decreased correct rejections in females, but not in males. FAD in NCM did not affect performance. Thus, FAD in the NCM impaired neuronal ASA but that did not lead to behavioral disruption suggesting the existence of resilience or compensatory responses. Moreover, impaired performance after systemic FAD suggests involvement of other aromatase-rich networks outside the auditory pathway in ASA. This work highlights how transient estrogen synthesis disruption can modulate higher-order processing in an animal model of vocal communication.

The neurology of creativity: 2023 Hower lecture

AbstractThe neurology of creativity implies network activity; no singular cerebral area is invoked. A clinician‐scientist can develop a creative research project from a single patient, combined with critical scientific alliances, careful observations, and correlations. The developing nervous system poses additional complexity, as changes are expected over time in physiologic circumstances, to which must be added compensatory responses to underlying pathology. The arts represent an especially productive area to study the neurology of creativity, especially with functional imaging, tractography, and intracranial electrophysiology. Music activates widespread bilateral areas, including temporal, orbitofrontal, insular, fusiform, and cerebellar cortex. There are different neuronal clusters for different levels of sound volume, duration, timbre, and pitch. Heschl's gyrus and the arcuate fasciculus correlate with pitch. The orbitofrontal cortex is involved in expectancy generation and appears to be active with no music and then deactivates with music, as if the cortex has an editing function. This appears to correlate with the default mode network being key during improvisation, whereas the central executive network is invoked in effortful, repetitive playing. Furthermore, plasticity is associated with music, from the pathologic development of musicogenic seizures, to protection from musician's dystonia in pianists who begin lessons before age 9 years, to benefits of increased temporal cortex in older adults taking piano lessons after six months. Creativity, reducing negativity bias, and juggling life s priorities are key to countering burnout and building resilience.

The Role of Angiogenesis Mediators in the Mobilization of Early and Late Endothelial Progenitor Cells from the Bone Marrow in Coronary Heart Disease

Background. A severe form of coronary heart disease (CHD) is ischemic cardiomyopathy (ICMP), the pathogenesis of which has not been fully studied. Disturbances in the mobilization of endothelial progenitor cells (EPC) due to an imbalance of angiogenesis mediators may exacerbate ischemia in ICMP. The aim — to establish the peculiarities of changes in the balance of early and late EPС and subpopulations of VEGFR2+ cells in the blood and bone marrow in relation to the content of angiogenesis mediators and the number of desquamated endothelial cells (DEK) in the blood of patients with CHD, suffering and not suffering from ICMP. Methods. A single-stage, clinical, controlled (case-control) study was conducted from March 2019 to June 2022. 52 patients with CHD who had a history of myocardial infarction were examined: 30 people suffering from ICMP and 22 people not suffering from ICMP, as well as 15 healthy donors. The content of VEGFR2+, VEGFR2+CD34+CD14+ (early EPC), VEGFR2+CD34+CD14– (late EPC), VEGFR2+CD34–CD14+, VEGFR2+CD34–CD14– cells in patients with CHD in the blood (before surgery) and bone marrow (sampling was performed at the beginning of coronary bypass) and in healthy individuals in the blood, as well as (in both groups) the content of CD45–CD146+ DEC in the blood was determined by flow cytometry. The concentration of SDF-1, VEGF-A, MCP-1, GM-CSF, G-CSF in blood plasma was measured by multiplex immunofluorescence analysis. Results. The development of CHD without cardiomyopathy was accompanied by an increase in the content of VEGFR2+CD34+CD14+ and VEGFR2+ cells (0.74 [0.46; 1.23]% and 10.00 [8.20; 11.60]%, respectively, versus 0.19 [0.13; 0.32]%, p 0.001 and 5.40 [4.30; 6.50]%, p = 0.005) and concentrations of SDF-1, MCP-1, GM-CSF (respectively 60.00 [50.00; 81.00] pg/ml; 223.0 [180.0; 297.0] pg/ml; 2.10 [1.45; 3.40] pg/ml versus 30.00 [5.00; 45.00] pg/ml, p = 0.041; 175.1 [140.0; 204.0] pg/ml, p = 0.046; 0.96 [0.46; 1.41] pg/ml, p = 0.038) in the blood relative to the norm. No such changes were observed in patients with ICMP. Regardless of the presence of ICMP, the content of VEGFR2+CD34+CD14–, VEGFR2+CD34–CD14+, VEGFR2+CD34–CD14– cells, VEGF-A, G-CSF in the blood of patients with CHD varied within physiological values, and the number of DEC exceeded the norm (7.26 [5.43; 17.94]×105/l, p = 0.039). The number of VEGFR2+ cells and their immunophenotypes in the bone marrow of patients with ICMP did not differ from the parameters in patients with CHD without cardiomyopathy. Prolonged bleeding from the venopuncture area was registered in one CHD patient without cardiomyopathy. Conclusion. The development of ICMP is associated with the absence of a compensatory response to atherogenesis in the form of increased mobilization of early EPC from the bone marrow due to the absence of a reaction associated with hyperproduction of SDF-1, MCP-1, GM-CSF, which is characteristic of CHD without cardiomyopathy. The content of EPС, VEGFR2+CD34–CD14+ and VEGFR2+CD34–CD14– cells, VEGF-A and G-CSF in the blood in СHD corresponds to physiological values, regardless of the presence of ICMP. The generation of EPC in the bone marrow in ICMP is not impaired.

Natural Killer Cell Infiltration in Prostate Cancers Predict Improved Patient Outcomes.

Natural killer (NK) cells are non-antigen specific innate immune cells that can be redirected to targets of interest using multiple strategies, although none are currently FDA-approved. We sought to evaluate NK cell infiltration into tumors to develop an improved understanding of which histologies may be most amenable to NK cell-based therapies currently in the developmental pipeline. DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from tumors from 45 cancer types (N = 90,916 for all cancers and N = 3365 for prostate cancer) submitted to Caris Life Sciences. NK cell fractions and immune deconvolution were inferred from RNA-seq data using quanTIseq. Real-world overall survival (OS) and treatment status was determined and Kaplan-Meier estimates were calculated. Statistical significance was determined using X2 and Mann-Whitney U tests, with corrections for multiple comparisons where appropriate. In both a pan-tumor and prostate cancer (PCa)-specific setting, we demonstrated that NK cells represent a substantial proportion of the total cellular infiltrate (median range 2-9% for all tumors). Higher NK cell infiltration was associated with improved OS in 28 of 45 cancer types, including (PCa). NK cell infiltration was negatively correlated with common driver mutations and androgen receptor variants (AR-V7) in primary prostate biopsies, while positively correlated with negative immune regulators. Higher levels of NK cell infiltration were associated with patterns consistent with a compensatory anti-inflammatory response. Using the largest available dataset to date, we demonstrated that NK cells infiltrate a broad range of tumors, including both primary and metastatic PCa. NK cell infiltration is associated with improved PCa patient outcomes. This study demonstrates that NK cells are capable of trafficking to both primary and metastatic PCa and are a viable option for immunotherapy approaches moving forward. Future development of strategies to enhance tumor-infiltrating NK cell-mediated cytolytic activity and activation while limiting inhibitory pathways will be key.

Advances in basic research on glucagon and alpha cells.

The regulation of plasma amino acid levels by glucagon in humans first attracted the attention of researchers in the 1980s. Recent basic research using animal models of glucagon deficiency suggested that a major physiological role of glucagon is the regulation of amino acid metabolism rather than to increase blood glucose levels. In this regard, novel feedback regulatory mechanisms that are mediated by glucagon and amino acids have recently been described between islet alpha cells and the liver. Increasingly, hyperglucagonemia in humans with diabetes and/or nonalcoholic fatty liver diseases is reported to likely be a compensatory response to hepatic glucagon resistance. Severe glucagon resistance due to a glucagon receptor mutation in humans causes hyperaminoacidemia and islet alpha cell expansion combined with pancreatic hypertrophy. Notably, a recent report showed that the restoration of glucagon resistance by liver transplantation resolved not only hyperglucagonemia, but also pancreatic hypertrophy and other metabolic disorders. The mechanisms that regulate islet cell proliferation by amino acids largely remain unelucidated. Clarification of such mechanisms will increase our understanding of the pathophysiology of diseases related to glucagon.

Assessment of cardiovascular functioning following sport-related concussion: A physiological perspective

There is still much uncertainty surrounding the approach to diagnosing and managing a sport-related concussion (SRC). Neurobiological recovery may extend beyond clinical recovery following SRC, highlighting the need for objective physiological parameters to guide diagnosis and management. With an increased understanding of the connection between the heart and the brain, the utility of assessing cardiovascular functioning following SRC has gained attention. As such, this review focuses on the assessment of cardiovascular parameters in the context of SRC. Although conflicting results have been reported, decreased heart rate variability, blood pressure variability, and systolic (ejection) time, in addition to increased spontaneous baroreflex sensitivity and magnitude of atrial contraction have been shown in acute SRC. We propose that these findings result from the neurometabolic cascade triggered by a concussion and represent alterations in myocardial calcium handling, autonomic dysfunction, and an exaggerated compensatory response that attempts to maintain homeostasis following a SRC. Assessment of the cardiovascular system has the potential to assist in diagnosing and managing SRC, contributing to a more comprehensive and multimodal assessment strategy.

A40 THE ROLE OF HYPOXIA-INDUCIBLE FACTOR IN CELLULAR METABOLIC ADAPTATION UPON GIARDIA INFECTION

Abstract Background Recent findings have highlighted the integral role of oxygen tension in gastrointestinal (GI) homeostasis. During hypoxia when oxygen supply is limited, mammalian cells utilize the Hypoxia-Inducible Factor (HIF) complex to activate genes that promote cell survival and alter glucose metabolism. The GI system exists in a state of physiologic hypoxia, subject to further alterations by pathogens. Although tissue and blood parasites are known to influence tissue oxygen tension, little is known regarding the modulation of hypoxia and HIF by enteric parasites. Aims This project aims to characterize the effect of Giardia duodenalis, a common enteric protozoan that perturbs gastrointestinal function leading to diarrheal disease, on the cellular hypoxic response. We hypothesize that hypoxia-associated genes are activated upon Giardia infection, leading to an adaptive metabolic response with increased glycolytic flux to maintain cellular bioenergetic homeostasis. Methods Caco-2 colonic epithelial cells were infected with Giardia isolate GS/M (MOI 10) for 1.5 or 4.5 hours to capture early and peak HIF activation, under normoxic (21% O2) or hypoxic (1%O2, STEMCELL hypoxia incubator) conditions. RNA was extracted for RT-qPCR to assess transcriptional changes of known HIF-target genes. Intracellular metabolite analysis via liquid-chromatography mass-spectrometry (hydrophilic-interaction chromatography method) was performed to assess HIF-mediated metabolic changes in uninfected and Giardia-infected cells (MOI 10) exposed to the hypoxia mimetic DMOG or the HIF inhibitor PX-478. Results Under normoxic conditions, genes associated with compensatory cellular stress responses such as VEGFA, ANKRD37, GADD45A, and glycolysis-associated genes HK2, and LDHA are upregulated in Giardia-infected cells in a time-dependent manner (pampersand:003C0.05). Under hypoxic conditions, fewer HIF-target genes are upregulated (e.g., VEGFA, GADD45A, PGK1; pampersand:003C0.05), suggesting Giardia-infected cells behave similarly to uninfected cells with constant HIF activation. Analysis of the Caco-2 intracellular metabolome indicates HIF-dependent changes in amino acid (e.g., glycine, threonine) and nucleic acid (e.g., guanosine, inosine, uracil) metabolism. DMOG treatment altered the production of glycolytic intermediates (e.g., DHAP, PEP), confirming the promotion of glycolytic flux by HIF. Conclusions Both cell-stress-related and glucose-metabolism HIF target genes are activated upon Giardia infection. As well, some metabolic changes are dependent on HIF activation. These novel findings indicate Giardia promotes a hypoxic state in human intestinal cells, highlighting a metabolic cell rescue mechanism in response to enteropathogens. Furthermore, understanding the role of hypoxia in enteric parasitic infections will shed light on the potential of HIF as a therapeutic target. Funding Agencies Natural Sciences and Engineering Research Council of Canada (NSERC)

Associations between fears related to safety during sleep and self-reported sleep in men and women living in a low-socioeconomic status setting

South Africans living in low socioeconomic areas have self-reported unusually long sleep durations (approximately 9–10 h). One hypothesis is that these long durations may be a compensatory response to poor sleep quality as a result of stressful environments. This study aimed to investigate whether fear of not being safe during sleep is associated with markers of sleep quality or duration in men and women. South Africans (n = 411, 25–50 y, 57% women) of African-origin living in an urban township, characterised by high crime and poverty rates, participated in this study. Participants are part of a larger longitudinal cohort study: Modelling the Epidemiologic Transition Study (METS)–Microbiome. Customised questions were used to assess the presence or absence of fears related to feeling safe during sleep, and the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index were used to assess daytime sleepiness, sleep quality and insomnia symptom severity respectively. Adjusted logistic regression models indicated that participants who reported fears related to safety during sleep were more likely to report poor sleep quality (PSQI > 5) compared to participants not reporting such fears and that this relationship was stronger among men than women. This is one of the first studies outside American or European populations to suggest that poor quality sleep is associated with fear of personal safety in low-SES South African adults.

Traumatic Brain Injury Alters the Trajectory of Age-Related Mitochondrial Change.

Some epidemiologic studies associate traumatic brain injury (TBI) with Alzheimer's disease (AD). To test whether a TBI-induced acceleration of age-related mitochondrial change could potentially mediate the reported TBI-AD association. We administered unilateral controlled cortical impact (CCI) or sham injuries to 5-month-old C57BL/6J and tau transgenic rTg4510 mice. In the non-transgenics, we assessed behavior (1-5 days, 1 month, and 15 months), lesion size (1 and 15 months), respiratory chain enzymes (1 and 15 months), and mitochondrial DNA copy number (mtDNAcn) (1 and 15 months) after CCI/sham. In the transgenics we quantified post-injury mtDNAcn and tangle burden. In the non-transgenics CCI caused acute behavioral deficits that improved or resolved by 1-month post-injury. Protein-normalized complex I and cytochrome oxidase activities were not significantly altered at 1 or 15 months, although complex I activity in the CCI ipsilesional cortex declined during that period. Hippocampal mtDNAcn was not altered by injury at 1 month, increased with age, and rose to the greatest extent in the CCI contralesional hippocampus. In the injured then aged transgenics, the ipsilesional hippocampus contained less mtDNA and fewer tangles than the contralesional hippocampus; mtDNAcn and tangle counts did not correlate. As mice age their brains increase mtDNAcn as part of a compensatory response that preserves mitochondrial function, and TBI enhances this response. TBI may, therefore, increase the amount of compensation required to preserve late-life mitochondrial function. If TBI does modify AD risk, altering the trajectory or biology of aging-related mitochondrial changes could mediate the effect.