High Metabolic Demand Research Articles

The dependence of maximum oxygen uptake and utilization (V̇O2 max) on hemoglobin-oxygen affinity and altitude.

Oxygen transport from the lungs to peripheral tissue is dependent on the affinity of hemoglobin for oxygen. Recent experimental data have suggested that the maximum human capacity for oxygen uptake and utilization (V̇O2 max) at sea level and altitude (~3000 m) is sensitive to alterations in hemoglobin-oxygen affinity. However, the effect of such alterations on V̇O2 max at extreme altitudes remains largely unknown due to the rarity of mutations affecting hemoglobin-oxygen affinity. This work uses a mathematical model that couples pulmonary oxygen uptake with systemic oxygen utilization under conditions of high metabolic demand to investigate the effect of hemoglobin-oxygen affinity on V̇O2 max as a function of altitude. The model includes the effects of both diffusive and convective limitations on oxygen transport. Pulmonary oxygen uptake is calculated using a spatially-distributed model that accounts for the effects of hematocrit and hemoglobin-oxygen affinity. Systemic oxygen utilization is calculated assuming Michaelis-Menten kinetics. The pulmonary and systemic model components are solved iteratively to compute predicted arterial and venous oxygen levels. Values of V̇O2 max are predicted for several values of hemoglobin-oxygen affinity and hemoglobin concentration based on data from humans with hemoglobin mutations. The model predicts that increased hemoglobin-oxygen affinity leads to increased V̇O2 max at altitudes above ~4500 m.

Endothelial structure contributes to heterogeneity in brain capillary diameter.

The high metabolic demand of brain tissue is supported by a constant supply of blood flow through dense microvascular networks. Capillaries are the smallest class of vessels in the brain and their lumens vary in diameter between ~2 and 5 μm. This diameter range plays a significant role in optimizing blood flow resistance, blood cell distribution, and oxygen extraction. The control of capillary diameter has largely been ascribed to pericyte contractility, but it remains unclear if the architecture of the endothelial wall also contributes to capillary diameter. Here, we use public, large-scale volume electron microscopy data from mouse cortex (MICrONS Explorer, Cortical mm3) to examine how endothelial cell number, endothelial cell thickness, and pericyte coverage relates to microvascular lumen size. We find that transitional vessels near the penetrating arteriole and ascending venule are composed of two to six interlocked endothelial cells, while the capillaries intervening these zones are composed of either one or two endothelial cells, with roughly equal proportions. The luminal area and diameter are on average slightly larger with capillary segments composed of two interlocked endothelial cells vs one endothelial cell. However, this difference is insufficient to explain the full range of capillary diameters seen in vivo. This suggests that both endothelial structure and other influences, including pericyte tone, contribute to the basal diameter and optimized perfusion of brain capillaries.

Glucose oxidation drives trunk neural crest cell development and fate.

Bioenergetic metabolism is a key regulator of cellular function and signaling, but how it can instruct the behavior of cells and their fate during embryonic development remains largely unknown. Here, we investigated the role of glucose metabolism in the development of avian trunk neural crest cells (NCCs), a migratory stem cell population of the vertebrate embryo. We uncovered that trunk NCCs display glucose oxidation as a prominent metabolic phenotype, in contrast to what is seen for cranial NCCs, which instead rely on aerobic glycolysis. In addition, only one pathway downstream of glucose uptake is not sufficient for trunk NCC development. Indeed, glycolysis, mitochondrial respiration and the pentose phosphate pathway are all mobilized and integrated for the coordinated execution of diverse cellular programs, epithelial-to-mesenchymal transition, adhesion, locomotion, proliferation and differentiation, through regulation of specific gene expression. In the absence of glucose, the OXPHOS pathway fueled by pyruvate failed to promote trunk NCC adaptation to environmental stiffness, stemness maintenance and fate-decision making. These findings highlight the need for trunk NCCs to make the most of the glucose pathway potential to meet the high metabolic demands appropriate for their development.

PECULIARITIES OF THE COURSE OF THE DISEASE IN WOMEN WITH COVID-19

One of the most crucial topics at the moment is the viral infection caused by the SARS-CoV-2 coronavirus, which has acquired not only medical, but also, of course, social significance. The COVID-19 pandemic has challenged healthcare systems around the world.Pregnant women are the most vulnerable category of people, along with the elderly. Due to low immune reactivity, they are more susceptible to severe complications than others, which makes the problem of pregnancy in patients with COVID-19 a pressing issue.A successful pregnancy requires changes in the immune system of the pregnant woman to tolerate a genetically foreign fetus. These changes in the immune system, as well as in the cardiac, pulmonary, and other systems, can lead to increased susceptibility or increased morbidity and mortality due to infection during pregnancy. Considering the physiological adaptations associated with pregnancy, we found that the high metabolic demand to maintain normal intrauterine development increases the burden of oxidative stress during pregnancy. Intracellular redox changes associated with acute phase reactions at the maternal-fetal interface may be enhanced during pregnancy. Notably, mother-to-fetal transmission of SARS-CoV-2 has not been detected in most COVID-19 pregnancies. This relative absence of vertical transmission may be due to the presence of lactoferrin in the placenta, amniotic fluid, and breast secretions. However, the cytokine storm induced during COVID-19-associated pregnancies can cause severe inflammatory damage to the fetus and, if left uncontrolled, can subsequently lead to autism spectrum disorders and brain developmental abnormalities in newborns. Given this serious health threat to a child's growth and development, preventing COVID-19 during pregnancy should be a priority.We aimed to study risk factors and assess the course of pregnancy in women with COVID-19.The study was carried out within the framework of the research work "Clinical and pathogenetic substantiation of differentiated treatment of combined pathology of internal organs" (№0122U002209).

Tumor-associated macrophages: new insights on their metabolic regulation and their influence in cancer immunotherapy.

Tumor-associated macrophages (TAMs) are a dynamic and heterogeneous cell population of the tumor microenvironment (TME) that plays an essential role in tumor formation and progression. Cancer cells have a high metabolic demand for their rapid proliferation, survival, and progression. A comprehensive interpretation of pro-tumoral and antitumoral metabolic changes in TAMs is crucial for comprehending immune evasion mechanisms in cancer. The metabolic reprogramming of TAMs is a novel method for enhancing their antitumor effects. In this review, we provide an overview of the recent research on metabolic alterations of TAMs caused by TME, focusing primarily on glucose, amino acid, and fatty acid metabolism. In addition, this review discusses antitumor immunotherapies that influence the activity of TAMs by limiting their recruitment, triggering their depletion, and re-educate them, as well as metabolic profiles leading to an antitumoral phenotype. We highlighted the metabolic modulational roles of TAMs and their potential to enhance immunotherapy for cancer.

83-OR: Defining the Transcriptome and Epitranscriptome of the ß-Cell Compensation to Insulin Resistance

Type 2 diabetes (T2D) is characterized by decreased functional β-cell mass and poor compensation to insulin resistance. Thus, understanding of the mechanism(s) responsible for the physiological adaptation of β-cells to states of high metabolic demand is desirable. We aimed to dissect the transcriptome and m6A mRNA methylation landscape in the β-cell adaptation to insulin resistance. To this end we conducted RNA-sequencing in sorted β-cells and m6A-sequencing in whole islets from three mouse models: a) a dietary model (60% high-fat diet: Control-HF), b) a genetic model (liver-specific insulin receptor KO mouse on chow: LIRKO-C), and c) a superimposed dietary and genetic model of insulin resistance (LIRKO on a high fat diet: LIRKO-HF). These data were compared to littermate controls fed a chow diet (Control-C). Control-HF, LIRKO-C and LIRKO-HF each presented an increase in insulin resistance compared to Control-C. However, LIRKO-C and LIRKO-HF presented a robust insulin secretion capacity and a graded increase in β-cell proliferation and mass compared to Control-C. First, we correlated the transcriptome with surrogates of β-cell adaptation such as insulin secretion, β-cell mass or proliferation. Next, we intersected the genes that positively correlated with β-cell compensation with single-cell RNA seq datasets performed in islets from humans with or without T2D. This bioinformatics analyses identified extracellular matrix (ECM) as the most enriched pathway in the β-cell adaptation to insulin resistance. On the other hand, m6A-sequencing of Control-C, LIRKO-C and LIRKO-HF islets and the intersection of this dataset with the differentially methylated genes in human T2D islets, revealed enrichment in pathways associated with chromatin modifications. Together, these results point to ECM pathways as being important in the transcriptomic remodeling and that m6A acts on chromatin-modifying enzymes in the β-cell compensation to mammalian insulin resistance. Disclosure D.F.De jesus: None. Z.Zhang: Research Support; SinoVac. J.Wei: None. N.K.Brown: None. J.Hu: None. S.Kahraman: Employee; Boehringer Ingelheim Pharmaceuticals Inc. E.Dirice: None. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago. Funding American Diabetes Association (7-21-PDF-140 to D.F.DJ.); National Institutes of Health (R01067536)

#4344 CHANGES IN ENERGY METABOLISM IN THE KIDNEY WITH TUBULOINTERSTITIAL FIBROSIS: AN EX VIVO WHOLE TISSUE 2D-COSY APPROACH

Abstract Background and Aims Tubulointerstitial fibrosis is the common pathological manifestation in chronic kidney disease (CKD) and can indicate whether a patient will progress to kidney failure. The metabolic consequences of developing fibrosis are not well understood. This project aimed to investigate metabolic changes in the kidney cortex using an adenine-diet murine model of progressive CKD. Method C57Bl/6J mice were treated with an adenine-supplemented diet (0.2% adenine) or control diet for eight weeks. At the end of treatment, kidney function was assessed (serum creatinine, proteinuria), animals were euthanised, and the kidneys removed. A transverse section of the kidney was prepared for histology. Whole kidney cortical tissue was analysed using two-dimensional correlated spectroscopy (2D-COSY), a form of proton nuclear magnetic resonance (NMR) spectroscopy. Biochemical species, including metabolites and lipids, within the tissue were identified and compared with respective histological tubulointerstitial fibrosis level and traditional serum markers of kidney function, plasma creatinine and blood urea nitrogen. A 2D-COSY spectrum can be found in Figure 1A. Results The adenine-supplemented diet induced tubulointerstitial fibrosis, mirrored by increases in serum creatinine and blood urea nitrogen, indicating decreased kidney function. The 2D-COSY analysis demonstrated numerous changes in metabolites with parallel increasing levels of fibrosis that were detected. Increases in metabolites belonging to the glycolysis (D-glucose, glucose-6-phosphate and lactate) and pentose-phosphate (myo-inositol, D-ribose-5-phosphate, glucuronic acid) pathways were observed, as well as a decrease in lipid. Additionally, increases in creatinine, creatine and a number of amino acids were also observed. These changes are displayed in Table 1 and Figure 1B. Conclusion The primary cell type of the kidney cortex is the proximal tubular epithelial cell. Due to its unique function in water and solute transport, this cell has a very high metabolic demand and utilizes fatty acid oxidation as its primary source of energy. However, when these cells are under pathological stress that contributes to tubulointerstitial fibrosis, such as those present within this animal model of chronic kidney disease, metabolic dysfunction occurs. We observed significant decreases in various lipid signals belonging to fatty acids within the cell. These fatty acids are not being utilised and are instead esterified to triglycerides that accumulate in the kidney, causing lipotoxicity. Increased levels of glucose-6-phosphate, lactate and D-glucose, as well as increased myo-inositol, glucuronic acid D-ribose-5-phosphate are indicative of increased utilisation of the glycolysis and pentose phosphate pathway respectively as primary methods of energy metabolism. Here, we provide evidence that in tubulointerstitial fibrosis within the kidneys leads to a shift in the primary energy pathway used by proximal tubular epithelial cells. The study provides new insights into the changes in biochemical pathways that occur in the kidney during the development of CKD and its progression.

Cell metabolism-based optimization strategy of CAR-T cell function in cancer therapy.

Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR)-modified T cells has revolutionized the field of immune-oncology, showing remarkable efficacy against hematological malignancies. However, its success in solid tumors is limited by factors such as easy recurrence and poor efficacy. The effector function and persistence of CAR-T cells are critical to the success of therapy and are modulated by metabolic and nutrient-sensing mechanisms. Moreover, the immunosuppressive tumor microenvironment (TME), characterized by acidity, hypoxia, nutrient depletion, and metabolite accumulation caused by the high metabolic demands of tumor cells, can lead to T cell "exhaustion" and compromise the efficacy of CAR-T cells. In this review, we outline the metabolic characteristics of T cells at different stages of differentiation and summarize how these metabolic programs may be disrupted in the TME. We also discuss potential metabolic approaches to improve the efficacy and persistence of CAR-T cells, providing a new strategy for the clinical application of CAR-T cell therapy.

Phylogeny and evolution of erythrocytes in mammals.

In the past century, several authors have investigated the allometry of haematological parameters in mammals. As haematocrit and haemoglobin (Hb) concentration are almost constant within the Mammalia (although with notable exceptions), differences in other haematological parameters are mainly reducible to red blood cell size (mean corpuscular volume, MCV). Past studies testing for correlation between MCV and body mass have given contradictory results. Using phylogenetically informed regressions, here I demonstrate that the correlation between MCV and body mass is indirect, and is in reality due to the correlation between MCV and basal metabolic rate. This could be explained by the fact that small erythrocytes allow a fast release of oxygen in tissues with high metabolic demand. Nonetheless, hypoxia-adapted species show MCV greater than that predicted by their metabolic rate, while Ruminantia show the inverse. Interestingly, these species show the highest and lowest, respectively, Hb affinity for oxygen. In the present paper, I suggest that Hb-oxygen affinity, acting as a biological constraint for oxygen exchange, determines the size of red blood cells. Hb intrinsic affinity for oxygen shows little variation during evolution and modifying the levels of allosteric factors can be viewed as an adaption to adjust Hb-oxygen affinity to metabolic demands (the same also happens during ontogeny). Nonetheless, in some lineages, mutations raising Hb-oxygen affinity allowed some species to colonize hypoxic environments; in Ruminantia, instead, there was a drastic decrease, which cannot be adaptively explained.

Gaseous Persufflation to Preserve DCD Hearts: An Ovine Model

Donation after circulatory death (DCD) heart transplantation has become a clinical tool in the last 5 years. Outcomes are favourable in comparison with DBD (donation after brain death) organs. However, DCD transplantation remains a niche method employed in a few select centres due to the complexity of the procurement and storage techniques necessitated by the high metabolic demands of the heart. Gaseous persufflation, first described by Magnus in 1902, may be a simpler, cheaper, and more efficacious way of storing DCD or DBD hearts compared with current clinical techniques. While a small amount of work has been published on gas persufflation of hearts, a robust and replicable model describing procurement, persufflation, and reanimation that allows administration of reperfusion injury modulators, akin to a clinical scenario, is yet to be described.

Neurovascular Uncoupling Is Linked to Microcirculatory Dysfunction in Regions Outside the Ischemic Core Following Ischemic Stroke.

Background Normal brain function depends on the ability of the vasculature to increase blood flow to regions with high metabolic demands. Impaired neurovascular coupling, such as the local hyperemic response to neuronal activity, may contribute to poor neurological outcome after stroke despite successful recanalization, that is, futile recanalization. Methods and Results Mice implanted with chronic cranial windows were trained for awake head-fixation before experiments. One-hour occlusion of the anterior middle cerebral artery branch was induced using single-vessel photothrombosis. Cerebral perfusion and neurovascular coupling were assessed by optical coherence tomography and laser speckle contrast imaging. Capillaries and pericytes were studied in perfusion-fixed tissue by labeling lectin and platelet-derived growth factor receptor β. Arterial occlusion induced multiple spreading depolarizations over 1 hour associated with substantially reduced blood flow in the peri-ischemic cortex. Approximately half of the capillaries in the peri-ischemic area were no longer perfused at the 3- and 24-hour follow-up (45% [95% CI, 33%-58%] and 53% [95% CI, 39%-66%] reduction, respectively; P<0.0001), which was associated with contraction of an equivalent proportion of peri-ischemic capillary pericytes. The capillaries in the peri-ischemic cortex that remained perfused showed increased point prevalence of dynamic flow stalling (0.5% [95% CI, 0.2%-0.7%] at baseline, 5.1% [95% CI, 3.2%-6.5%] and 3.2% [95% CI, 1.1%-5.3%] at 3- and 24-hour follow-up, respectively; P=0.001). Whisker stimulation at the 3- and 24-hour follow-up led to reduced neurovascular coupling responses in the sensory cortex corresponding to the peri-ischemic region compared with that observed at baseline. Conclusions Arterial occlusion led to contraction of capillary pericytes and capillary flow stalling in the peri-ischemic cortex. Capillary dysfunction was associated with neurovascular uncoupling. Neurovascular coupling impairment associated with capillary dysfunction may be a mechanism that contributes to futile recanalization. Hence, the results from this study suggest a novel treatment target to improve neurological outcome after stroke.

Causal modelling demonstrates metabolic power is largely affected by gait kinematics and motor control in children with cerebral palsy.

Metabolic power (net energy consumed while walking per unit time) is, on average, two-to-three times greater in children with cerebral palsy (CP) than their typically developing peers, contributing to greater physical fatigue, lower levels of physical activity and greater risk of cardiovascular disease. The goal of this study was to identify the causal effects of clinical factors that may contribute to high metabolic power demand in children with CP. We included children who 1) visited Gillette Children's Specialty Healthcare for a quantitative gait assessment after the year 2000, 2) were formally diagnosed with CP, 3) were classified as level I-III under the Gross Motor Function Classification System and 4) were 18 years old or younger. We created a structural causal model that specified the assumed relationships of a child's gait pattern (i.e., gait deviation index, GDI) and common impairments (i.e., dynamic and selective motor control, strength, and spasticity) with metabolic power. We estimated causal effects using Bayesian additive regression trees, adjusting for factors identified by the causal model. There were 2157 children who met our criteria. We found that a child's gait pattern, as summarized by the GDI, affected metabolic power approximately twice as much as the next largest contributor. Selective motor control, dynamic motor control, and spasticity had the next largest effects. Among the factors we considered, strength had the smallest effect on metabolic power. Our results suggest that children with CP may benefit more from treatments that improve their gait pattern and motor control than treatments that improve spasticity or strength.

Epilepsy in mitochondrial diseases. Clinical lecture

Mitochondrial dysfunction mainly affects organs with high metabolic demand, primarily the brain. Epilepsy is a common phenotypic sign of both syndromic and non-syndromic mitochondrial diseases. Epilepsy in mitochondrial diseases is poorly treatable and is often an unfavorable prognostic sign. Patients with mitochondrial epilepsy are prescribed various anti-seizure medications. Mitochondriotoxic drugs should be avoided. Descriptions of MELAS-syndrome, MERRF-syndrome, Leigh-syndrome, NARP-syndrome are given.

Alterations of Mitochondrial Respiratory Function in Isolated Nephron Segments of Dahl Salt-Sensitive Rats in Salt-Induced Hypertension

Rationale: Mammalian kidneys actively reabsorb nearly 99% of the glomerular filtrate to maintain body fluid and solute homeostasis which requires a great amount of ATP generation and O2 consumption to meet these demands. A high salt diet increases glomerular filtration of Na+ and places a high metabolic demand on the renal tubules to reabsorb more Na+in order for the organism to maintain Na+ balance. Dahl salt-sensitive (SS) rats which mimic the human condition become hypertensive when fed a high salt diet. They are also known to reabsorb greater amounts of Na+ in the proximal tubules (PT) and medullary thick ascending limbs (mTAL) thereby requiring greater ATP production and O2consumption. We hypothesized that the mitochondrial respiratory function of the PT and mTAL would be altered when SS rats are fed a high salt diet in ways that reduce the ability of the kidney to function efficiency thereby leading to salt-induced hypertension. Method: Agilent Seahorse XF96 Extracellular Flux Analyzer was used to assess mitochondrial respiratory function in freshly bulk isolated PT and mTAL from age-matched SS rats during the development of salt-induced hypertension fed with 0.4% NaCl diet (low salt; LS) or 4.0% NaCl diet (high salt; HS) for 7, 14, and 21 days. The Seahorse “Cell Mito Stress Test Protocol” was slightly modified with a substrate addition step to assess the segment-specific and substrate-dependent tubular O2 consumption rate (OCR) under different perturbations, which was used to determine alterations in different mitochondrial respiratory parameters, including H+ leak and ATP production dependent OCR, in the PT and mTAL during the development of salt-induced hypertension. Results: Renal tubular OCR data show that PT of SS rats preferred to use lactate, glutamine, and palmitate, while mTAL preferred to use glucose, pyruvate, and lactate for ATP production under LS diet condition. HS diet resulted in significantly reduced substrate-induced OCR in PT but increased OCR in mTAL. In addition, HS induced a higher level of OCR in the baseline as well as when oligomycin (an inhibitor of F1F0-ATP synthase) was added to both PT and mTAL suspensions indicating that an increased proton leakage/uncoupling of mitochondria occurs in SS rats during the development of salt-induced hypertension. Conclusion: Our emergent data demonstrated that the mitochondrial respiratory function is differentially altered in the PT and mTAL of SS rats in response to different circulatory substrates during the development of salt-induced hypertension. These changes in metabolism appear to be necessary to meet the increased tubular workloads and need for greater ATP production and O2 utilization in both the PT and mTAL of SS rats. NIH R01-HL151587. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Upper-Limb Kinematic Behavior and Performance Fatigability of Elderly Participants Performing an Isometric Task: A Quasi-Experimental Study.

To understand the ULPSIT effects on upper-limb (UL) kinetics and performance fatigability in the elderly. Thirty-one (31) elderly participants (72.61 ± 5.23 years) performed an ULPSIT. The UL average acceleration (AA) and performance fatigability were measured using an inertial measurement unit (IMU) and time-to-task failure (TTF). The findings showed significant changes in AA in the X- and Z-axes (p < 0.05). AA differences in women started earlier in the baseline cutoff in the X-axis, and in men, started earlier between cutoffs in the Z-axis. TTF was positively related to AA in men until 60% TTF. ULPSIT produced changes in AA behavior, indicative of movement of the UL in the sagittal plane. AA behavior is sex related and suggests higher performance fatigability in women. Performance fatigability was positively related to AA only in men, where movement adjustments occurred in an early phase, though with increased activity time.

Identifying Neuroimaging Patterns in Mitochondrial Leukoencephalopathies (P8-4.001)

<h3>Objective:</h3> To identify patterns of white matter involvement in mitochondrial disease. <h3>Background:</h3> Mitochondrial disease has been estimated to affect 1 in 4300 individuals. Primary mitochondrial diseases (PMD) are caused by pathogenic variants in &gt;300 genes. PMD can present at any age with an average of 16 multi-systemic symptoms per patient and often involves the neurological system due to its high metabolic demand. There is limited knowledge regarding mitochondrial leukoencephalopathies. In this study, we reviewed patterns of white matter involvement on MRI in patients with genetically confirmed PMD. <h3>Design/Methods:</h3> Retrospective chart review of 186 patients with genetically confirmed PMD was conducted. MRI studies available for 153 patients were analyzed to identify presence of white matter involvement. Neuroimaging patterns were delineated based on location, type of involvement (leukodystrophy vs hypomyelination), T1 and T2 appearance, cystic changes, volume loss, atrophy, restricted diffusion, contrast enhancement and associated brain structure involvement. Information was collected regarding CSF protein level, plasma lactate level, and lactate peak on magnetic resonance spectroscopy. <h3>Results:</h3> White matter involvement was observed in 61 out of 153 patients with MRI studies available to review. Genetic diagnosis of these patients included genes involved in mtDNA translation (<i>C12ORF65, MRPS34, RMND1</i>), mtDNA depletion (<i>FBXL4</i>), oxidative phosphorylation (<i>AIFM1, EARS2, CARS2, FARS2, VARS2</i>), complex I function (<i>NDUFS1, NUBPL</i>), complex II function (<i>SDHB</i>), complex IV function (<i>SURF1</i>), single large scale mtDNA deletion, mtDNA transcription (<i>MT-TL1</i>), pyruvate dehydrogenase complex (<i>PDH, ECHS1, PDHA1</i>) and thiamine transport (<i>SLC19A3</i>). Leukodystrophy pattern was seen in 14 while hypomyelination was observed in 16 patients. Location was periventricular in 23, diffuse in 15 and involving corpus callosum in 25 patients. Restricted diffusion was observed in 18, cystic changes in 10, volume loss in 14 and associated cerebral/cerebellar atrophy in 11 patients. <h3>Conclusions:</h3> Leukoencephalopathy with specific imaging patterns in neurologically complex patients with multisystemic presentations should warrant detailed evaluation for mitochondrial disease. <b>Disclosure:</b> Dr. Sharma has nothing to disclose. James Peterson has nothing to disclose. CESAR ALVES has nothing to disclose. Dr. Goldstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Reneo Pharmaceuticals .

β Cell and Autophagy: What Do We Know?

Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure.

Implication of Ferroptosis in Cholangiocarcinoma: A Potential Future Target?

Cholangiocarcinoma (CCA), the second most common liver neoplasm, has a poor overall 5-year survival rate of less than 10%. A deeper understanding of the molecular pathogenesis contributing to CCA progression is essential for developing better therapeutic approaches to manage this disease. Ferroptosis, an oxidative iron-dependent form of regulated cell death, has been reported to be involved in tumorigenesis and progression. In particular, ferroptosis and inflammation, which are common issues in cholangiocarcinogenesis and CCA development, might be in concert with disease progression. Notably, the key feature of cancer cells is "iron addiction", which is crucial for the high metabolic demand in carcinogenesis and cancer progression. Additionally, iron metabolism is of great importance in ferroptosis. Moreover, that cancer cells are vulnerable to ferroptosis might be a possible mechanism of CCA development. Although the underlying mechanism of how ferroptosis is implicated in CCA development requires further investigation, developing a new strategy combined with a pro-ferroptotic treatment would be an exciting CCA treatment approach in the future.

Deep learning-based middle cerebral artery blood flow abnormality detection using flow velocity waveform derived from transcranial Doppler ultrasound

Since the brain is unlike any other organ in that it cannot store energy and has a high metabolic demand, constant blood flow is essential for healthy brain function. The maximum flow velocity waveform that is produced by transcranial doppler echo ultrasonography has different qualities for a healthy subject and a critically ill patient with conditions such as intraparenchymal or subarachnoid hemorrhage, hydrocephalus, or traumatic brain injury. Depending on the degree of the injury, the symptoms of traumatic brain damage can present themselves right away or not until days or weeks later. To aid in the early and accurate detection of patients with severe brain conditions, a classification system is proposedthat can distinguish between healthy control and patient utilizing the maximum flow velocity waveform derived from Transcranial doppler ultrasound. In this research, we manually labelled the data to remove mediocre and corrupted signals and pre-processed low-quality signals into high-quality ones using a Cycle Generative Adversarial Network (CycleGAN). This study proposes a two-stream deep learning model, DopplerNet2+, based on a Self-organized Operational Neural Network (Self-ONN), which achieves an overall accuracy, precision, recall, sensitivity, f1 score, and specificity of 99.45%, 99.45%, 99.45%, and 99.37% for the classification issue. DopplerNet2+ has a better area under the curve (AUC) of 1.00 and a better Kolmogorov-Smirnov (KS) statistic of 0.996 at the 0.812 thresholds than 11 other Self-ONN models trained with different inputs. The results show that the proposed models can successfully carry out the targeted classification task.

Regulation of the Blood-Brain Barrier in Health and Disease.

The neurovascular unit is a dynamic microenvironment with tightly controlled signaling and transport coordinated by the blood-brain barrier (BBB). A properly functioning BBB allows sufficient movement of ions and macromolecules to meet the high metabolic demand of the central nervous system (CNS), while protecting the brain from pathogenic and noxious insults. This review describes the main cell types comprising the BBB and unique molecular signatures of these cells. Additionally, major signaling pathways for BBB development and maintenance are highlighted. Finally, we describe the pathophysiology of BBB diseases, their relationship to barrier dysfunction, and identify avenues for therapeutic intervention.