Compensatory Response Research Articles

The potential for predicting neonatal disabilities in preterm infants

The urgent task of modern pediatricians and neonatologists is to predict the course of the early neonatal period, during which the basic adaptive mechanisms of newborn children are in an unstable state. This is particularly important for the study of premature newborns, who are at high risk for an unfavorable outcome.Purpose. The aim of this study was to investigate the nature of early neonatal adaptation in children born between 32- and 36-weeks’ gestation, from mothers with burdened obstetric and gynecological histories and concomitant medical conditions.Material and methods. Out of 75 patients, we divided children born against a background of placental abruption and pre-eclampsia into separate groups. We provide a comparative analysis of their obstetric, gynecological, and medical histories, as well as their pre-dictive factors, somatic status dynamics, and laboratory and instrumental examinationsResults. Analysis of the data showed that in late preterm newborns, the presence of placental abruption in the history of 100% of cases led to the development of general somatic distress, with deterioration in hemodynamic and respiratory parameters, requiring transfer to the second phase of care. In children born preterm due to severe preeclampsia or other causes, stable severe conditions were observed in 33.3 and 39.6%, respectively, and 53.9 to 60% of infants required respiratory support.Conclusion. These findings allow for individualized assessment of a newborn’s condition in the first few days of life, based on predictive factors that may lead to a breakdown in compensatory responses.

ETIOPATHOGENETIC MECHANISMS OF IMMUNE DYSFUNCTION IN COMBATANTS WITH LOWER LIMB SOFT TISSUE INJURIES UNDER CHRONIC STRESS

Introduction. Combat injuries, including gunshot, shrapnel, and mine-explosive wounds, affect a significant number of soldiers in modern warfare. Notably, most of these injuries involve damage to the soft tissues of the extremities. Surgeons have expressed concerns regarding the unsatisfactory treatment outcomes in this group of combatants, attributing one of the primary challenges to the limited understanding of immune dysfunction pathogenesis in military trauma cases. This study aims to address this gap by examining immune system dysfunctions in combat-related injuries. The objective of this study is to thoroughly analyze and synthesize the key stages of immune dysfunction occurring over extended periods post-combat trauma, including the subsequent development of traumatic disease and various wound complications. Materials and Methods. The rising prevalence of combat trauma among soldiers has intensified interest in studying this issue, prompting surgeons and traumatologists to address its various medical aspects comprehensively. The literature search focused on recent publications, allowing for a targeted analysis of the immunological aspects relevant to military medical traumatology. Results. In the initial stages of severe or combined injuries affecting various tissues—such as tubular bones, joints, blood vessels, and peripheral nerves—systemic inflammatory response syndrome (SIRS) commonly occurs. This stage is marked by an intense activation of innate antibacterial and immune-protective responses, leading to a significant increase in inflammation. This initial response is soon replaced by a prolonged phase known as compensatory anti-inflammatory response syndrome. During this period, immune-protective responses sharply decrease, certain immunocompetent cells become inhibited, and lymphopenia develops. This phase is often accompanied by infectious contamination of wounds with pathogenic and opportunistic microorganisms, resulting in both local purulent-necrotic processes and potentially severe systemic complications, such as septic shock, sepsis, multiple organ failure, and others. The final stage, known as persistent inflammatory, immunosuppressive, catabolic syndrome, is characterized by the chronic progression of traumatic disease, accompanied by ongoing immune system dysfunction in combatants. Conclusion. In the early period of traumatic injury, the wounded experience sharp inflammatory processes and activation of immune defense mechanisms. At subsequent stages, severe disruptions in the functioning of the immune system, damage to internal organs, and the development of catabolic syndrome are recorded. These changes, especially those resulted from exposure to chronic combat stress preceding the injury, aggravate the processes of infectious decontamination of wounds, regeneration of damaged tissues, and the general process of combatant rehabilitation.

Plasma essential amino acid levels in first episode psychosis at baseline and after antipsychotic treatment

This study assessed plasma levels of essential amino acids (EAA) in drug-naïve first episode psychosis (FEP) patients at diagnosis and after 10 weeks of antipsychotic treatment. Forty FEP patients were enrolled at baseline, with blood samples collected before and after a 10-week antipsychotic treatment period. Plasma EAA levels were measured using an LC/MS/MS method. Psychotic symptoms were evaluated using standardized inventories before and after treatment. A decrease in BPRS score of more than 40% was used to indicate treatment response. Thirty-five healthy volunteers served as the control group. Baseline plasma levels of Thr, Met, Leu, Lys, His, and Tyr were higher in FEP patients than in healthy controls. After 10 weeks of treatment, Leu, His, and Tyr increased further, primarily in treatment-responsive patients. Conversely, Val level was lower than controls in patients at baseline and remained unchanged after treatment. Increased EAA levels were correlated with lower (less severe) scores in positive symptom scales. Treatment non-responders had persistently low Tyr/large neutral amino acid (LNAA) ratio. Tyr/LNAA ratio increased after treatment, specifically in treatment-responders. Phe/Tyr ratio decreased post-treatment in both responder and non-responder groups. Elevated EAA levels in FEP patients may signify compensatory responses to increased physiological demand for neurotransmitters or energy. Combining specific EAA supplementation with antipsychotic treatment may enhance treatment response in these patients.

NMDA receptors regulate the firing rate set point of hippocampal circuits without altering single-cell dynamics.

Understanding how neuronal circuits stabilize their activity is a fundamental yet poorly understood aspect of neuroscience. Here, we show that hippocampal network properties, such as firing rate distribution and dimensionality, are actively regulated, despite perturbations and single-cell drift. Continuous inhibition of N-methyl-D-aspartate receptors (NMDARs) exvivo lowers the excitation/inhibition ratio and network firing rates while preserving resilience to perturbations. This establishes a new network firing rate set point via NMDAR-eEF2K signaling pathway. NMDARs' capacity to modulate and stabilize network firing is mediated by excitatory synapses and the intrinsic excitability of parvalbumin-positive neurons, respectively. In behaving mice, continuous NMDAR blockade in CA1 reduces network firing without altering single-neuron drift or triggering a compensatory response. These findings expand NMDAR function beyond their canonical role in synaptic plasticity and raise the possibility that some NMDAR-dependent behavioral effects are mediated by their unique regulation of population activity set points.

From oxygen shortage to neurocognitive challenges: behavioral patterns and imaging insights

Environmental hypoxia, resulting from reduced oxygen supply, poses a significant risk of dysfunctioning and damaging the neurocognitive system, particularly in relation to anxiety and stress. Inadequate oxygenation can lead to acute and chronic brain damage. Scholars used behavioral, hemodynamic, and electromagnetic neurofunctional techniques to investigate the effects of normobaric and hypobaric hypoxia on neurocognitive systems. They found a correlation between hypoxia, altered psychomotor responses, and changes in EEG alpha, theta, beta, and gamma rhythms, which affect spatial attention and memory. Hypoxia affects event related potential (ERP) components differently depending on latency. Perceptual responses N1 and P2 remain largely unaffected, while the amplitudes of preattentive MMN, vMMN, and P3a are significantly altered. Late latency components related to attention, particularly P3b, are also altered. These changes illustrate the spectrum from sensory detection to more complex cognitive processing, highlighting the brain's efficiency in managing information. Interestingly, the amplitudes of P3b, ADAN and CNV can increase with increased cognitive demands in hypoxia. This suggests a compensatory response. Prolonged exposure exacerbates these effects, resulting in compensatory delayed behavioral responses and alterations in behavioral monitoring and conflict inhibitory control, as reflected by reduced amplitudes in some attention related ERP components, including N2, N2pc, and ERN. Thus, neurocognitive function and integrity are under stress. ERP sources and hemodynamic images reveal that vulnerable brain regions include the frontal prefrontal cortices, hippocampus, basal ganglia, and parietal and visual cortices, which are essential for attention related processes like decision making and spatial memory. The auditory system appears less affected.

Hibernation reduces GABA signaling in the brainstem to enhance motor activity of breathing at cool temperatures

BackgroundNeural circuits produce reliable activity patterns despite disturbances in the environment. For this to occur, neurons elicit synaptic plasticity during perturbations. However, recent work suggests that plasticity not only regulates circuit activity during disturbances, but these modifications may also linger to stabilize circuits during future perturbations. The implementation of such a regulation scheme for real-life environmental challenges of animals remains unclear. Amphibians provide insight into this problem in a rather extreme way, as circuits that generate breathing are inactive for several months during underwater hibernation and use compensatory plasticity to promote ventilation upon emergence.ResultsUsing ex vivo brainstem preparations and electrophysiology, we find that hibernation in American bullfrogs reduces GABAA receptor (GABAAR) inhibition in respiratory rhythm generating circuits and motor neurons, consistent with a compensatory response to chronic inactivity. Although GABAARs are normally critical for breathing, baseline network output at warm temperatures was not affected. However, when assessed across a range of temperatures, hibernators with reduced GABAAR signaling had greater activity at cooler temperatures, enhancing respiratory motor output under conditions that otherwise strongly depress breathing.ConclusionsHibernation reduces GABAAR signaling to promote robust respiratory output only at cooler temperatures. Although frogs do not ventilate lungs during underwater hibernation, we suggest this would be beneficial for stabilizing breathing when the animal passes through a large temperature range during emergence in the spring. More broadly, these results demonstrate that compensatory synaptic plasticity can increase the operating range of circuits in harsh environments, thereby promoting adaptive behavior in conditions that suppress activity.

A novel (-)-(2S)-7,4'-dihydroxyflavanone compound for treating age-related diabetes mellitus through immunoinformatics-guided activation of CISD3.

The iron-sulfur domain (CISD) proteins of CDGSH are classified into three classes: CISD1, CISD2, and CISD3. During premature ageing, mutations that affect these proteins, namely their binding sites, could result in reduced protein production and an inability to preserve cellular integrity. Consequently, this leads to the development of conditions such as diabetes. Notably, CISD3 plays a crucial role in the management of age-related disorders such as Wolfram syndrome, which is often referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Computational analyses have predicted that CISD3 regulates the redox state, safeguards the endoplasmic reticulum and mitochondria, and maintains intracellular calcium levels. CISD3, a member of a recently discovered gene family associated with the CDGSH iron protein apoptotic compensatory response, fulfils a crucial function in mitigating the effects of accelerated ageing. The compound "(-)-(2S)-7,4'-Dihydroxyflavanone" has been discovered by computational drug design as a possible activator of CISD3. It shows potential therapeutic benefits in ameliorating metabolic dysfunction and enhancing glucose regulation. The ligand binds to the binding pocket of the CISD3 protein, increasing the stability of the protein and enhancing its functionality. The current research investigates the binding processes of the molecule in various structures and its anticipated effects on these tissues, therefore providing valuable insights into the mitigation of age-related diabetes and metabolic dysfunction. The projected tripling of the worldwide population of individuals aged 50 and above by 2050 necessitates the urgent development of immunoinformatics-based approaches, including pharmaceutical therapies that target CISD3, to prevent age-related pathologies. The stimulation of CISD3, namely by compounds such as "(-)-(2S)-7,4'-Dihydroxyflavanone", has the potential to counteract telomere shortening and improve metabolic pathways.

Amino Acid Deprivation in Glioblastoma: The Role in Survival and the Tumour Microenvironment—A Narrative Review

Background: Glioblastoma is the most common and aggressive primary brain tumour, characterised by its invasive nature and complex metabolic profile. Emerging research highlights the role of amino acids (AAs) in glioblastoma metabolism, influencing tumour growth and the surrounding microenvironment. Methods: This narrative review synthesises recent pre-clinical studies focusing on the metabolic functions of AAs in glioblastoma. Key areas include the effects of AA deprivation on tumour growth, adaptive mechanisms, and the tumour microenvironment. Results: The effects related to arginine, glutamine, methionine, and cysteine deprivation have been more extensively reported. Arginine deprivation in arginine-auxotrophic glioblastomas induces apoptosis and affects cell adhesion, while glutamine deprivation disrupts metabolic pathways and enhances autophagy. Methionine and cysteine deprivation impact lipid metabolism and ferroptosis. Tumour adaptive mechanisms present challenges, and potential compensatory responses have been identified. The response of the microenvironment to AA deprivation, including immune modulation, is critical to determining therapeutic outcomes. Conclusions: Targeting AA metabolism offers a promising approach for glioblastoma treatment, with potential targeted drugs showing clinical promise. However, the complexity of tumour adaptive mechanisms and their impact on the microenvironment necessitates further research to optimise combination therapies and improve therapeutic efficacy.

Photosynthetic Electron Flows and Networks of Metabolite Trafficking to Sustain Metabolism in Photosynthetic Systems.

Photosynthetic eukaryotes have metabolic pathways that occur in distinct subcellular compartments. However, because metabolites synthesized in one compartment, including fixed carbon compounds and reductant generated by photosynthetic electron flows, may be integral to processes in other compartments, the cells must efficiently move metabolites among the different compartments. This review examines the various photosynthetic electron flows used to generate ATP and fixed carbon and the trafficking of metabolites in the green alga Chlamydomomas reinhardtii; information on other algae and plants is provided to add depth and nuance to the discussion. We emphasized the trafficking of metabolites across the envelope membranes of the two energy powerhouse organelles of the cell, the chloroplast and mitochondrion, the nature and roles of the major mobile metabolites that move among these compartments, and the specific or presumed transporters involved in that trafficking. These transporters include sugar-phosphate (sugar-P)/inorganic phosphate (Pi) transporters and dicarboxylate transporters, although, in many cases, we know little about the substrate specificities of these transporters, how their activities are regulated/coordinated, compensatory responses among transporters when specific transporters are compromised, associations between transporters and other cellular proteins, and the possibilities for forming specific 'megacomplexes' involving interactions between enzymes of central metabolism with specific transport proteins. Finally, we discuss metabolite trafficking associated with specific biological processes that occur under various environmental conditions to help to maintain the cell's fitness. These processes include C4 metabolism in plants and the carbon concentrating mechanism, photorespiration, and fermentation metabolism in algae.

The oncogenic axis YAP/MYC/EZH2 impairs PTEN tumor suppression activity enhancing lung tumorigenicity

The tumor suppressor PTEN (phosphatase and tensin homolog deleted in chromosome 10) is genetically deleted or downregulated in many cancer types. Loss of PTEN protein expression is frequently found in lung cancer while genetic alterations are less abundant. PTEN expression is regulated at multiple genetic and epigenetic levels and even partial reduction of its expression increases cancer occurrence. We show that YAP and TAZ cooperate with EZH2, and MYC to transcriptionally repress onco-suppressor genes, including PTEN, in non-small cell lung cancer (NSCLC) cells. YAP/TAZ-EZH2-MYC transcriptional regulators form a nuclear complex that represses PTEN transcription, while their combinatorial targeting restores PTEN expression, attenuates NSCLC cell growth, and prevents compensatory responses induced by single treatments. Datasets analysis of NSCLC patients revealed that PTEN expression is negatively correlated to YAP/TAZ, EZH2 and MYC and that low expression of PTEN is predictive of poor prognosis, especially at earlier stages of the disease. These findings highlight the repressive role of the YAP/TAZ-EZH2-MYC axis on tumor-suppressor genes and offer a potential therapeutic strategy for lung cancer patients with low PTEN levels.

Inhibiting mtDNA transcript translation alters Alzheimer's disease-associated biology.

Alzheimer's disease (AD) features changes in mitochondrial structure and function. Investigators debate where to position mitochondrial pathology within the chronology and context of other AD features. To address whether mitochondrial dysfunction alters AD-implicated genes and proteins, we treated SH-SY5Y cells and induced pluripotent stem cell (iPSC)-derived neurons with chloramphenicol, an antibiotic that inhibits mtDNA-generated transcript translation. We characterized adaptive, AD-associated gene, and AD-associated protein responses. SH-SY5Y cells and iPSC neurons responded to mtDNA transcript translation inhibition by increasing mtDNA copy number and transcription. Nuclear-expressed respiratory chain mRNA and protein levels also changed. There were AD-consistent concordant and model-specific changes in amyloid precursor protein, beta amyloid, apolipoprotein E, tau, and α-synuclein biology. Primary mitochondrial dysfunction induces compensatory organelle responses, changes nuclear gene expression, and alters the biology of AD-associated genes and proteins in ways that may recapitulate brain aging and AD molecular phenomena. In AD, mitochondrial dysfunction could represent a disease cause or consequence. We inhibited mitochondrial translation in human neuronal cells and neurons. Mitochondrial and nuclear gene expression shifted in adaptive-consistent patterns. APP, Aβ, APOE, tau, and α-synuclein biology changed in AD-consistent patterns. Mitochondrial stress creates an environment that promotes AD pathology.

Data-independent acquisition proteomic analysis of the brain microvasculature in Alzheimer’s disease identifies major pathways of dysfunction and upregulation of cytoprotective responses

Brain microvascular dysfunction is an important feature of Alzheimer’s disease (AD). To better understand the brain microvascular molecular signatures of AD, we processed and analyzed isolated human brain microvessels by data-independent acquisition liquid chromatography with tandem mass spectrometry (DIA LC–MS/MS) to generate a quantitative dataset at the peptide and protein level. Brain microvessels were isolated from parietal cortex grey matter using protocols that preserve viability for downstream functional studies. Our cohort included 23 subjects with clinical and neuropathologic concordance for Alzheimer’s disease, and 21 age-matched controls. In our analysis, we identified 168 proteins whose abundance was significantly increased, and no proteins that were significantly decreased in AD. The most highly increased proteins included amyloid beta, tau, midkine, SPARC related modular calcium binding 1 (SMOC1), and fatty acid binding protein 7 (FABP7). Additionally, Gene Ontology (GO) enrichment analysis identified the enrichment of increased proteins involved in cellular detoxification and antioxidative responses. A systematic evaluation of protein functions using the UniProt database identified groupings into common functional themes including the regulation of cellular proliferation, cellular differentiation and survival, inflammation, extracellular matrix, cell stress responses, metabolism, coagulation and heme breakdown, protein degradation, cytoskeleton, subcellular trafficking, cell motility, and cell signaling. This suggests that AD brain microvessels exist in a stressed state of increased energy demand, and mount a compensatory response to ongoing oxidative and cellular damage that is associated with AD. We also used public RNAseq databases to identify cell-type enriched genes that were detected at the protein level and found no changes in abundance of these proteins between control and AD groups, indicating that changes in cellular composition of the isolated microvessels were minimal between AD and no-AD groups. Using public data, we additionally found that under half of the proteins that were significantly increased in AD microvessels had concordant changes in brain microvascular mRNA, implying substantial discordance between gene and protein levels. Together, our results offer novel insights into the molecular underpinnings of brain microvascular dysfunction in AD.

Altered Proteasome Composition in Aging Brains, Genetic Proteasome Augmentation Mitigates Age-Related Cognitive Declines, and Acute Proteasome Agonist Treatment Rescues Age-Related Cognitive Deficits in Mice.

The aging brain experiences a significant decline in proteasome function, The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains driven by reduced functionality of aged proteasome. This is matched by a decline in 20S proteasome but an increase in 26S proteasome. Our data suggests this may be a compensatory response to reduced functionality. By overexpressing the proteasome subunit PSMB5 in the neurons of mice, enhancing proteasome function, we slowed age-related declines in spatial learning and memory as well neuromuscular declines. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.

Neuronal alterations in AKT isotype expression in schizophrenia.

Schizophrenia is characterized by substantial alterations in brain function, and previous studies suggest insulin signaling pathways, particularly involving AKT, are implicated in the pathophysiology of the disorder. This study demonstrates elevated mRNA expression of AKT1-3 in neurons from schizophrenia subjects, contrary to unchanged or diminished total AKT protein expression reported in previous postmortem studies, suggesting a potential decoupling of transcript and protein levels. Sex-specific differential AKT activity was observed, indicating divergent roles in males and females with schizophrenia. Alongside AKT, upregulation of PDPK1, a critical component of the insulin signaling pathway, and several protein phosphatases known to regulate AKT were detected. Moreover, enhanced expression of the transcription factor FOXO1, a regulator of glucose metabolism, hints at possible compensatory mechanisms related to insulin signaling dysregulation. Findings were largely independent of antipsychotic medication use, suggesting inherent alterations in schizophrenia. These results highlight the significance of AKT and related signaling pathways in schizophrenia, proposing that these changes might represent a compensatory response to a primary defect of canonical insulin signaling pathways. This research underscores the need for a detailed understanding of these signaling pathways for the development of effective therapeutic strategies.

An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease.

Tubular aggregate myopathy (TAM) is a heritable myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates (TAs). Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca2+ entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.

Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension.

Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare. We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics. We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN, coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-β/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH. Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.

Profiling growth performance, insulin-like growth factors (IGFs), and IGF-binding proteins (IGFBPs) in rainbow trout lacking IGFBP-2b.

Insulin-like growth factor binding proteins (IGFBP) regulate insulin-like growth factor (IGF) signaling, but IGFBP-specific functions are not well characterized in fishes. A line of rainbow trout (Oncorhynchus mykiss) lacking a functional IGFBP-2b was produced using gene editing and subsequent breeding to an F2 generation. This loss-of-function model (2bKO) was subjected to either continuous feeding or feed deprivation (3 wk) followed by refeeding (1 wk). During continuous feeding, the 2bKO line displayed faster specific growth rate for both body weight and fork length, higher feed intake, and reduced feed conversion ratio compared to a wild type (WT) line. However, loss of IGFBP-2b did not affect the feed deprivation or refeeding response in terms of weight loss or weight gain, respectively. Several components of the IGF/IGFBP system were affected by loss of IGFBP2b. Total serum IGF-1 in the 2bKO line was reduced to 0.5 - 0.8-fold of the WT line although the concentration of free serum IGF-1 was not affected. Gene expression differences include reduced abundance of igfbp1a1, igfbp1b2, igfbp5b2, and igfbp6b1 transcripts, and elevated igf2 and igfbp6b2 transcripts in liver of the 2bKO line. Collectively, these findings suggest that although IGFBP-2b is a carrier of circulating IGF-1 in salmonids, the presence of IGFBP-2a and compensatory responses of other IGF/IGFBP system components support an anabolic response that improved growth performance in the loss-of-function model.

Vitamin D-Parathyroid Hormone-Fibroblast Growth Factor 23 Axis and Cardiac Remodeling.

Cardiac remodeling is a compensatory adaptive response to chronic heart failure (HF) altering the structure, function, and metabolism of the heart. Many nutritional and metabolic diseases can aggravate the pathophysiological development of cardiac remodeling. Vitamin D deficiency leads to cardiac remodeling by activating the renin-angiotensin-aldosterone system (RAAS), resulting in enhanced inflammation and directly promoting cardiac fibrosis and extracellular matrix deposition. Hyperparathyroidism upregulates protein kinase A or protein kinase C, enhances intracellular calcium influx, promotes oxidative stress, activates RAAS, and increases aldosterone levels, thereby aggravating cardiac remodeling. Besides, fibroblast growth factor 23 (FGF23) plays a direct role in the heart, resulting in ventricular hypertrophy and myocardial fibrosis. Vitamin D deficiency leads to hyperparathyroidism, which in turn increases the level of FGF23. Elevated levels of FGF23 further inhibit vitamin D synthesis. Evidence exists that vitamin D deficiency, hyperparathyroidism, and marked elevations in FGF23 concentration form a vicious cycle and are believed to contribute directly to cardiac remodeling. Therefore, the purpose of this article is to introduce the specific effects of the above substances on the heart and to explain the significance of understanding the vitamin D-parathyroid hormone-FGF23 axis in improving or even reversing cardiac remodeling, thus contributing to the treatment of patients with HF.

Bayesian inference of state feedback control parameters for fo perturbation responses in cerebellar ataxia.

Behavioral speech tasks have been widely used to understand the mechanisms of speech motor control in typical speakers as well as in various clinical populations. However, determining which neural functions differ between typical speakers and clinical populations based on behavioral data alone is difficult because multiple mechanisms may lead to the same behavioral differences. For example, individuals with cerebellar ataxia (CA) produce atypically large compensatory responses to pitch perturbations in their auditory feedback, compared to typical speakers, but this pattern could have many explanations. Here, computational modeling techniques were used to address this challenge. Bayesian inference was used to fit a state feedback control (SFC) model of voice fundamental frequency (fo) control to the behavioral pitch perturbation responses of speakers with CA and typical speakers. This fitting process resulted in estimates of posterior likelihood distributions for five model parameters (sensory feedback delays, absolute and relative levels of auditory and somatosensory feedback noise, and controller gain), which were compared between the two groups. Results suggest that the speakers with CA may proportionally weight auditory and somatosensory feedback differently from typical speakers. Specifically, the CA group showed a greater relative sensitivity to auditory feedback than the control group. There were also large group differences in the controller gain parameter, suggesting increased motor output responses to target errors in the CA group. These modeling results generate hypotheses about how CA may affect the speech motor system, which could help guide future empirical investigations in CA. This study also demonstrates the overall proof-of-principle of using this Bayesian inference approach to understand behavioral speech data in terms of interpretable parameters of speech motor control models.

Hibernation reduces GABA signaling in the brainstem to enhance motor activity of breathing at cool temperatures.

Neural circuits produce reliable activity patterns despite disturbances in the environment. For this to occur, neurons elicit synaptic plasticity during perturbations. However, recent work suggests that plasticity not only regulates circuit activity during disturbances, but these modifications may also linger to stabilize circuits during future perturbations. The implementation of such a regulation scheme for real-life environmental challenges of animals remains unclear. Amphibians provide insight into this problem in a rather extreme way, as circuits that generate breathing are inactive for several months during underwater hibernation and use compensatory plasticity to promote ventilation upon emergence. Using ex vivo brainstem preparations and electrophysiology, we find that hibernation in American bullfrogs reduces GABA A receptor (GABA A R) inhibition in respiratory rhythm generating circuits and motor neurons, consistent with a compensatory response to chronic inactivity. Although GABA A Rs are normally critical for breathing, baseline network output at warm temperatures was not affected. However, when assessed across a range of temperatures, hibernators with reduced GABA A R signaling had greater activity at cooler temperatures, enhancing respiratory motor output under conditions that otherwise strongly depress breathing. Hibernation reduces GABA A R signaling to promote robust respiratory output only at cooler temperatures. Although animals do not ventilate lungs during hibernation, we suggest this would be beneficial for stabilizing breathing when the animal passes through a large temperature range during emergence in the spring. More broadly, these results demonstrate that compensatory synaptic plasticity can increase the operating range of circuits in harsh environments, thereby promoting adaptive behavior in conditions that suppress activity.