Recent multi-omics work shows that the diurnal rhythmicity of kidney function is associated with circadian oscillations in renal mRNA, protein and metabolite abundances. Yet circadian regulation of renal lncRNAs, which a...Recent multi-omics work shows that the diurnal rhythmicity of kidney function is associated with circadian oscillations in renal mRNA, protein and metabolite abundances. Yet circadian regulation of renal lncRNAs, which are emerging as important modulators of diverse (patho)physiological processes, remains largely unexplored. Here, we provide a comprehensive characterization of renal lncRNA expression across cell types and circadian time points using bulk RNA-Seq and single-nucleus RNA-Seq (snRNA-seq) using kidney samples from male mice. Although the majority of lncRNAs are lowly expressed and only a fraction are annotated, their profiles sufficed to distinguish nearly all renal cell types. Compared with mRNAs, lncRNAs were more cell-type specific and an inverse correlation between cell-type specificity and expression level was evident. To assess the role of the circadian clock, we used mice lacking the core-clock regulator BMAL1 in renal tubules. Approximately one-sixth of lncRNAs and one-third of mRNAs were rhythmic. In contrast with mRNAs, lncRNAs exhibited an asymmetric temporal distribution between night and day, with peak expression occurring preferentially during the inactive phase of the mice. Bmal1 deletion partially disrupted rhythmicity in both biotypes and altered overall expression levels; lncRNAs were predominantly upregulated. These findings uncover the diversity of renal lncRNAs, their cellular distribution and their circadian regulation in male mice.
Valero-Breton M, Portal-Rodriguez M, Tacchi F
… +10 more, Salgado-Valdovinos J, Miranda-Pilar MC, Cifuentes-Silva E, Martínez-Pérez MI, Godoy M, Bonicioli J, Olguin H, Peñailillo L, Soto JA, Cabello-Verrugio C
BACKGROUND: Resistance training has been shown to activate the protein synthesis pathway, leading to muscle growth in humans. However, this type of exercise has shown equivocal results in animal studies due to the diffic...BACKGROUND: Resistance training has been shown to activate the protein synthesis pathway, leading to muscle growth in humans. However, this type of exercise has shown equivocal results in animal studies due to the difficulty of mimicking muscle overload in vivo. This study aimed to determine whether ladder-based exercise in mice induces canonical molecular, cellular, and functional adaptations to training. METHODS: Mice performed a single exercise session or 6 weeks of training in the ladder climb. Acute responses included mTOR phosphorylation, puromycin incorporation, and mRNA levels of myogenic regulatory factors (MRF). Chronic adaptations were assessed by strength, fat-free mass, physical performance, and blood lactate levels to confirm the training load. Sarcomeric proteins were analyzed using Western blot, while histology measured muscle fiber diameter and satellite cell (SC) fusion. The SC amount was quantified by flow cytometry. RESULTS: After a single exercise bout, mTOR phosphorylation increased at one and 3 h, with puromycin incorporation and MRF mRNA levels elevated at 8 h. After 6 weeks of training, the mice showed increased skeletal muscle strength and fat-free mass, with no changes in physical performance. Muscle-specific adaptations included increases in sarcomeric proteins and fiber diameters. SC adaptations were associated with an increased pool and enhanced capacity to fuse with muscle fibers. CONCLUSIONS: Our results demonstrate that ladder-based resistance exercise in mice induces molecular, cellular, and functional responses that are directionally consistent with adaptations reported after human resistance training, supporting its value for investigating the molecular and cellular mechanisms underlying this training.
AIM: The mammalian tracheal epithelium is composed of different cell types distributed along the proximal-distal axis. Nevertheless, variations in expression and function of ion channels and transporters participating in...AIM: The mammalian tracheal epithelium is composed of different cell types distributed along the proximal-distal axis. Nevertheless, variations in expression and function of ion channels and transporters participating in fluid absorption and secretion have never been studied separately in proximal and distal mouse trachea. This work aims to characterize basal and stimulated absorption and secretion of fluid obtained from proximal and distal trachea from the same animal. METHODS: Ussing chamber was performed using a custom-made tissue slider allowing small tracheal sections mounting, where response to agonists and blockers was recorded. The role of NKCC1 co-transporter was studied using the Slc12a2 mouse. A genetically tomato-induced mouse model was used to assess co-expression of NKCC1 and ASCL3 by immunofluorescence. Animals were instilled with interleukins (ILs) to determine changes in absorption, secretion, and mucus properties. RESULTS: Proximal trachea didn't participate in sodium absorption but exhibited higher cAMP- and succinate-induced anion secretion than the distal section. NBCe1-dependent bicarbonate and TMEM16A-driven chloride secretion were significantly higher in distal trachea. NKCC1+ cells were found in the submucosal glands (SMGs) and abundant patches of NKCC1+ cells in the distal region. Isolated NKCC1+ cells co-expressing ASCL3 were also detected. ILs treatment changed the electrophysiological properties of the distal trachea exclusively. CONCLUSIONS: Our experiments determined that the mouse trachea organizes its functions differentially in proximal and distal regions, based on the functional distribution of channels, transporters, and receptors. While the distal trachea changed its responses to agonists inducing anion secretion, the proximal trachea was unperturbed by ILs addition.
Ribeiro F, Di Geronimo B, Cacciani N
… +7 more, Widgren A, Hedström Y, Moriscot AS, Kasson PM, Kamerlin SCL, Bergquist J, Larsson L
Acta Physiol (Oxf)
· 2026 Jul · PMID 42316426
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BACKGROUND: Critical illness myopathy is a common and devastating consequence of critical care, causing dramatic loss of muscle mass and function in intensive care unit patients. Functional deficits often exceed the loss...BACKGROUND: Critical illness myopathy is a common and devastating consequence of critical care, causing dramatic loss of muscle mass and function in intensive care unit patients. Functional deficits often exceed the loss in muscle mass and myosin content. However, the mechanisms underlying the loss of force and emergence of myosin-expressing non-force-generating fibers remain elusive. METHODS: Myosin dysfunction was investigated in six intensive care unit patients exposed to a 12-day mechanical ventilation and immobilization period using mass spectrometry-based proteomics and molecular dynamics simulations. RESULTS: Previous single muscle fiber analyses revealed decreased fiber size and specific force from the 1st to the 12th days in all patients. A subset of myosin-expressing fibers exhibiting a complete loss of contractile function was identified in three of the patients despite similar atrophy levels (~30%, p < 0.05) after 12 days. All fibers had decreased specific force after 12 days of mechanical ventilation, but 9% to 21% of the fibers were non-force generating. The decline in specific force was linked to 27 post-translational myosin modifications, including oxidation, ubiquitination, acetylation, and methylation. Molecular dynamics simulations indicated oxidation-induced rigidity of the myosin head, predicted to compromise the flexibility of the actin-binding and converter domains. Non-force-generating fibers exhibited a unique proteomic signature predicted to enhance myosin motor domain exposure and rigidity. CONCLUSION: In addition to muscle wasting and myosin loss, abnormal myosin post-translational modifications contribute to muscle weakness in ICU patients with CIM, including the development of muscle fibers incapable of generating contractile force.
Menzel M, Dumitru ID, Peters J
… +4 more, Hövener JB, Pravdivtsev AN, Bondar AN, Beitz E
Acta Physiol (Oxf)
· 2026 Jul · PMID 42289603
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AIM: Human monocarboxylate transporters 1-4, MCT, are key for the lactate/H exchange between glycolytic and oxidative cancer cells, white and red muscle fibers, or in the astrocyte-neuron shuttle. The common MCT transpor...AIM: Human monocarboxylate transporters 1-4, MCT, are key for the lactate/H exchange between glycolytic and oxidative cancer cells, white and red muscle fibers, or in the astrocyte-neuron shuttle. The common MCT transport mechanism involves three conserved residues, that is, a substrate-attracting Lys and a conformation-locking Asp/Arg salt bridge (positions 38 and 309/313 in MCT1). Yet, it remained unclear which sites define isoform-specific substrate affinity and preferred transport directionality. METHODS: Here, we analyzed structural differences in the binding sites of MCT1-4 and determined their impact on the biophysical transport properties and inhibitor binding using radiolabeled transport assays in yeast. RESULTS: We found differences in amino acid positions with sidechain hydroxyl groups. While the higher affinity MCT1 and MCT2 carry Phe/Ser-OH (pos. 367/371 in MCT1), the lower affinity MCT3 and MCT4 have Tyr-OH/Gly. Mutation of Phe/Ser-OH in MCT1 to Tyr-OH/Gly markedly decreased the affinity for lactate and pyruvate, while it did not change the affinity for propionate. The maximal transport velocity increased with decreasing affinity, and the preferred transport directionality shifted toward export. Likewise, replacing Met151 by Ala shifted transport bias possibly by eliminating conformation-stabilizing sulfur-aromatic interactions. Moreover, these mutations lowered the activity of the clinical candidate MCT1 inhibitor AZD3965 by three orders of magnitude providing insight into the molecular drug binding mode and explaining the strong preference for MCT1 over MCT4. CONCLUSIONS: Together, subtle changes in the arrangement of sidechains in the MCT binding site determine basic monocarboxylate/H transport properties that impact lactate-related physiology, namely cellular metabolism, reprogramming, and signaling.
Excessive extracellular accumulation of K plays a key role in the induction and propagation of seizures associated with temporal lobe epilepsy (TLE), and astrocytes are largely responsible for K clearance from the extrac...Excessive extracellular accumulation of K plays a key role in the induction and propagation of seizures associated with temporal lobe epilepsy (TLE), and astrocytes are largely responsible for K clearance from the extracellular space. Here, we review the TLE-related changes in the content and/or activity of proteins contributing to K transport across the astrocytic cell membranes. Seizures, whether genetic or acquired, are linked with decreased expression and/or mislocalization of the two key astroglia-specific drivers of K uptake: the inward rectifying potassium channel K4.1 and its spatial and functional partner, the water channel aquaporin 4 (AQP4). Among neural cells of the CNS, the high K-responsive α2 isoform of Na/K-ATPase is specific for astrocytes and is substantially inactivated in the brains of TLE patients and experimental animals, albeit not always in epilepsies with a genetic background. The above data consistently support the involvement of malfunctional astrocytic K transport as a factor facilitating seizures. By contrast, complex and variable, region-dependent dynamics of the two-pore domain potassium channels (K2P; TWIK, TASK, and TREK) were observed in astrocytes in the hippocampus, rendering their contribution to seizures difficult to interpret. Anti-seizure medication targeting metabolic processes not directly related to astrocytic K transport often reversed the unfavorably changed status of the astrocytic mediators of K buffering.
AIM: Standard laboratory housing (21°C) imposes chronic cold stress on mice, yet its fundamental impact on cardiac plasticity remains poorly defined. We systematically interrogated how environmental temperature dictates...AIM: Standard laboratory housing (21°C) imposes chronic cold stress on mice, yet its fundamental impact on cardiac plasticity remains poorly defined. We systematically interrogated how environmental temperature dictates cardiac responses to endurance exercise, doxorubicin (DOX)-induced cardiotoxicity, and aging. METHODS: Male mice were housed at standard room temperature (RT) or thermoneutrality (30°C, TN) and subjected to exercise, detraining, DOX treatment, or natural aging. Cardiac remodeling was evaluated by integrating physiological phenotyping (echocardiography, body composition) with comprehensive transcriptomic and proteomic profiling. RESULTS: Housing temperature fundamentally alters cardiac molecular baselines and adaptive trajectories. Exercise at TN elicited a coordinated, extracellular matrix (ECM)-focused transcriptional program, improving contractile function without inducing overt hypertrophy. Conversely, RT triggered a broad, uncoordinated stress response. Notably, while RT permitted classic regression of exercise-induced hypertrophy, detraining at TN revealed a unique cardiac structural economy, where cardiac mass significantly dropped below sedentary controls while maintaining enhanced functional efficiency. In pathological models, RT-induced compensatory survival pathways masked the true structural severity of DOX cardiotoxicity and paradoxically buffered against fibrosis. Furthermore, RT exacerbated cardiac aging phenotypes, inducing widespread fibrosis and upregulating senescence markers and specific microRNAs that remained quiescent under TN. CONCLUSION: Environmental temperature profoundly reshapes cardiac adaptive plasticity. The chronic thermal stress of standard housing distorts intrinsic molecular signaling, highlighting thermoneutrality as a crucial baseline for revealing true physiological adaptations and ensuring the translational validity of cardiovascular models.
Munro ML, Silva RV, Ohline SM
… +6 more, Khaing EP, Chan JA, Ibrahim MF, Tausi TF, Abraham WC, Jones PP
Acta Physiol (Oxf)
· 2026 Jul · PMID 42249616
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AIM: The ryanodine receptor (RyR2) is an intracellular Ca release channel which mediates numerous cellular functions across different tissues. Dysregulation of RyR2 channel activity leads to pathological Ca release, whic...AIM: The ryanodine receptor (RyR2) is an intracellular Ca release channel which mediates numerous cellular functions across different tissues. Dysregulation of RyR2 channel activity leads to pathological Ca release, which often underlies disrupted cellular signaling in disease states. In the heart, RyR2 channels forms discrete clusters and calcium release units (CRUs) which control channel activity. These structures demonstrate nanoscale remodeling in disease states associated with pathological Ca release activity in the heart. Hence, these nanoscale structures are critical in regulating Ca release in health and disease. RyR2 is also expressed in brain; however, whether analogous clusters and CRUs form in neurons remains unexplored. METHODS: Using super-resolution imaging, we assessed RyR2 organization in CA1 pyramidal neurons of wild-type mice. Furthermore, we used the APP/PS1 mouse model of Alzheimer's disease (AD) to assess whether there is nanoscale remodeling of RyR2 in a setting associated with pathological Ca release in neurons. RESULTS: Here, we provide the first identification and detailed characterization of RyR2 clusters in central nervous system neurons, which are comparable to those reported in the heart. Moreover, we observed a decrease in RyR2 cluster size and reduced CRU organization in AD mice at an age associated with high plaque burden and cognitive deficits. This remodeling is analogous to that reported in pathological states in the heart. CONCLUSION: Together, these findings implicate the nanoscale remodeling of RyR2 clusters and CRUs as a novel mechanism underlying Ca channel dysregulation and neuronal dysfunction in AD.
BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac desmosome disease, as more than 50% of affected patients carry pathogenic variants in desmosome protein-coding genes. In this study, we focused on t...BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac desmosome disease, as more than 50% of affected patients carry pathogenic variants in desmosome protein-coding genes. In this study, we focused on the role and mechanisms of pathogenic and non-pathogenic autoantibodies against intercalated disc (ICD) proteins such as desmoglein2 (DSG2) in ACM patients, healthy relatives (HR), and murine ACM models. MATERIALS AND METHODS: IgG fractions from ACM patients, HR, healthy controls, and murine ACM models were isolated. Besides ELISA and cleavage assay, dissociation assay, immunostaining, Triton-X-100 assay, Western blots, and atomic force microscopy were performed in murine cardiac slices, HL-1 cells, or induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs). RESULTS: IgG fractions from ACM patients and HR, but not murine ACM model-derived or grouped healthy controls IgG (G-HC), revealed positive ICD staining. Three out of six ACM patients derived IgGs that reduced cardiomyocyte cohesion. Pathogenic autoantibodies, bound to DSG2 in healthy and ACM hiPSC-CMs, cleaved and reduced DSG2 interaction at the molecular level. We investigated GSK-3β contribution to the cardiomyocyte cohesion loss and observed GSK-3β reduced baseline cohesion in cultured cardiomyocytes and cardiac slices. Among five ACM-IgGs, three HR-IgGs tested, three pathogenic ACM-IgGs activated GSK-3β upstream of p38MAPK, leading to phosphorylation and junctional loss of β-catenin. GSK-3β inhibition rescued the loss of cell cohesion in ACM hiPSC-CMs. CONCLUSION: Pathogenic autoantibodies targeting DSG2 are present in ACM patients and impair cardiomyocyte cohesion in a GSK-3β-dependent manner. In contrast, autoantibodies are absent in murine ACM models and are non-pathogenic in some patients and HR.
AIM: To test the hypothesis that Alzheimer-like metabolic neurodegeneration rat model leads to an autonomic dysfunction, memory impairment, and hippocampal amyloid pathology and that long-term chemogenetic stimulation of...AIM: To test the hypothesis that Alzheimer-like metabolic neurodegeneration rat model leads to an autonomic dysfunction, memory impairment, and hippocampal amyloid pathology and that long-term chemogenetic stimulation of the dorsal motor nucleus of the vagus reverses these alterations. METHODS: Male and female transgenic Long Evans rats received intracerebroventricular streptozotocin to induce sporadic Alzheimer-like pathology. Cardiovascular parameters and sympathetic and parasympathetic tone were evaluated in conscious animals. Episodic-like memory was assessed using the novel object recognition test. Hippocampal amyloid density was quantified by immunofluorescence. In male rats, cholinergic neurons of the dorsal motor nucleus of the vagus were selectively activated for 15 days using a chemogenetic approach, and autonomic, cognitive, and neuropathological outcomes were reassessed. RESULTS: In male rats, the intracerebroventricular streptozotocin induced a significant increase in cardiac sympathetic tone, reduced object discrimination index performance, and increased hippocampal amyloid density compared with vehicle-treated controls, without altering mean arterial pressure or heart rate. Female rats showed no significant autonomic, memory, or hippocampal alterations at the same time point. Long-term chemogenetic stimulation of cholinergic neurons in the dorsal motor nucleus of the vagus in male rats reduced sympathetic tone to control levels, improved recognition memory, and attenuated hippocampal amyloid density compared with the non-stimulated control group. CONCLUSION: These findings demonstrate a link between autonomic imbalance, memory dysfunction, and hippocampal amyloid pathology, and selective stimulation of the dorsal motor nucleus of the vagus restores autonomic balance and improves episodic-like memory and neuropathological outcomes, identifying this brainstem nucleus as a physiologically relevant therapeutic target in Alzheimer-related neuropathology.
Solid tumors are characterized by profound metabolic and vascular abnormalities that generate a hostile tumor microenvironment (TME) marked by extracellular acidosis, hypoxia, and nutrient deprivation. While the conseque...Solid tumors are characterized by profound metabolic and vascular abnormalities that generate a hostile tumor microenvironment (TME) marked by extracellular acidosis, hypoxia, and nutrient deprivation. While the consequences of these conditions for cancer cell behavior have been extensively studied, their impact on anti-tumor immune responses-particularly T cell function-has only recently gained attention. In this review, we summarize and critically discuss current knowledge on how acidic TME conditions affect the cytotoxic CD8+ T cells which are essential for anti-tumor immunity, and the protumorigenic, regulatory T cells (Tregs). An emerging body of literature shows that TME acidosis restricts cytotoxic CD8+ T cell motility and tumor penetration, suppresses cytokine production and secretion despite preserved transcription, impairs proliferation, and reduces cytotoxic killing capacity. These effects are closely linked to acid-induced metabolic reprogramming, including inhibition of glycolysis, altered mTOR and MYC signaling, and a shift toward fatty acid-dependent oxidative metabolism. In contrast, Tregs, which are metabolically adapted to rely on oxidative phosphorylation and lactate utilization, are comparatively resilient to acidic stress, and acidosis can enhance their suppressive capacity, thereby further skewing the immune balance toward tolerance. We highlight emerging evidence that tumor acidosis modulates immune checkpoint pathways, including pH-sensitive signaling through VISTA and regulation of PD-L1 expression, with important implications for immunotherapy sensitivity. We posit that limiting tumor acidosis may enable restoration of anti-tumor T cell function and improve therapeutic response to immune checkpoint blockade and adoptive T cell therapies.
Acta Physiol (Oxf)
· 2026 Jun · PMID 42162954
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AIM: Aerobic metabolism supplies ~90% of the ATP for neural activity. In frogs, activity has large aerobic needs typical of an average vertebrate, but surprisingly, can shift to using only glycolysis upon emergence from...AIM: Aerobic metabolism supplies ~90% of the ATP for neural activity. In frogs, activity has large aerobic needs typical of an average vertebrate, but surprisingly, can shift to using only glycolysis upon emergence from hibernation. We hypothesized that hibernation triggers a global reduction in the aerobic cost of neural function. METHODS: We simultaneously measured activity of the brainstem respiratory network via motor nerves and tissue O partial pressure (pO) in vitro from control and hibernated bullfrogs (4 weeks cold submergence; 4°C). To identify which functions differentially consume O, we sequentially blocked activity and various cellular processes requiring activity-independent ion regulation and used the resulting tissue pO change (ΔpO) as an index of O consumed. We further assessed how activity varies as a function of tissue pO and how O consumption varies across network activity levels. RESULTS: Despite similar network activity levels, we provide three lines of evidence that hibernation reduces its aerobic requirement. First, hibernators consume less O for baseline activity. Second, network output remains stable from baseline to anoxia, whereas moderate hypoxia disrupts controls. Finally, accelerating activity does not enhance O consumption as in controls, but aerobic metabolism ultimately increases during seizure-like activity. CONCLUSION: Hibernating frogs reduce aerobic needs for sustaining physiological levels of neural activity, revealing how they overcome the challenge of restarting motor circuits on the background of hypoxia during emergence from hibernation. More broadly, vertebrate neural circuits seemingly constrained by aerobic metabolism can exhibit substantial plasticity in the aerobic requirements for function.
AIM: Opioid-induced respiratory depression (OIRD) is the leading cause of death following opioid overdose, due to its effects on central rhythm generation, and airway and thoracic constriction. While the effects on rhyth...AIM: Opioid-induced respiratory depression (OIRD) is the leading cause of death following opioid overdose, due to its effects on central rhythm generation, and airway and thoracic constriction. While the effects on rhythm generation have been well documented, the effects of fentanyl on airway constriction are less well understood. We tested the hypothesis that the lower airways uniquely contribute to fentanyl-induced airway constriction and may provide a potential additional therapeutic target for overdose reversal. METHODS: Urethane-anesthetized mice were mechanically ventilated while pressure and airflow signals were recorded in vivo before and following intraperitoneal injection of fentanyl (500 μg/kg). The effects of naloxone, salbutamol, atropine, and positive-end expiratory pressure (PEEP) were evaluated to determine the extent of lower airway contributions to airflow obstruction during overdose. RESULTS: In addition to fentanyl's known depressive effects on respiratory drive, the introduction of fentanyl further disrupted airway patency by increasing dynamic resistance and decreasing lung compliance. These effects on respiration were not observed with naloxone alone and were reversed through administration of salbutamol, atropine, or introduction of PEEP. Importantly, opioid reversal with naloxone also produced a transient overshoot in dynamic resistance and lung compliance immediately following administration. We also observed an increase in physiological sighing following opioid removal. CONCLUSIONS: The lower airways contribute to fentanyl-induced airway constriction and serve as a potential additional therapeutic target following overdose. Fast-acting pharmacological agents may be used in tandem with naloxone to reduce changes in dynamic resistance and lung compliance produced by fentanyl while also limiting any adverse effects of naloxone itself.
Acta Physiol (Oxf)
· 2026 Jun · PMID 42153240
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AIMS: The mechanism of isosmotic water reabsorption in the kidney proximal tubule, with a focus on the interaction between the lateral Na/K-ATPase, apical water pathways mediated by AQP1 and SGLT1, and paracellular water...AIMS: The mechanism of isosmotic water reabsorption in the kidney proximal tubule, with a focus on the interaction between the lateral Na/K-ATPase, apical water pathways mediated by AQP1 and SGLT1, and paracellular water flow through Claudin-2. METHODS: A mathematical model of proximal tubular transport was used to compute coupled ion, solute, and water fluxes. The model included apical ENaC and a full electrogenic Na/K-ATPase formulation that incorporated its electromotive force, E, as a thermodynamic constraint linked to ATP hydrolysis at the pump site. RESULTS: Published cellular cation concentrations indicate metabolic stress in excised tubules, providing biophysical rationale for interpreting enhanced NHE3 activity and proton secretion in isolated proximal tubules as consequences of reduced ΔG, while modeling apical Na entry under non-stressed conditions by ENaC. Active Na transport generated a slightly hyperosmotic and hyperbaric lateral intercellular space, driving fluid efflux across the interspace basement membrane. Without ion recirculation, the absorbed fluid remained hyperosmotic. Isosmotic reabsorption therefore required ion recirculation between serosal fluid and the lateral intercellular space. SGLT1-mediated glucose uptake redistributed water flow between AQP1, SGLT1 and the paracellular pathway, whereas total water reabsorption remained closely linked to active Na transport, consistent with experiments. CONCLUSION: Proximal tubular water reabsorption is not explained by passive osmotic equilibration alone, but emerges from thermodynamic coupling between active Na transport, water permeability pathways, and regulated ion recirculation. The proximal tubule therefore functions as an ATP-consuming epithelial fluid pump that maintains isosmotic reabsorption by using additional metabolic energy to convert initially hyperosmotic absorbate into isosmotic reabsorbed fluid.
Acta Physiol (Oxf)
· 2026 Jun · PMID 42153234
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Single-neuron recordings from the medial temporal lobe of patients undergoing epilepsy surgery have revealed "concept cells" that respond selectively and invariantly to meaningful stimuli such as specific people, places,...Single-neuron recordings from the medial temporal lobe of patients undergoing epilepsy surgery have revealed "concept cells" that respond selectively and invariantly to meaningful stimuli such as specific people, places, or objects. These responses offer a unique window into how individual neurons encode high-level, multimodal representations-the building blocks of episodic memory-that differ from the more distributed, often hierarchical representations supporting semantic memory in the neocortex. Episodic and semantic memory, the systems for storing past experiences and conceptual knowledge, have traditionally been regarded as distinct. However, converging evidence from neuroimaging, lesion studies, and electrophysiological recordings challenges this strict dichotomy. This review synthesizes findings from human single-neuron recordings to re-examine the traditional distinction between episodic and semantic memory. We propose that the primary difference between the two systems lies in the structure of the associations they support: sparse, arbitrary links supporting episodic memory in the hippocampus versus ordered, hierarchical representations supporting semantic memory in the neocortex.
AIM: A hyperdynamic circulation in type 2 diabetes (T2D) has been proposed. We investigated this hypothesis in patients admitted to a tertiary care hospital in Denmark. METHODS: Cardiac index (CI) and systemic vascular r...AIM: A hyperdynamic circulation in type 2 diabetes (T2D) has been proposed. We investigated this hypothesis in patients admitted to a tertiary care hospital in Denmark. METHODS: Cardiac index (CI) and systemic vascular resistance (SVR) were estimated noninvasively in 933 patients admitted to the medical division of the emergency department (ED) of Bispebjerg University Hospital, Copenhagen, Denmark, between May 2019 and January 2023. The population included 154 people with T2D. RESULTS: Among people with T2D, CI was 17% higher (p < 0.0001) and SVR was 24% lower (p < 0.0001) compared to people without T2D. In linear regression models adjusted for age, sex, smoking status, body mass index, comorbidities, and medication for hypertension, T2D was independently associated with increased CI and decreased SVR (p < 0.001). This association remained significant after propensity matching on age, sex, BMI, hypertension, ischemic heart disease, and congestive heart failure. People with T2D treated with insulin (n = 43) exhibited higher CI (p = 0.04) and lower SVR (p = 0.003) than non-insulin-treated people with T2D (n = 111). CONCLUSIONS: Our findings support the notion that hyperdynamic circulation is an intrinsic feature of T2D, but further studies should explore its relevance for prognosis, risk stratification, and targeted interventions.