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Time for post-exercise phosphocreatine-recovery (PCr-R), deemed a robust index of mitochondrial function in vivo, was previously reported to be elevated (signifying impaired ATP production) in veterans with Gulf War illness (GWI). Here we sought to replicate the finding and assess the impact of contravening previous eligibility requirements. The replication sample comprised white males. Cases reported ≥ moderate muscle-weakness to match the organ assessed to an organ affected; controls lacked recent headache or multiple symptoms. The expansion sample added cases without muscle-weakness, controls with recent headache, females, nonwhites. PCr-R, following pedal-depression-exercise, was compared in veterans with GWI versus controls (sample N = 38). In the replication sample, PCr-R results closely matched the prior report: PCr-R veterans with GWI mean(SD) = 47.7(16.5); control mean(SD) = 30.3(9.2), p = 0.017. (Prior-study PCr-R veterans with GWI mean(SD) = 46.1(17.9), control mean(SD) = 29.0(8.7), p = 0.023. Combined replication + prior samples: p = 0.001.) No case-control difference was observed in the expansion sample. In cases, PCr-R related to muscle-weakness: PCr-R = 29.9(7.1), 38.2(8.9), 47.8(15.2) for muscle-weakness rated none/low, intermediate, and high respectively (p for trend = 0.02), validating desirability of matching tissue assessed to tissue affected. In controls, headache/multiple symptoms, sex, and ethnicity each mattered (affecting PCr-R significantly). This study affirms mitochondrial/bioenergetic impairment in veterans with GWI. The importance of careful case/control selection is underscored.

Climate change has rapidly altered marine ecosystems and is expected to continue to push systems and species beyond historical baselines into novel conditions. Projecting responses of organisms and populations to these novel environmental conditions often requires extrapolations beyond observed conditions, challenging the predictive limits of statistical modeling capabilities. Bioenergetics modeling provides the mechanistic basis for projecting climate change effects on marine living resources in novel conditions, has a long history of development, and has been applied widely to fish and other taxa. We provide our perspective on 4 opportunities that will advance the ability of bioenergetics-based models to depict changes in the productivity and distribution of fishes and other marine organisms, leading to more robust projections of climate impacts. These are (1) improved depiction of bioenergetics processes to derive realistic individual-level response(s) to complex changes in environmental conditions, (2) innovations in scaling individual-level bioenergetics to project responses at the population and food web levels, (3) more realistic coupling between spatial dynamics and bioenergetics to better represent the local- to regional-scale differences in the effects of climate change on the spatial distributions of organisms, and (4) innovations in model validation to ensure that the next generation of bioenergetics-based models can be used with known and sufficient confidence. Our focus on specific opportunities will enable critical advancements in bioenergetics modeling and position the modeling community to make more accurate and robust projections of the effects of climate change on individuals, populations, food webs, and ecosystems.

The proton-motive force (PMF), consisting of a pH gradient and a membrane potential (ΔΨ) underpins many processes essential to bacterial growth and/or survival. Yet bacteria often enter a bioenergetically diminished state characterized by a low PMF. Consequently, they have increased tolerance for diverse stressors, including clinical antibiotics. Despite the ubiquity of low metabolic rates in the environment, the extent to which bacteria have agency over entry into such a low-bioenergetic state has received relatively little attention. Here, we tested the hypothesis that production of redox-active metabolites (RAMs) could drive such a physiological transition. Pseudomonas aeruginosa is an opportunistic pathogen that produces phenazines, model RAMs that are highly toxic in the presence of molecular oxygen (O2). Under oxic conditions, the phenazines pyocyanin and phenazine-1- carboximide, as well as toxoflavin--a RAM produced by Burkholderia species--suppress the ΔΨ in distinct ways across distributions of single cells, reduce the efficiency of proton pumping, and lower cellular adenosine-triphosphate (ATP) levels. In planktonic culture, the degree and rate by which each RAM lowers the ΔΨ correlates with the protection it confers against antibiotics that strongly impact cellular energy flux. This bioenergetic suppression requires the RAM's presence and corresponds to its cellular reduction rate and abiotic oxidation rate by O2; it can be reversed by increasing the ΔΨ with nigericin. RAMs similarly impact the bioenergetic state of cells in (hyp)oxic biofilm aggregates. Collectively, these findings demonstrate that bacteria can suppress their bioenergetic state by the production of endogenous toxins in a manner that bolsters stress resilience. [ABSTRACT FROM AUTHOR]

Realizing visual perception performance using robust metal oxide devices is highly desirable for brain‐inspired neuromorphic computing, visual prosthetics, and artificial intelligence. SnO2, a representative transparent semiconductor, has attracted considerable attention for its potential in ultraviolet photodetectors and photosynaptic devices operating in solar‐blind spectral ranges. This problem has been circumvented by lowering the electron concentration and reducing the persistent photoconductivity (PPC), one of the essential properties of photosynaptic devices. In this case, the electron concentration and PPC properties in SnO2 must be controlled independently. This paper reports the successful control of PPC in SnO2 by controllable addition of Zn and Sr ions, which act as acceptors to annihilate the charge carriers and as a reductant to form oxygen vacancies, respectively. Zn and Sr‐added SnO2 exhibits superior synaptic performance with low energy consumption, successfully imitating the biological synapses without a gate electrode. As a result, the PPC remains at about 40% even after 20 seconds of turning off the ultraviolet light, and energy consumption is reduced to 1–10 fJ, similar to energy consumption with biological synapses. A novel optical sensor that can receive analog signals is demonstrated using a photosynaptic device with Zn and Sr‐added SnO2 thin films. [ABSTRACT FROM AUTHOR]

Microwave ablation (MWA) is based on the energy absorbed by biological tissue through microwave emission, which raises the temperature of the tumor to perform the treatment. MWA has the advantage of causing minimal bleeding and treating deep tumors. In this study, MWA for various slot design situations in a microwave coaxial antenna (MCA) was simulated through numerical analysis. For the slot design, the number of slots and the distance between slots were determined by the analysis parameters. A tumor developed inside the liver tissue was implemented, and the temperature distribution of the tumor and surrounding liver tissue was calculated for all cases selected for numerical analysis. The Helmholtz electromagnetic equation was used to calculate the electromagnetic field inside the tissue, and the modified Pennes bioheat equation was used to calculate the temperature change in the tissue due to the emitted microwave. Treatment effects were quantitatively analyzed for each slot design condition through an apoptotic variable based on the calculated temperature distribution. Lastly, conditions that produce optimal treatment effects were derived depending on the number of slots. The analysis showed that as the distance between the slots increased from 0.5 to 3.5 mm, the optimal treatment effect was obtained when the number of slots was 4, 3, 3, and 2, respectively, and the microwave input power at that time was 3.0, 2.8, 2.6, and 3.0 W, respectively. This is expected to allow for more rigorous and more therapeutically effective MWA. [ABSTRACT FROM AUTHOR]

Iron is critical for neuronal activity and metabolism, and iron dysregulation alters these functions in age-related neurodegenerative disorders, such as Alzheimer's disease (AD). AD is a chronic neurodegenerative disease characterized by progressive neuronal dysfunction, memory loss and decreased cognitive function. AD patients exhibit elevated iron levels in the brain compared to age-matched non-AD individuals. However, the degree to which iron overload contributes to AD pathogenesis is unclear. Here, we evaluated the involvement of ferroptosis, an iron-dependent cell death process, in mediating AD-like pathologies in C. elegans. Results showed that iron accumulation occurred prior to the loss of neuronal function as worms age. In addition, energetic imbalance was an early event in iron-induced loss of neuronal function. Furthermore, the loss of neuronal function was, in part, due to increased mitochondrial reactive oxygen species mediated oxidative damage, ultimately resulting in ferroptotic cell death. The mitochondrial redox environment and ferroptosis were modulated by pharmacologic processes that exacerbate or abolish iron accumulation both in wild-type worms and worms with increased levels of neuronal amyloid beta (Aβ). However, neuronal Aβ worms were more sensitive to ferroptosis-mediated neuronal loss, and this increased toxicity was ameliorated by limiting the uptake of ferrous iron through knockout of divalent metal transporter 1 (DMT1). In addition, DMT1 knockout completely suppressed phenotypic measures of Aβ toxicity with age. Overall, our findings suggest that iron-induced ferroptosis alters the mitochondrial redox environment to drive oxidative damage when neuronal Aβ is overexpressed. DMT1 knockout abolishes neuronal Aβ−associated pathologies by reducing neuronal iron uptake. [Display omitted] • Energetic imbalance is an early event in iron-induced loss of neuronal function. • Neuronal Aβ increases susceptibility to ferroptosis mediated oxidative damage. • Divalent metal transporter 1 knockout protects against iron-induced oxidative damage and ferroptosis. [ABSTRACT FROM AUTHOR]

While prostaglandin E2 (PGE2) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by comparative single-cell RNA sequencing of immune cells infiltrating human cancers and syngeneic tumors in female mice. PGE receptors EP4 and EP2 are expressed in lymphocytes and myeloid cells, and their expression is associated with the downregulation of oxidative phosphorylation (OXPHOS) and MYC targets, glycolysis and ribosomal proteins (RPs). Mechanistically, CD8+ T cells express EP4 and EP2 upon TCR activation, and PGE2 blocks IL-2-STAT5 signaling by downregulating Il2ra, which downregulates c-Myc and PGC-1 to decrease OXPHOS, glycolysis, and RPs, impairing migration, expansion, survival, and antitumor activity. Similarly, EP4 and EP2 are induced upon macrophage activation, and PGE2 downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE2-EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells. Mechanisms of prostaglandin E2 (PGE2)-mediated immunosuppression in the tumor microenvironment (TME) have been previously reported. Here, the authors profile PGE2 functions in human cancer, suggesting that prostaglandin E2-mediated signaling impairs the activity of human CD8+ T cells and macrophages by altering bioenergetics and ribosome biogenesis. [ABSTRACT FROM AUTHOR]

Priority 1: critical WHO pathogen Acinetobacter baumannii depends on ATP synthesis and ATP:ADP homeostasis and its bifunctional F1FO‐ATP synthase. While synthesizing ATP, it regulates ATP cleavage by its inhibitory ε subunit to prevent wasteful ATP consumption. We determined cryo‐electron microscopy structures of the ATPase active A. baumannii F1‐αßγεΔ134–139 mutant in four distinct conformational states, revealing four transition states and structural transformation of the ε's C‐terminal domain, forming the switch of an ATP hydrolysis off‐ and an ATP synthesis on‐state based. These alterations go in concert with altered motions and interactions in the catalytic‐ and rotary subunits of this engine. These A. baumannii interacting sites provide novel pathogen‐specific targets for inhibitors, with the aim of ATP depletion and/or ATP synthesis and growth inhibition. Furthermore, the presented diversity to other bacterial F‐ATP synthases extends the view of structural elements regulating such a catalyst. [ABSTRACT FROM AUTHOR]

The mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT) is a biocide widely used as a preservative in various commercial products. This biocide has also been used as an active ingredient in humidifier disinfectants in South Korea, resulting in serious health effects among users. Recent evidence suggests that the underlying mechanism of CMIT/MIT-initiated toxicity might be associated with defects in mitochondrial functions. The aim of this study was to utilize the C2C12 skeletal muscle model to investigate the effects of CMIT/MIT on mitochondrial function and relevant molecular pathways associated with skeletal muscle dysfunction. Data demonstrated that exposure to CMIT/MIT during myogenic differentiation induced significant mitochondrial excess production of reactive oxygen species (ROS) and a decrease in intracellular ATP levels. Notably, CMIT/MIT significantly inhibited mitochondrial oxidative phosphorylation (Oxphos) and reduced mitochondrial mass at a lower concentration than the biocide amount, which diminished the viability of myotubes. CMIT/MIT induced activation of autophagy flux and decreased protein expression levels of myosin heavy chain (MHC). Taken together, CMIT/MIT exposure produced damage in C2C12 myotubes by impairing mitochondrial bioenergetics and activating autophagy. Our findings contribute to an increased understanding of the underlying mechanisms associated with CMIT/MIT-induced adverse skeletal muscle health effects. [ABSTRACT FROM AUTHOR]

Background: Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear. Methods: We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer's Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer's Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites. Results: MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P < 0.005). Conclusions: Our study indicates that mtDNA-CN measured in blood is predictive of AD and is associated with AD biomarkers including plasma NFL particularly in females. Further, we illustrate that decreased mtDNA-CN possibly increases AD risk through dysregulation of mitochondrial lipid metabolism and inflammation. [ABSTRACT FROM AUTHOR]

Diatoms are photosynthetic microalgae widely diffused around the globe and well adapted to thrive in diverse environments. Their success is closely related to the nanostructured biosilica shell (frustule) that serves as exoskeleton. Said structures have attracted great attention, thanks to their hierarchically ordered network of micro‐ and nanopores. Frustules display high specific surface, mechanical resistance and photonic properties, useful for the design of functional and complex materials, with applications including sensing, biomedicine, optoelectronics and energy storage and conversion. Current technology allows to alter the chemical composition of extracted frustules with a diverse array of elements, via chemical and biochemical strategies, without compromising their valuable morphology. We started our research on diatoms from the viewpoint of material scientists, envisaging the possibilities of these nanostructured silica shells as a general platform to obtain functional materials for several applications via chemical functionalization. Our first paper in the field was published in ChemPlusChem ten years ago. Ten years later, in this Perspective, we gather the most recent and relevant functional materials derived from diatom biosilica to show the growth and diversification that this field is currently experiencing, and the key role it will play in the near future. [ABSTRACT FROM AUTHOR]

Aging represents the leading risk factor for developing neurodegenerative disorders. One of the nine hallmarks of aging is mitochondrial dysfunction. Age-related mitochondrial alterations have been shown to affect mitochondrial energy metabolism, reduction-oxidation homeostasis, and mitochondrial dynamics. Previous reports have shown that induced pluripotent stem cells (iPSCs) from aged donors do not keep the aging signature at the transcriptomic level. However, not all aspects of aging have been investigated, and especially not the mitochondria-related aging signature. Therefore, the present study compared the mitochondrial function in iPSCs from healthy aged donors compared to those of young donors. We addressed whether aged iPSCs may be used as drug-screening models of "aging in a dish" to identify therapies alleviating mitochondria aging. Compared to iPSCs from young donors, we demonstrate that iPSCs from aged donors show impaired mitochondrial bioenergetics and exhibit a rise in reactive oxygen species generation. Furthermore, aged iPSCs present a lower mitochondrial mass and alterations in the morphology of the mitochondrial network when compared to iPSCs from young donors. This study provides the first evidence that the aging phenotype is present at the mitochondrial level in iPSCs from aged donors, ranging from bioenergetics to mitochondrial network morphology. This model might be used to screen mitochondria-targeting drugs to promote healthy aging at the mitochondrial level. [ABSTRACT FROM AUTHOR]

Mitochondria play an important role in cellular function, not only as a major site of adenosine triphosphate (ATP) production but also by regulating energy expenditure, apoptosis signaling, control of the cell cycle, cellular growth, cell differentiation, transportation of metabolites, and production of reactive oxygen species. Interaction with electromagnetic waves can lead to dysregulation or alterations in the patterns of energy activities in the mitochondria. Ultraviolet light (UV) can be found in sunlight and artificial sources, such as lamps. UV radiation can cause damage to DNA, proteins, and lipids. Besides that, UV radiation is largely used in microorganism disinfection. To establish possible alterations in mitochondrial bioenergetics, this study proposes to investigate the UV (at two distinct intervals) effects on isolated mitochondria from mice liver to obtain direct responses and selective permeability of the internal membrane information. UVA‐371 and UVC‐255 nm lamps were used to irradiate, at different doses varying from 22.5 to 756 mJ/cm2, isolated mitochondria samples. Mitochondrial respiration pathways were investigated by high‐resolution respirometry, and possible mitochondrial membrane damages were evaluated by mitochondrial swelling by spectrophotometer analysis. UVC irradiation results (in the higher dose) indicate decrease in 75% of mitochondrial bioenergetics capacity, such as limitation of oxidative phosphorylation in 60% and increased energy dissipation in 30%. Mitochondrial swelling experiments (spectrophotometer) indicated inner membrane damage, and consequently a loss of selective permeability. Direct correlation between irradiation and effect responses was observed, mitochondrial bioenergetics is severely affected by UVC radiation, but (UVA) radiation did not present bioenergetic alterations. These alterations can contribute to improving the knowledge behind the cell death mechanism in disinfection UV light and UV therapy such as phototherapy. [ABSTRACT FROM AUTHOR]

Background: Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson's disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. Methods: aSYN PFFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. Results: In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. Conclusions: Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD. [ABSTRACT FROM AUTHOR]

Cellular bioenergetics and mitochondrial dynamics are crucial for the secretion of insulin by pancreatic beta cells in response to elevated levels of blood glucose. To elucidate the interactions between energy production and mitochondrial fission/fusion dynamics, we combine live-cell mitochondria imaging with biophysical-based modeling and graph-based network analysis. The aim is to determine the mechanism that regulates mitochondrial morphology and balances metabolic demands in pancreatic beta cells. A minimalistic differential equation-based model for beta cells is constructed that includes glycolysis, oxidative phosphorylation, calcium dynamics, and fission/fusion dynamics, with ATP synthase flux and proton leak flux as main regulators of mitochondrial dynamics. The model shows that mitochondrial fission occurs in response to hyperglycemia, starvation, ATP synthase inhibition, uncoupling, and diabetic conditions, in which the rate of proton leakage exceeds the rate of mitochondrial ATP synthesis. Under these metabolic challenges, the propensities of tip-to-tip fusion events simulated from the microscopy images of the mitochondrial networks are lower than those in the control group and prevent the formation of mitochondrial networks. The study provides a quantitative framework that couples bioenergetic regulation with mitochondrial dynamics, offering insights into how mitochondria adapt to metabolic challenges. A study combined experiments, image analysis and mathematical modeling to understand the coupling between bioenergetics and mitochondrial dynamics and investigates how excess nutrients and starvation affect mitochondrial morphology. [ABSTRACT FROM AUTHOR]

Reduced muscle contractility and mitochondrial bioenergetics are the hallmarks of systolic heart failure. There is currently no therapy targeting both. Here, we show that gene delivery of Perm1 via adeno-associated virus (AAV) simultaneously enhances cardiac contractility and mitochondrial biogenesis in C57BL6 mice. Moreover, we found that PERM1 interacts with troponin C (TnC), a key contractile protein in striated muscle, and that AAV-Perm1 led to the upregulation of TnC. This study suggests that gene delivery of Perm1 may be a novel therapeutic approach to treat systolic heart failure by simultaneously restoring cardiac contractility and mitochondrial bioenergetics. NEW & NOTEWORTHY:Perm1 gene delivered with AAV9 enhances cardiac contractility in mice, and it is concomitant with the increase of mitochondrial bioenergetics and upregulation of TnC. This is the first study showing that PERM1, previously known as a striated muscle-specific mitochondrial regulator, also positively regulates cardiac contractility. [ABSTRACT FROM AUTHOR]

The somatic and psychological concepts of pain are expanded to include the perspective of the enactment approach. Pain is therefore now (also) conceptualized as a "5E process": Embodied, Embedded, Enacted, Emotive, and Extended. Pain is therefore, in contrast to a biopsychosocial concept, also understood as a relational and emergent process of finding meaning through an experienced body that is inextricably linked to the world that we shape and that shapes us. This model of understanding is discussed in relation to body psychotherapy, in particular bioenergetic analysis. Specifically, this is related to posture, personal experience, and self-expression under stress. [ABSTRACT FROM AUTHOR]

Metastasis is one of the main causes of relapse and subsequent high mortality from cancer. Metastases can contain very few cells and spread throughout the body. Despite the existing variety of diagnostic imaging methods, in practice, the resolution of note of them allows unambiguously diagnosing the presence of a tumor (clump of cancer cells) smaller than 1–2 mm in size. After surgery and tumor removal, patients are typically offered chemotherapy, external beam radiation therapy, or - or -emitter radionuclide therapy. This therapy has side effects that lead to additional risks and may interfere with continued treatment. Recently, a number of works, in contrast to the traditional approach, have proposed using short-range radionuclides instead of - or -emitters [1–3]. It is convenient to use Auger or conversion electron emitters as short-acting therapeutic agents. Auger electrons and conversion electrons have a short range and high specific linear energy loss in biological tissue: they are capable of damaging cells within a few tens of microns, but do not have a radiotoxic effect over long distances, without damaging healthy cells and tissues. The most efficient and convenient Auger and conversion electron emitters for practical use include Rh ( min), which has the lowest ratio of the number of quanta to electrons [1] and can be obtained by a generator method. The predecessors of Rh ( min) in the generator can be Ru ( days) or Pd ( days). In order to clarify the prospects for producing these precursors, we have measured the rates of Ru() Ru and Pd() Pd reactions upon neutron irradiation of metal ruthenium of natural isotopic composition and metal palladium, enriched in the Pd isotope to 96.36 , in a horizontal experimental channel of the IR-8 reactor. [ABSTRACT FROM AUTHOR]

Regenerative medicine aims to restore, replace, and regenerate human cells, tissues, and organs. Despite significant advancements, many cell therapy trials for cardiovascular diseases face challenges like cell survival and immune compatibility, with benefits largely stemming from paracrine effects. Two promising therapeutic tools have been recently emerged in cardiovascular diseases: extracellular vesicles (EVs) and mitochondrial transfer. Concerning EVs, the first pivotal study with EV-enriched secretome derived from cardiovascular progenitor cells has been done treating heart failure. This first in man demonstrated the safety and feasibility of repeated intravenous infusions and highlighted significant clinical improvements, including enhanced cardiac function and reduced symptoms in heart failure patients. The second study uncovered a novel mechanism of endothelial regeneration through mitochondrial transfer via tunneling nanotubes (TNTs). This research showed that mesenchymal stromal cells (MSCs) transfer mitochondria to endothelial cells, significantly enhancing their bioenergetics and vessel-forming capabilities. This mitochondrial transfer was crucial for endothelial cell engraftment and function, offering a new strategy for vascular regeneration without the need for additional cell types. Combining EV and mitochondrial strategies presents new clinical opportunities. These approaches could revolutionize regenerative medicine, offering new hope for treating cardiovascular and other degenerative diseases. Continued research and clinical trials will be crucial in optimizing these therapies, potentially leading to personalized medicine approaches that enhance patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by chronic inflammation and progressive cartilage degradation, ultimately leading to joint dysfunction and disability. Oleocanthal (OC), a bioactive phenolic compound derived from extra virgin olive oil, has garnered significant attention due to its potent anti-inflammatory properties, which are comparable to those of non-steroidal anti-inflammatory drugs (NSAIDs). This study pioneers the investigation into the effects of OC on the Protease-Activated Receptor-2 (PAR-2) mediated inflammatory pathway in OA, aiming to validate its efficacy as a functional food-based therapeutic intervention. Methods: To simulate cartilage tissue in vitro, human bone marrow-derived mesenchymal stem cells (BMSCs) were differentiated into chondrocytes. An inflammatory OA-like environment was induced in these chondrocytes using lipopolysaccharide (LPS) to mimic the pathological conditions of OA. The therapeutic effects of OC were evaluated by treating these inflamed chondrocytes with various concentrations of OC. The study focused on assessing key inflammatory markers, catabolic enzymes, and mitochondrial function to elucidate the protective mechanisms of OC. Mitochondrial function, specifically mitochondrial membrane potential (ΔΨm), was assessed using Rhodamine 123 staining, a fluorescent dye that selectively accumulates in active mitochondria. The integrity of ΔΨm serves as an indicator of mitochondrial and bioenergetic function. Additionally, Western blotting was employed to analyze protein expression levels, while real-time polymerase chain reaction (RT-PCR) was used to quantify gene expression of inflammatory cytokines and catabolic enzymes. Flow cytometry was utilized to measure cell viability and apoptosis, providing a comprehensive evaluation of OC's therapeutic effects on chondrocytes. Results: The results demonstrated that OC significantly downregulated PAR-2 expression in a dose-dependent manner, leading to a substantial reduction in pro-inflammatory cytokines, including TNF-α, IL-1β, and MCP-1. Furthermore, OC attenuated the expression of catabolic markers such as SOX4 and ADAMTS5, which are critically involved in cartilage matrix degradation. Importantly, OC was found to preserve mitochondrial membrane potential (ΔΨm) in chondrocytes subjected to inflammatory stress, as evidenced by Rhodamine 123 staining, indicating a protective effect on cellular bioenergetics. Additionally, OC modulated the Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL)/Receptor Activator of Nuclear Factor Kappa-Β (RANK) pathway, suggesting a broader therapeutic action against the multifactorial pathogenesis of OA. Conclusions: This study is the first to elucidate the modulatory effects of OC on the PAR-2 mediated inflammatory pathway in OA, revealing its potential as a multifaceted therapeutic agent that not only mitigates inflammation but also protects cartilage integrity. The preservation of mitochondrial function and modulation of the RANKL/RANK pathway further underscores OC's comprehensive therapeutic potential in counteracting the complex pathogenesis of OA. These findings position OC as a promising candidate for integration into nutritional interventions aimed at managing OA. However, further research is warranted to fully explore OC's therapeutic potential across different stages of OA and its long-term effects in musculoskeletal disorders. [ABSTRACT FROM AUTHOR]

High-resolution respirometry in human permeabilized muscle fibers is extensively used for analysis of mitochondrial adaptions to nutrition and exercise interventions, and is linked to athletic performance. However, the lack of standardization of experimental conditions limits quantitative inter- and intra-laboratory comparisons. In our study, an international team of investigators measured mitochondrial respiration of permeabilized muscle fibers obtained from three biopsies (vastus lateralis) from the same healthy volunteer to avoid inter-individual variability. High-resolution respirometry assays were performed together at the same laboratory to assess whether the heterogenity in published results are due to the effects of respiration media (MiR05 versus Z) with or without the myosin inhibitor blebbistatin at low- and high-oxygen regimes. Our findings reveal significant differences between respiration media for OXPHOS and ETcapacities supported by NADH&succinate-linked substrates at different oxygen concentrations. Respiratory capacities were approximately 1.5-fold higher in MiR05 at high-oxygen regimes compared to medium Z near air saturation. The presence or absence of blebbistatin in human permeabilized muscle fiber preparations was without effect on oxygen flux. Our study constitutes a basis to harmonize and establish optimum experimental conditions for respirometric studies of permeabilized human skeletal muscle fibers to improve reproducibility. [Display omitted] • Understanding muscle energetics' link to athletic performance is crucial. • Harmonizing mitochondrial bioenergetics protocols is critical for inter-study data analysis. • Medium composition and oxygen concentration influence muscle mitochondria respiratory capacity in permeabilized fibers. • Optimizing experimental protocols is pivotal for precise athletic performance evaluation. [ABSTRACT FROM AUTHOR]

In today's era of wireless communication, interaction of electromagnetic energy and living biological systems is unavoidable -- both in far field and in near field of the radiating antenna. Consequent basic safety limits on radiation levels are enforced through Specific Absorption Rate (SAR) limits. Practical measurement and validation of these SAR values require the deployment of phantom models containing tissue equivalent dielectric liquids -- these liquids are conventionally single layer and homogeneous in nature. However, structured basis to formulate these custom made homogeneous phantom liquids representing arbitrary combinations of stacked tissue layers has not been properly reported in literature. To address the issue, this paper develops and illustrates a novel structured technique to define equivalent permittivity and loss tangent of homogeneous phantom liquid representing arbitrary combinations of stacked tissue layers -- both in far field and in near field exposure scenarios. Electric field distribution and later on point SAR distribution inside different tissue layers have been attempted to replicate as closely as possible using equivalent homogeneous phantom liquid with properly tuned permittivity and loss tangent values. The fitting procedure involves minimization of the absolute/normalized maximum difference (of electric field and point SAR) between the original multilayer tissue and the modelled single layer homogeneous equivalent. This generalized technique is applied to two distinct multilayer (four layers are considered) biological models at 2.45 GHz where one is composed of four layers of equal thicknesses while the other one has four layers with unequal thicknesses. Moreover, the proposed technique has been tested and validated in the two abovementioned multilayer biological models for both far field (plane wave irradiation) and near field (in close proximity to antenna) exposure scenarios. This technique is quite successful in achieving equivalent dielectric liquids in which original point SAR data and its overall distribution across different layers can be realistically replicated while attempting point wise matching at several spatial points. In some cases, the original electric field/point SAR values are achieved with reduced precision near layer interfaces with significant dielectric contrast. Thus, the proposed technique can significantly contribute to accurately measure, validate, and reflect the true spatial SAR distributions in original multilayer biological models using the derived homogeneous tissue equivalent phantom liquids. [ABSTRACT FROM AUTHOR]

Low aerobic capacity is strongly associated with all-cause mortality and risk for Alzheimer's disease (AD). Individuals with early dementia and AD have lower aerobic capacity compared to age-matched controls. The mechanism by which aerobic capacity influences AD risk is unknown but is likely mediated by sexual dimorphism and tissue-level differences in mitochondrial energetics. Here, we used rats selectively bred for large differences in intrinsic aerobic exercise capacity. Brain tissue from 18-month and 24-month-old female and male low-capacity runner (LCR) and high-capacity runner (HCR) rats were analyzed for markers of mitochondrial function and AD-associated pathologies. LCR rats, irrespective of sex, exhibited a greater increase in brain amyloid beta (Aβ42) and tau hyperphosphorylation (pTauthr181/total tau) with aging. In female LCR rats, brain mitochondrial respiration at states 3, 4, and FCCP-induced uncoupling, when stimulated with pyruvate/malate, was reduced at 18 and 24 months, leading to lower ATP-linked mitochondrial respiration compared to mitochondria from HCR rats. Male LCR rats also showed reduced complex II-stimulated mitochondrial respiration (succinate + rotenone) at 24 months compared to HCR rats. Differences in mitochondrial respiration were associated with tau hyperphosphorylation and Aβ42 alterations in both HCR and LCR strains. Proteomic analysis unveiled a distinct difference in the mitochondrial proteome, wherein female LCR rats displayed diminished mitochondrial translation and oxidative phosphorylation (OXPHOS) proteins at 18 months compared to female HCR rats. Conversely, male LCR rats exhibited increased OXPHOS protein abundance but reduced tricarboxylic acid (TCA) cycle proteins compared to male HCR rats. These findings underscore a robust association between intrinsic aerobic exercise capacity, brain mitochondrial function, and AD pathologies during aging. [ABSTRACT FROM AUTHOR]

Biological resilience, broadly defined as the ability to recover from an acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences are likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue, and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3 and 17.8 years spanning across different tissues, tissue regions, and cell types including (1) fibroblasts from skin and from the heart separated into the left ventricle (LV), right ventricle (RV), left atrium (LA), and right atrium (RA); (2) astrocytes from the prefrontal cortex and hippocampus; and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration was assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach; we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50 µM-H2O2), metabolic (1 mM-glucose), and proteostasis (0.1 µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor-specific. For example, astrocytes had a higher oxygen consumption rate and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA, respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to the age and developmental status of donors as potential predictive markers. [ABSTRACT FROM AUTHOR]

Patients with Alzheimer's disease and related dementia (ADRD) are faced with a formidable challenge of focal amyloid deposits and cerebral amyloid angiopathy (CAA). The treatment of amyloid deposits in ADRD by targeting only oxidative stress, inflammation and hyperlipidemia has not yielded significant positive clinical outcomes. The chronic high-fat diet (HFD), or gut dysbiosis, is one of the major contributors of ADRD in part by disrupted transport, epigenetic DNMT1 and the folate 1-carbon metabolism (FOCM) cycle, i.e., rhythmic methylation/de-methylation on DNA, an active part of epigenetic memory during genes turning off and on by the gene writer (DNMT1) and eraser (TET2/FTO) and the transsulfuration pathway by mitochondrial 3-mercaptopyruvate sulfur transferase (3MST)-producing H2S. The repeat CAG expansion and m6A disorder causes senescence and AD. We aim to target the paradigm-shift pathway of the gut–brain microbiome axis that selectively inhibits amyloid deposits and increases mitochondrial transsulfuration and H2S. We have observed an increase in DNMT1 and decreased FTO levels in the cortex of the brain of AD mice. Interestingly, we also observed that probiotic lactobacillus-producing post-biotic folate and lactone/ketone effectively prevented FOCM-associated gut dysbiosis and amyloid deposits. The s-adenosine-methionine (SAM) transporter (SLC25A) was increased by hyperhomocysteinemia (HHcy). Thus, we hypothesize that chronic gut dysbiosis induces SLC25A, the gene writer, and HHcy, and decreases the gene eraser, leading to a decrease in SLC7A and mitochondrial transsulfuration H2S production and bioenergetics. Lactobacillus engulfs lipids/cholesterol and a tri-directional post-biotic, folic acid (an antioxidant and inhibitor of beta amyloid deposits; reduces Hcy levels), and the lactate ketone body (fuel for mitochondria) producer increases SLC7A and H2S (an antioxidant, potent vasodilator and neurotransmitter gas) production and inhibits amyloid deposits. Therefore, it is important to discuss whether lactobacillus downregulates SLC25A and DNMT1 and upregulates TET2/FTO, inhibiting β-amyloid deposits by lowering homocysteine. It is also important to discuss whether lactobacillus upregulates SLC7A and inhibits β-amyloid deposits by increasing the mitochondrial transsulfuration of H2S production. [ABSTRACT FROM AUTHOR]

Mitochondria are pivotal contributors to cancer mechanisms due to their homeostatic and pathological roles in cellular bioenergetics, biosynthesis, metabolism, signaling, and survival. During transformation and tumor initiation, mitochondrial function is often disrupted by oncogenic mutations, leading to a metabolic profile distinct from precursor cells. In this review, we focus on hepatocellular carcinoma, a cancer arising from metabolically robust and nutrient rich hepatocytes, and discuss the mechanistic impact of altered metabolism in this setting. We provide distinctions between normal mitochondrial activity versus disease‐related function which yielded therapeutic opportunities, along with highlighting recent preclinical and clinical efforts focused on targeting mitochondrial metabolism. Finally, several novel strategies for exploiting mitochondrial programs to eliminate hepatocellular carcinoma cells in metabolism‐specific contexts are presented to integrate these concepts and gain foresight into the future of mitochondria‐focused therapeutics. [ABSTRACT FROM AUTHOR]

Mitochondrial quality control is finely tuned bymitophagy, the selective degradation of mitochondria through autophagy, and mitochondrial biogenesis. Removal of damaged mitochondria is essential to preserve cellular bioenergetics and prevent detrimental events such as sustained mitoROS production, pro-apoptotic cytochrome c release or mtDNA leakage. The array of tools available to study mitophagy is very limited but in constant development. Almost a decade ago, we developed a method to assess mitophagy flux using MitoTracker Deep Red in combination with lysosomal inhibitors. Now, using the novel tandem-fluorescence reporter mito-QC (mCherry-GFP-FIS1101-152) that allows to differentiate between healthy mitochondria (mCherry+GFP+) and mitolysosomes (mCherry+GFP-), we have developed a robust and quantitative method to assess mitophagy by flow cytometry. This approach has been validated in ARPE-19 cells using PINK1/Parkindependent (CCCP) and PINK1/Parkin-independent (DFP) positive controls and complementary techniques. Furthermore, we show that the mito-QC reporter can be multiplexed, especially if using spectral flow cytometry, to simultaneously study other cellular parameters such as viability or ROS production. Using this technique, we evaluated and characterized two prospective mitophagy inducers and further dissected their mechanism of action. Finally, using mito-QC reporter mice, we developed a protocol to measure mitophagy levels in the retina ex vivo. This novel methodology will propelmitophagy research forward and accelerate the discovery of novel mitophagy modulators. [ABSTRACT FROM AUTHOR]

Background: Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT. Methods: Rimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed. Results: mtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice. Limitations: The lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions. Conclusions: The present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Spiking neural networks (SNNs) have received increasing attention due to their high biological plausibility and energy efficiency. The binary spike-based information propagation enables efficient sparse computation in event-based and static computer vision applications. However, the weight precision and especially the membrane potential precision remain as high-precision values (e.g., 32 bits) in state-of-the-art SNN algorithms. Each neuron in an SNN stores the membrane potential over time and typically updates its value in every time step. Such frequent read/write operations of high-precision membrane potential incur storage andmemory access overhead in SNNs, which undermines the SNNs' compatibility with resource-constrained hardware. To resolve this inefficiency, prior works have explored the time step reduction and low-precision representation of membrane potential at a limited scale and reported significant accuracy drops. Furthermore, while recent advances in on-device AI present pruning and quantization optimization with different architectures and datasets, simultaneous pruning with quantization is highly under-explored in SNNs. In this work, we present SpQuant-SNN, a fully-quantized spiking neural network with ultra-low precision weights, membrane potential, and high spatial-channel sparsity, enabling the end-to-end low precision with significantly reduced operations on SNN. First, we propose an integer-only quantization scheme for the membrane potential with a stacked surrogate gradient function, a simple-yet-effective method that enables the smooth learning process of quantized SNN training. Second, we implement spatial-channel pruning with membrane potential prior, toward reducing the layer-wise computational complexity, and floating-point operations (FLOPs) in SNNs. Finally, to further improve the accuracy of low-precision and sparse SNN, we propose a self-adaptive learnable potential threshold for SNN training. Equipped with high biological adaptiveness, minimal computations, and memory utilization, SpQuant-SNN achieves state-of-the-art performance across multiple SNN models for both event-based and static image datasets, including both image classification and object detection tasks. The proposed SpQuant-SNN achieved up to 13× memory reduction and >4.7× FLOPs reduction with <1.8% accuracy degradation for both classification and object detection tasks, compared to the SOTA baseline. [ABSTRACT FROM AUTHOR]

Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell's survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson's disease, and cancer, as well as rare metabolic disorders, like Kearns–Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health. [ABSTRACT FROM AUTHOR]

There are various sources of plant-active substances with biological activities, such as antioxidant, antibacterial, immunomodulatory, and anti-inflammatory. It is very necessary to rapidly, efficiently, and environmentally friendly extract these active substances in the food, medicine, and cosmetics industries. Among them, ultra-high pressure (UHP) with high hydrostatic pressure (HHP) has been widely applied in food non-thermal processing and extraction in recent years. The UHP can be expected to extract the plant active substances for the higher extraction yield and lower extraction time, compared with the traditional solid-liquid extraction. This review aims to introduce the development of UHP in food processing, in order to extract the flavonoids, polyphenols, polysaccharides, and saponins. The principles, processes, and applications were also covered to extract the various active substances, such as flavonoids, polyphenols, polysaccharides, and saponins. The assisted UHP extraction included the three stages: pressure boost, holding, and relief stage, which determined the extraction performance of UHP. Since the UHP tended to destroy the raw tissues, cell walls, cell membranes, and organelles, the solvents were penetrated into tissue cells to dissolve the soluble components for the high mass transfer and the release rate of cell contents. UHP processing included raw material pretreatment, sample treatment, UHP extraction, separation, and purification. The efficiency of UHP extraction depended on the operating conditions. The solvent, pressure level, and extraction temperature were the three most important parameters of the performance of UHP extraction. Furthermore, the UHP extraction was still an effective way to extract polysaccharides, although there were some effects on the structure and biological activity of polysaccharides. Compared with the traditional heat reflux extraction, the UHP extraction was carried out at room temperature or lower temperature, in order to reduce the impact of heat. The simple, rapid, and efficient UHP extraction effectively shortened the extraction time to improve the biological activity for energy saving. A huge market prospect and development potential were found in the UHP-assisted extraction. Previous studies were focused mainly on the extraction optimization and mechanism. Only a relatively few studies explored the performance of antioxidant, antibacterial, and biological activities in the active substances after UHP extraction. And even fewer studies were focused on in vivo antioxidant activities. Many challenges also remained in the UHP application to extract the active substances, such as the imperfect theoretical basis of UHP extraction and high equipment cost. It is necessary to explore the synergistic extraction of UHP combined with other extraction methods. The safer, larger volume and lower cost of UHP equipment can be developed to explore the influence of UHP extraction on the biological activity and antioxidant effect of active substances, particularly the mechanisms behind them. The finding can be expected to promote the wide application and sustainable development of UHP extraction in various fields. Keywords: ultra-high pressure; active substances; extraction principle; extraction procedure; application [ABSTRACT FROM AUTHOR]

How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2’-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in murine macrophages’ mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from decreased pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (Mpc1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogenrelated nuclear receptor alpha (Esrra). Consequently, Esrra exhibits weakened binding to the Mpc1 promoter. This outcome arises from the impaired interaction between Esrra and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and, consequently reduced ATP production in tolerized murine and human macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of Mpc1 and Esrra and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedented mechanism of host tolerance to infection involving the Ppargc1a/Esrra axis in its influence on Mpc1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings pave the way for developing treatments to bolster host resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens. [ABSTRACT FROM AUTHOR]

The molecular mechanisms leading to saliva secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren’s syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of salivary gland immune cell infiltration and glandular hypofunction. SS-like disease was induced by treatment with DMXAA, a small molecule agonist of murine STING. We have previously shown that the extent of salivary secretion is correlated with the magnitude of intracellular Ca2+ signals (Takano et al., 2021). Contrary to our expectations, despite a significant reduction in fluid secretion, neural stimulation resulted in enhanced Ca2+ signals with altered spatiotemporal characteristics in vivo. Muscarinic stimulation resulted in reduced activation of the Ca2+-activated Cl- channel, TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca2+. Super-resolution microscopy revealed a disruption in the colocalization of Inositol 1,4,5-trisphosphate receptor Ca2+ release channels with TMEM16a, and channel activation was reduced when intracellular Ca2+ buffering was increased. These data indicate altered local peripheral coupling between the channels. Appropriate Ca2+ signaling is also pivotal for mitochondrial morphology and bioenergetics. Disrupted mitochondrial morphology and reduced oxygen consumption rate were observed in DMXAA-treated animals. In summary, early in SS disease, dysregulated Ca2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction. [ABSTRACT FROM AUTHOR]

ABSTRACT Through killing and instilling fear in their prey, large terrestrial carnivores shape the structure and function of ecosystems globally. Most large carnivore species have experienced severe range and population declines due to human activities, and many are now threatened with extinction. Consequently, the impacts of these predators on food webs have been diminished or lost completely from many ecosystems. Kill rates provide a fundamental metric for understanding large carnivore ecology and assessing and comparing predation within and across ecological communities. Our systematic review of large terrestrial mammalian carnivore kill rates reveals significant positive geographic (North America, Europe, and Africa) and taxonomic (grey wolf Canis lupus, puma Puma concolor, lion Panthera leo, and Eurasian lynx Lynx lynx) bias, with most studies apparently motivated by human–carnivore conflict over access to ungulate prey and wildlife management objectives. Our current understanding of the behaviour and functional roles of many large carnivore species and populations thus remains limited. By synthesising and comparing kill rates, we show that solitary carnivores (e.g. brown bears Ursus arctos and most felids) exhibit higher per capita kill rates than social carnivores. However, ungulate predation by bears is typically limited to predation of neonates during a short period. Lower per capita kill rates by social carnivores suggests group living significantly reduces energetic demands, or, alternatively, that group‐living carnivores defend and consume a greater proportion of large prey carcasses, or may acquire more food through other means (e.g. scavenging, kleptoparasitism) than solitary hunters. Kill and consumption rates for Canidae – measured as kilograms of prey per kilogram of carnivore per day – are positively correlated with body mass, consistent with increasing energy costs associated with a cursorial hunting strategy. By contrast, ambush predators such as felids show an opposite trend, and thus the potential energetic advantage of an ambush hunting strategy for carnivores as body mass increases. Additionally, ungulate kill rates remain relatively constant across solitary felid body sizes, indicative of energetic constraints and optimal foraging. Kill rate estimates also reveal potential insights into trophic structuring within carnivore guilds, with subordinate carnivores often killing more than their larger counterparts, which may be indicative of having to cope with food losses to scavengers and dominant competitors. Subordinate carnivores may thus serve an important role in provisioning food to other trophic levels within their respective ecosystems. Importantly, kill rates also clarify misconceptions around the predatory behaviour of carnivores (e.g. spotted hyaenas Crocuta crocuta and wolverines Gulo gulo are often considered scavengers rather than the capable hunters that they are) and thus the potential impacts of various carnivore species on their ecological communities. Despite the importance of kill rates in understanding predator–prey interactions, their utility is not widely recognised, and insufficient research limits our ability to fully appreciate and predict the consequences of modified predation regimes, justify current management actions affecting carnivores, or inform effective conservation measures. Together with other important research on predator–prey interactions, robust kill rate studies that address the research deficiencies we highlight will provide a deeper understanding of the foraging behaviours and potential ecosystem impacts of many of the world's carnivores, thus aiding effective conservation and management actions. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA. Methods: Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids. Results: Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells. Conclusions: The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis. [ABSTRACT FROM AUTHOR]

Motivation: Learning cellular dynamics through reconstruction of the underlying cellular potential energy landscape (aka Waddington landscape) from time-series single-cell RNA sequencing (scRNA-seq) data is a current challenge. Prevailing data-driven computational methods can be hampered by the lack of physical principles to guide learning from complex data, resulting in reduced prediction accuracy and interpretability when applied to infer cell population dynamics. Results: Here, we propose PI-SDE, a physics-informed neural stochastic differential equation (SDE) framework that combines the Hamilton–Jacobi (HJ) equation and neural SDE to learn cellular dynamics. Grounded in potential energy theory of biological systems, PI-SDE integrates the principle of least action by enforcing the HJ equation when reconstructing cellular potential energy function. This approach not only facilitates accurate predictions, but also improves interpretability, especially in the reconstructed potential energy landscape. Through benchmarking on two real scRNA-seq datasets, we demonstrate the importance of incorporating the HJ regularization term in dynamic inference, especially in predicting gene expression at held-out time points. Meanwhile, the learned potential energy landscape provides biologically interpretable insights into the process of cell differentiation. Our framework enhances model performance, while maintaining robustness and stability. Availability: PI-SDE software is available at https://github.com/QiJiang-QJ/PI-SDE. [ABSTRACT FROM AUTHOR]

Bioenergetics models are powerful tools used to address a range of questions in fish biology. However, these models are rarely informed by free‐swimming activity data, introducing error. To quantify the costs of activity in free‐swimming fish, calibrations produced from standardized laboratory trials can be applied to estimate energy expenditure from sensor data for specific tags and species. Using swim tunnel respirometry, we calibrated acceleration sensor‐equipped transmitting tags to estimate the aerobic metabolic rates (ṀO2) of lake trout (Salvelinus namaycush) at three environmentally relevant temperatures. Aerobic and swim performance were also assessed. Like other calibrations, we found strong relationships between ṀO2 and acceleration or swimming speed, and jackknife validations and data simulations suggest that our models accurately predict metabolic costs of activity in adult lake trout (~5% algebraic error and ~20% absolute error). Aerobic and swim performance metrics were similar to those reported in other studies, but their critical swimming speed was lower than expected. Additionally, lake trout exhibited a wide aerobic scope, suggesting that the avoidance of waters ≥15°C may be related to selection for optimal growing temperatures. The ability to quantify the free‐swimming energetic costs of activity will advance our understanding of lake trout ecology and may yield improvements to bioenergetics model. [ABSTRACT FROM AUTHOR]

Hydrogels are renowned for their complex structures and unique physicochemical properties, establishing them as key materials in bioenergy harvesting applications. They are used in various applications, including triboelectric nanogenerators, piezoelectric, hydraulic, thermoelectric, and biofuel cells. Among these, hydrogels as key materials for thermoelectric applications represent a technology capable of continuously converting biological energy (thermal energy) into electrical energy. This technology shows great potential and commercial value in body monitoring, energy storage, and human‐machine interaction applications. Given its rapid development, a timely review focusing on the research progress of hydrogels and their composites in thermoelectric technology is presented. This review discusses various types of hydrogels used for thermoelectric power generation and refrigeration, their unique properties, strategies for enhancing their thermoelectric performance, and their applications in the field. Finally, the remaining challenges and feasible strategies are identified for improving the efficiency, stability, application range, and system‐level integration of next‐generation hydrogels for thermoelectric applications. [ABSTRACT FROM AUTHOR]

Oxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by lipid biosynthetic machinery localized in the IMM and class-specific lipid transporters that limit lipid traffic in and out of mitochondria. This unique lipid composition appears to be essential for functions of mitochondria, particularly OXPHOS, by its effects on direct lipid-to-protein interactions, membrane properties, and cristae ultrastructure. This review highlights the biological significance of mitochondrial lipids, with a particular spotlight on the role of lipids in mitochondrial bioenergetics. We describe pathways for the biosynthesis of mitochondrial lipids and provide evidence for their roles in physiology, their implications in human disease, and the mechanisms by which they regulate mitochondrial bioenergetics. In this review, Decker and Funai discuss how mitochondrial membrane lipids influence the bioenergetics of oxidative phosphorylation. The discussions include their syntheses, implications in human disease, and outstanding questions on the biophysical mechanisms that drive these influences. [ABSTRACT FROM AUTHOR]

Mobile consumers track fluctuating resources across heterogeneous landscapes to grow and survive. In river networks, the abundance and accessibility of food and the energetic consequences of foraging vary among habitats and through time, providing a shifting mosaic of growth opportunities for mobile consumers. However, a framework integrating the spatiotemporal dynamics of growth potential within riverscapes has been lacking. We present the concept of foodscapes to depict the dynamic changes in food abundance, food accessibility, and consumer physiology that contribute to spatial and temporal variation of fish growth in rivers. Drawing on case studies of salmonid fishes from Alaska to California, we illustrate how foodscapes can provide a plethora of foraging, growth, and life history opportunities that potentially contribute to population resilience. We identify knowledge gaps in understanding foodscapes and approaches for stewardship that focus on restoring diverse foraging and growth opportunities for fish and other mobile consumers in river networks. [ABSTRACT FROM AUTHOR]

Polar cod (Boreogadus saida) is an endemic key species of the Arctic Ocean ecosystem. The ecology of this forage fish is well studied in Arctic shelf habitats where a large part of its population lives. However, knowledge about its ecology in the central Arctic Ocean (CAO), including its use of the sea‐ice habitat, is hitherto very limited. To increase this knowledge, samples were collected at the under‐ice surface during several expeditions to the CAO between 2012 and 2020, including the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition. The diet of immature B. saida and the taxonomic composition of their potential prey were analysed, showing that both sympagic and pelagic species were important prey items. Stomach contents included expected prey such as copepods and amphipods. Surprisingly, more rarely observed prey such as appendicularians, chaetognaths, and euphausiids were also found to be important. Comparisons of the fish stomach contents with prey distribution data suggests opportunistic feeding. However, relative prey density and catchability are important factors that determine which type of prey is ingested. Prey that ensures limited energy expenditure on hunting and feeding is often found in the stomach contents even though it is not the dominant species present in the environment. To investigate the importance of prey quality and quantity for the growth of B. saida in this area, we measured energy content of dominant prey species and used a bioenergetic model to quantify the effect of variations in diet on growth rate potential. The modeling results suggest that diet variability was largely explained by stomach fullness and, to a lesser degree, the energetic content of the prey. Our results suggest that under climate change, immature B. saida may be at least equally sensitive to a loss in the number of efficiently hunted prey than to a reduction in the prey's energy content. Consequences for the growth and survival of B. saida will not depend on prey presence alone, but also on prey catchability, digestibility, and energy content. [ABSTRACT FROM AUTHOR]

Monitoring the metabolic cost or oxygen consumption associated with rest and exercise is crucial to understanding the impact of disease or physical training on the health of individuals. Traditionally, measuring the skeletal muscle oxygen cost associated with exercise/muscle contractions can be rather expensive or invasive (i.e., muscle biopsies). More recently, specific protocols designed around the use of near-infrared spectroscopy (NIRS) have been shown to provide a quick, noninvasive easy-to-use tool to measure skeletal muscle oxygen consumption (M V ˙ o 2 ). However, the data and results from NIRS devices are often misunderstood. Thus the primary purpose of this sourcebook update is to provide several experimental protocols students can utilize to improve their understanding of NIRS technology, learn how to analyze results from NIRS devices, and better understand how muscle contraction intensity and type (isometric, concentric, or eccentric) influence the oxygen cost of muscle contractions. NEW & NOTEWORTHY: Compared to traditional methods, near-infrared spectroscopy (NIRS) provides a relatively cheap and easy-to-use noninvasive technique to measure skeletal muscle oxygen uptake following exercise. This laboratory not only enables students to learn about the basics of NIRS and muscle energetics but also addresses more complex questions regarding skeletal muscle physiology. [ABSTRACT FROM AUTHOR]

Aims: Seawater immersion significantly aggravated organ dysfunction following hemorrhagic shock, leading to higher mortality rate. However, the effective treatment is still unavailable in clinic. Mitochondria were involved in the onset and development of multiple organ function disorders; whether mitochondria participate in the cardiac dysfunction following seawater immersion combined with hemorrhagic shock remains poorly understood. Hence, we investigated the role and possible mechanism of mitochondria in seawater immersion combined with hemorrhage shock–induced cardiac dysfunction. Results: Mitochondrial fission protein dynamin-related protein 1 (Drp1) was activated and translocated from the cytoplasm to mitochondria in the heart following seawater immersion combined with hemorrhagic shock, leading to excessive mitochondrial fission. Excessive mitochondrial fission disrupted mitochondrial function and structure and activated mitophagy and apoptosis. At the same time, excessive mitochondrial fission resulted in disturbance of myocardial structure and hemodynamic disorders and ultimately provoked multiple organ dysfunction and high mortality. Further studies showed that the mitochondrial division inhibitor mitochondrial division inhibitor-1 can significantly reverse Drp1 mitochondrial translocation and inhibit mitochondrial fragmentation, reactive oxygen species (ROS) accumulation, mitophagy, and apoptosis and then protect circulation and vital organ functions, prolonging animal survival. Innovation: Our findings indicate that Drp1-mediated mitochondrial fission could be a novel therapeutic targets for the treatment of seawater immersion combined with hemorrhagic shock. Conclusion: Drp1 mitochondrial translocation played an important role in the cardiac dysfunction after seawater immersion combined with hemorrhage shock. Drp1-mediated excessive mitochondrial fission leads to cardiac dysfunction due to the mitochondrial structure and bioenergetics impairment. [ABSTRACT FROM AUTHOR]

Many river systems within the Central Valley of California have been disconnected from their floodplains, hypothesized to be partially responsible for declining Chinook salmon populations (Oncorhynchus tshawytscha). The primary floodplain of the system, Yolo By‐Pass (known regionally as "Yolo Bypass"), offered an opportunity to examine whether improved connectivity between the floodplain and river could limit negative climate change effects on salmon populations. Specifically, the top of the floodplain (Fremont Weir) is being modified to provide Sacramento River Chinook salmon better access to floodplain rearing habitat. We estimated restoration effects on the Yolo By‐Pass flood regime now and under future climate scenarios using flow rating curves. Additionally, we used temperature and flow‐specific effects on Chinook salmon population dynamics within the Yolo By‐Pass and Sacramento River complex to describe how the restoration project and climate change may interact to affect juvenile Chinook salmon biomass production. Our results indicate that the Fremont Weir restoration project will extend the frequency, timing, and duration of Yolo By‐Pass flooding. Our production model indicates that the modification will result in greater salmon entrainment rates into the Yolo By‐Pass, where salmon growth rates, survival rates, and biomass production were higher when compared to the Sacramento River main stem. The project appears to benefit all regional runs of Chinook salmon, which should help support life history diversity. Our results suggest that the weir modification should benefit native fish from the Central Valley that use floodplain habitat and that these benefits may be resilient to challenges created by a changing climate. [ABSTRACT FROM AUTHOR]

In remote sensing scene classification (RSSC), restrictions on real-time processing on power consumption, performance, and resources necessitate the compression of neural networks. Unlike artificial neural networks (ANNs), spiking neural networks (SNNs) convey information through spikes, offering superior energy efficiency and biological plausibility. However, the high latency of SNNs restricts their practical application in RSSC. Therefore, there is an urgent need to research ultra-low-latency SNNs. As latency decreases, the performance of the SNN significantly deteriorates. To address this challenge, we propose a novel spatio-temporal pruning method that enhances the feature capture capability of ultra-low-latency SNNs. Our approach integrates spatial fundamental structures during the training process, which are subsequently pruned. We conduct a comprehensive evaluation of the impacts of these structures across classic network architectures, such as VGG and ResNet, demonstrating the generalizability of our method. Furthermore, we develop an ultra-low-latency training framework for SNNs to validate the effectiveness of our approach. In this paper, we successfully achieve high-performance ultra-low-latency SNNs with a single time step for the first time in RSSC. Remarkably, our SNN with one time step achieves at least 200 times faster inference time while maintaining a performance comparable to those of other state-of-the-art methods. [ABSTRACT FROM AUTHOR]

• IAC significantly affects the nitrogen removal performance of the PN/A system. • Rate-limiting step of mature PN/A biofilms was independent of IAC. • IAC does not affect the ecological niche differentiation of Ca. Brocadia and Ca. Jettenia. • Enhanced nitrogen removal performance via IAC regulation. One-stage partial nitrification coupled with anammox (PN/A) technology effectively reduces the energy consumption of a biological nitrogen removal system. Inhibiting nitrite-oxidizing bacteria (NOB) is essential for this technology to maintain efficient nitrogen removal performance. Initial ammonium concentration (IAC) affects the degree of inhibited NOB. In this study, the effect of the IAC on a PN/A biofilm was investigated in a moving bed biofilm reactor. The results showed that nitrogen removal efficiency decreased from 82.49% ± 1.90% to 64.57% ± 3.96% after the IAC was reduced from 60 to 20 mg N/L, while the nitrate production ratio increased from 13.87% ± 0.90% to 26.50% ± 3.76%. NOB activity increased to 1,133.86 mg N/m2/day after the IAC decreased, approximately 4-fold, indicating that the IAC plays an important inhibitory role in NOB. The rate-limiting step in the mature biofilm of the PN/A system is the nitritation process and is not shifted by the IAC. The analysis of the microbial community structure in the biofilm indicates that the IAC was the dominant factor in changes in community structure. Ca. Brocadia and Ca. Jettenia were the main anammox bacteria, and Nitrosomonas and Nitrospira were the main AOB and NOB, respectively. IAC did not affect the difference in growth between Ca. Brocadia and Ca. Jettenia. Thus, modulating the IAC promoted the PN/A process with efficient nitrogen removal performance at medium to low ammonium concentrations. [Display omitted] [ABSTRACT FROM AUTHOR]

Mitophagy is a mechanism that maintains mitochondrial integrity and homeostasis and is thought to promote longevity and reduce the risk of age-related neurodegenerative diseases, including Alzheimer's disease (AD). Here, we investigate the abundance of mitochondrial reactive oxygen species (ROS), mitochondrial function, and mitophagy in primary fibroblasts from patients with sporadic AD (sAD) and normal healthy controls. The results show increased levels of mitochondrial ROS, changes in mitochondrial morphology, altered bioenergetic properties, and defects in autophagy, mitophagy, and lysosome-mediated degradation pathways in sAD fibroblasts relative to control fibroblasts. Interestingly, lysosome abundance and the staining of lysosomal markers remained high, while the capacity of lysosome-dependent degradation was lower in sAD fibroblasts than in controls fibroblasts. Nicotinamide riboside supplementation decreased mitochondrial ROS, while capacity for lysosomal degradation remained unchanged in sAD fibroblasts relative to healthy control fibroblasts. These findings provide insight into molecular mechanisms involving the dysregulation of lysosome and autophagy/mitophagy pathways that may contribute significantly to clinical signs and pathological features of sAD. [Display omitted] • Mitochondrial reactive oxygen species (ROS) level is elevated in the AD fibroblasts. • The systematic changes of mitochondrial morphology and bioenergetics changes exist in AD fibroblasts. • Lysosome signaling is increased but lysosome degradation capacity is decreased in AD fibroblasts. • Supplementation with NAD + precursor nicotinamide riboside (NR) can reduce mitochondrial ROS level in AD fibroblasts. [ABSTRACT FROM AUTHOR]

Fibrosis is the tissue scarring characterized by excess deposition of extracellular matrix (ECM) proteins, mainly collagens. A fibrotic response can take place in any tissue of the body and is the result of an imbalanced reaction to inflammation and wound healing. Metabolism has emerged as a major driver of fibrotic diseases. While glycolytic shifts appear to be a key metabolic switch in activated stromal ECM-producing cells, several other cell types such as immune cells, whose functions are intricately connected to their metabolic characteristics, form a complex network of pro-fibrotic cellular crosstalk. This review purports to clarify shared and particular cellular responses and mechanisms across organs and etiologies. We discuss the impact of the cell-type specific metabolic reprogramming in fibrotic diseases in both experimental and human pathology settings, providing a rationale for new therapeutic interventions based on metabolism-targeted antifibrotic agents. [Display omitted] • Cell-type-specific metabolic alterations represent a major driver of organ fibrosis. • Defective mitochondrial function in parenchymal cells contributes to fibrogenesis. • Glycolysis is key for the activation of stromal extracellular matrix-producing cells. • Metabolism-targeting drugs have emerged as promising antifibrotic agents. [ABSTRACT FROM AUTHOR]

Photorespiration is an essential process related to photosynthesis that is initiated following the oxygenation reaction catalyzed by rubisco, the initial enzyme of the Calvin–Benson–Bassham cycle. This reaction produces an inhibitory intermediate that is recycled back into the Calvin–Benson–Bassham cycle by photorespiration which requires the use of energy and the release of a portion of the carbon as CO2. The energy use and CO2 release of canonical photorespiration form a foundation for biochemical models used to describe and predict leaf carbon exchange and energy use (ATP and NAPDH). The ATP and NADPH demand of canonical photorespiration is thought to be different than that of the Calvin–Benson–Bassham cycle, requiring increased flexibility in the ratio of ATP and NADPH from the light reactions. Photorespiration requires many reactions across the chloroplasts, mitochondria and peroxisomes and involves many intermediates. Growing evidence indicates that these intermediates do not all stay in photorespiration as typically assumed and instead feed into other aspects of metabolism and leave as glycine, serine, and methylene‐THF. Here we discuss how alternative flux through and from canonical photorespiration alters the ATP and NADPH requirements of metabolism following rubisco oxygenation using additional derivations of biochemical models of leaf photosynthesis and energetics. Using these new derivations, we determine that the ATP and NADPH demands of photorespiration are highly sensitive to alternative flux in ways that fundamentally changes how photorespiration contributes to the ratio of total ATP and NADPH demand. Specifically, alternative flows of carbon through photorespiration could reduce ATP and NADPH demand ratio to values below what is produced from linear electron transport. Summary statement: All carbon produced following rubisco‐catalyzed reaction with oxygen may not flow through textbook photorespiration. Here we review the consequences of this "noncanonical" carbon flow to the ATP and NADPH demands of this vital process. [ABSTRACT FROM AUTHOR]