High Metabolic Demand Research Articles

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

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

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

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

Identifying Neuroimaging Patterns in Mitochondrial Leukoencephalopathies (P8-4.001)

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

β Cell and Autophagy: What Do We Know?

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

Implication of Ferroptosis in Cholangiocarcinoma: A Potential Future Target?

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

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

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

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

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

Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?

Cancer cells within tumor masses are chronically exposed to stress caused by nutrient deprivation, oxygen limitation, and high metabolic demand. They also accumulate hundreds of mutations, potentially generating aberrant proteins that can induce proteotoxic stress. Finally, cancer cells are exposed to various damages during chemotherapy. In a growing tumor, transformed cells eventually adapt to these conditions, eluding the death-inducing outcomes of signaling cascades triggered by chronic stress. One such extreme outcome is ferroptosis, a form of iron-dependent non-apoptotic cell death mediated by lipid peroxidation. Not surprisingly, the tumor suppressor p53 is involved in this process, with evidence suggesting that it acts as a pro-ferroptotic factor and that its ferroptosis-inducing activity may be relevant for tumor suppression. Missense alterations of the TP53 gene are extremely frequent in human cancers and give rise to mutant p53 proteins (mutp53) that lose tumor suppressive function and can acquire powerful oncogenic activities. This suggests that p53 mutation provides a selective advantage during tumor progression, raising interesting questions on the impact of p53 mutant proteins in modulating the ferroptotic process. Here, we explore the role of p53 and its cancer-related mutants in ferroptosis, using a perspective centered on the resistance/sensitivity of cancer cells to exogenous and endogenous stress conditions that can trigger ferroptotic cell death. We speculate that an accurate molecular understanding of this particular axis may improve cancer treatment options.

Mitochondrial dynamics in neurological diseases: a narrative review.

The mitochondrion is a crucial organelle for aerobic respiration and energy metabolism. It undergoes dynamic changes, including changes in its shape, function, and distribution through fission, fusion, and movement. Under normal conditions, mitochondrial dynamics are in homeostasis. However, once the balance is upset, the nervous system, which has high metabolic demands, will most likely be affected. Recent studies have shown that the imbalance of mitochondrial dynamics is involved in the occurrence and development of various neurological diseases. However, whether the regulation of mitochondrial dynamics can be used to treat neurological diseases is still unclear. We aimed to comprehensively analyze mitochondrial dynamics regulation and its potential role in the treatment of neurological diseases. A comprehensive literature review was carried out to understand the mechanisms and applications of mitochondrial dynamics in neurological diseases based on the literature available in PubMed, Web of Science, and Google Scholar. This review discusses the molecular mechanisms related to mitochondrial dynamics and expounds upon the role of mitochondrial dynamics in the occurrence and development of neurodegenerative diseases, epilepsy, cerebrovascular disease, and brain tumors. Several clinically tested drugs with fewer side effects have been shown to improve the mitochondrial dynamics and nervous system function in neurological diseases. Disorders of mitochondrial dynamics can cause various neurological diseases. Elucidation of mechanisms and applications involved in mitochondrial dynamics will inform the development of new therapeutic targets and strategies for neurological diseases. Dynamin-related protein 1 (Drp1), as a highly relevant molecular for mitochondrial dynamics, might be a potential target for treating neurological diseases in the future.

Complex Life Histories Alter Patterns of Mercury Exposure and Accumulation in a Pond-Breeding Amphibian.

Quantifying how contaminants change across life cycles of species that undergo metamorphosis is critical to assessing organismal risk, particularly for consumers. Pond-breeding amphibians can dominate aquatic animal biomass as larvae and are terrestrial prey as juveniles and adults. Thus, amphibians can be vectors of mercury exposure in both aquatic and terrestrial food webs. However, it is still unclear how mercury concentrations are affected by exogenous (e.g., habitat or diet) vs endogenous factors (e.g., catabolism during hibernation) as amphibians undergo large diet shifts and periods of fasting during ontogeny. We measured total mercury (THg), methylmercury (MeHg), and isotopic compositions (δ 13C, δ15N) in boreal chorus frogs (Pseudacris maculata) across five life stages in two Colorado (USA) metapopulations. We found large differences in concentrations and percent MeHg (of THg) among life stages. Frog MeHg concentrations peaked during metamorphosis and hibernation coinciding with the most energetically demanding life cycle stages. Indeed, life history transitions involving periods of fasting coupled with high metabolic demands led to large increases in mercury concentrations. The endogenous processes of metamorphosis and hibernation resulted in MeHg bioamplification, thus decoupling it from the light isotopic proxies of diet and trophic position. These step changes are not often considered in conventional expectations of how MeHg concentrations within organisms are assessed.

Transient and Sustained Ganglion Cell Light Responses Are Differentially Modulated by Intrinsically Produced Reactive Oxygen Species Acting upon Specific Voltage-Gated Na+ Channel Isoforms.

Increasing spike rates drive greater neuronal energy demand. In turn, mitochondrial ATP production leads to the generation of reactive oxygen species (ROS) that can modulate ion channel gating. Does ROS production autoregulate the excitability of a neuron? We investigated the links between retinal ganglion cell (RGC) excitability and spike activity-driven ROS production in male and female mice. Changes to the light-evoked and current-evoked spike patterns of functionally identified αRGC subtypes, along with their NaV channel-gating properties, were recorded during experimentally induced decreases and increases of intracellular ROS. During periods of highest spike rates (e.g., following light onset in ON sustained RGCs and light offset in OFF sustained RGCs), these αRGC subtypes responded to reductions of ROS (induced by catalase or glutathione monoethyl ester) with higher spike rates. Increases in ROS (induced by mercaptosuccinate, antimycin-A, or H2O2) lowered spike rates. In ON and OFF transient RGCs, there were no changes in spike rate during ROS decreases but increased ROS increased spiking. This suggests that endogenous ROS are intrinsic neuromodulators in RGCs having high metabolic demands but not in RGCs with lower energy needs. We identified ROS-induced shifts in the voltage-dependent gating of specific isoforms of NaV channels that account for the modulation of ON and OFF sustained RGC spike frequency by ROS-mediated feedback. ROS-induced changes to NaV channel gating, affecting activation and inactivation kinetics, are consistent with the differing spike pattern alterations observed in RGC subtypes. Cell-autonomous generation of ROS during spiking contributes to tuning the spike patterns of RGCs.SIGNIFICANCE STATEMENT Energy production within retinal ganglion cells (RGCs) is accompanied by metabolic by-products harmful to cellular function. How these by-products modulate the excitability of RGCs bears heavily on visual function and the etiology of optic neuropathies. A novel hypothesis of how RGC metabolism can produce automodulation of electrical signaling was tested by identifying the characteristics and biophysical origins of changes to the excitability of RGCs caused by oxidizing by-products in the retina. This impacts our understanding of the pathophysiology of RGC dysfunction, supporting an emerging model in which increases in oxidizing chemical species during energy production, but not necessarily bioenergetic failure, lead to preferential degeneration of specific subtypes of RGCs, yielding loss of different aspects of visual capacity.

Clinical spectrum of infants with thiamine responsive pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disorder caused by hypertension in blood vessels from heart to lungs. Exclusively breastfed infants are at the highest risk due to their high metabolic demand and low thiamine level in mothers. Symptoms are observed to be sometimes precipitated with the presence of co morbidity such as sepsis and lower respiratory tract infections. This study explains 10 cases with varied clinical presentation and response to management of different grades of infantile pulmonary arterial hypertension.

How mouthbrooding cichlid mothers avoid consuming their brood

When offspring number in the tens or hundreds, fish had to get inventive to keep them safe and a few came up with one ingenious strategy: they hold their eggs in their mouths until the youngsters hatch. ‘Mouthbrooding is an adaptation in response to predation pressure’, says Suzy Renn from Reed College, USA. But, when cichlid (Astatotilapia burtoni) mothers gather their eggs into their mouths, dining is off the menu for 2–3 weeks, which takes its toll. The mothers lose weight (body mass) until they regain the ability to eat – once the fry are liberated – and they begin preparing for their next clutch. All of this is tightly coordinated by circuits in the brain, but exactly which neurotransmitters and hormones are key to the precise regulation of the fish's behaviour wasn't clear. Renn and Joshua Faber-Hammond, also from Reed College, monitored the brains of mouthbrooding cichlid mothers to find out which genes were activated at different stages of the process to coordinate the physical changes that accompany cichlid parenthood.Renn collected samples of the A. burtoni mothers’ brains 2 days after spawning when their eggs were fresh in their mouths, 14 days after spawning when the fry were almost ready for release, 2 days after the fry had been set free and 14 days after fry release, when the mothers were preparing to lay another clutch. Then, Faber-Hammond analysed the brain mRNA, which is produced when a gene is expressed for protein production, to identify which genes are activated when the mothers go without food while brooding their young and afterwards, during recovery.Identifying 128 genes whose abundance varied as the fish progressed through their parenting odyssey, it was clear that genes involved in controlling when animals become more nurturing, when they feed and metabolic activity all played essential roles at different stages. Most impressively, the gene expression levels of two neuropeptides – neurotensin and galanin, both of which impact the bond between parent and young in various creatures – which had been high when the fry were in the mother's mouth, plummeted after mothers released their offspring. ‘That could mean that the signals in the brain that increase parental care in fish may be some of the same signals that increase parental care in frogs, birds and even mice’, says Renn, explaining that the reductions are probably associated with the mothers gearing up to protect their young once free.Genes that are involved in regulating appetite also featured large, with genes for hormones and neuropeptides that supress appetite surging when the mothers were mouthbrooding, while the expression of hormones that stimulate appetite increased once they could resume feeding after releasing their young. However, some appetite-stimulating genes increased their activity while the mothers were brooding, which ‘underscores the complexity of feeding regulation under a situation of voluntary starvation’, says Renn.The duo also noticed that genes that encode proteins involved in energy production became more active when the mothers were fasting, in addition to genes that are known to turn down metabolism in fasting or hibernating creatures. ‘That we see these changes … occurring in brain samples may reflect high metabolic demand of neural tissue’, says Renn. Meanwhile, the expression of genes that encode proteins that carry oxygen plummeted toward the end of mouthbrooding, while expression of those encoding proteins that protect the brain from damage rocketed.‘The gene expression patterns reveal how the female brain may resolve trade-offs between metabolic demands and parental care’, says Renn, adding that many of the changes found in the brain probably also occur in the bodies of the mouthbrooding mothers.

Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning.

Cyanide exposure can occur in various settings such as industry and metallurgy. The primary mechanism of injury is cellular hypoxia from Complex IV (CIV) inhibition. This leads to decreased ATP production and increased reactive oxygen species production. The brain and the heart are the organs most affected due to their high metabolic demand. While the cardiac effects of cyanide are well known, the cerebral effects on cellular function are less well described. We investigated cerebral metabolism with a combination of brain respirometry, microdialysis, and western blotting using a rodent model of sub-lethal cyanide poisoning. Twenty rodents were divided into two groups: control (n = 10) and sub-lethal cyanide (n = 10). Cerebral microdialysis was performed during a 2mg/kg/h cyanide exposure to obtain real-time measurements of cerebral metabolic status. At the end of the exposure (90min), brain-isolated mitochondria were measured for mitochondrial respiration. Brain tissue ATP concentrations, acyl-Coenzyme A thioesters, and mitochondrial content were also measured. The cyanide group showed significantly increased lactate and decreased hypotension with decreased cerebral CIV-linked mitochondrial respiration. There was also a significant decrease in cerebral ATP concentration in the cyanide group and a significantly higher cerebral lactate-to-pyruvate ratio (LPR). In addition, we also found decreased expression of Complex III and IV protein expression in brain tissue from the cyanide group. Finally, there was no change in acyl-coenzyme A thioesters between the two groups. The key finding demonstrates mitochondrial dysfunction in brain tissue that corresponds with a decrease in mitochondrial function, ATP concentrations, and an elevated LPR indicating brain dysfunction at a sub-lethal dose of cyanide.

Depth distribution of the bigeye hound sharkIago omanensisand other deep-sea species observed by baited-camera in the Red Sea

AbstractThe Red Sea is a largely homogeneous water column beyond the top 300 m, unique in exhibiting warm bottom water (~21.5 °C) at depths down to ~2900 m. The unusual conditions coupled with barriers to colonization by primary deep-sea species has resulted in an impoverished but distinct deep fauna. This study presents a rare investigation of the deep Red Sea. The bigeye hound sharkIago omanensisis a known deep-sea shark in the Red Sea. However, its full depth distribution has never been conclusively studied. Here, we confirm with videographic evidence the presence ofI. omanensisat depths to 2522 m in the Red Sea, along with observations of other deep-sea species.Iago omanensiswas the only species of scavenging fish observed and only in moderate numbers. The additional six species were mostly crustacea in low abundance. The lack of scavenging species present in the deep Red Sea is likely explained by the low productivity of the overlying surface waters and unusually warm water temperature resulting in low energetic input but high metabolic demands in deep communities.

Targeting Na-H exchanger 1 overcomes nuclear factor kappa B-mediated tumor resistance to radiotherapy

Intrinsic or acquired radioresistance often limits the efficacy of radiation therapy (RT), thereby leading to local control failure. Cancerous cells have abnormal pH dynamics due to high metabolic demands, but it is unclear how pH dynamics contribute to radioresistance. In this study, we investigated the role of Na-H exchange 1 (NHE1), the major intracellular pH (pHi) regulator, in RT response. We observed that RT increased NHE1 expression and modulated pHi in MDA-MB-231 human breast cancer cells. When combined with RT, pharmacological NHE1 inhibition by 5-(N-Ethyl-N-isopropyl)amiloride (EIPA) reduced pHi and clonogenic survival. EIPA attenuated radiation-damaged DNA repair, increasing G2/M cell cycle arrest. The combination of EIPA and RT increased apoptotic cell death while decreasing phosphorylation of NF-κB p65. Similarly, the knockdown of NHE1 increased radiosensitivity with lower pHi and increased apoptosis. Consistent with in vitro data, the EIPA plus RT inhibited the growth of MDA-MB-231 xenograft tumors in mice to a greater extent than either EIPA or RT alone. EIPA abrogated the RT-induced increase in NHE1 and phospho-NF-κB p65 expression in tumor tissues. Such coincidence of increased NHE1 level, pHi, and NF-κB activation was also found in radioresistant MDA-MB-231 cells, which were reversed by EIPA treatment. Bioinformatics analysis of RNA sequencing data revealed that inhibiting NHE1 reversed three core gene networks that were up-regulated in radioresistant cells and correlated with high NHE1 expression in patient samples: NF-κB, senescence, and extracellular matrix. Taken together, our findings suggest that NHE1 contributes to RT resistance via NF-κB-mediated signaling networks, and NHE1 may be a promising target for improving RT outcomes.

Effects of nursing a large litter and ovarian response to gonadotropins at weaning on subsequent fertility in first parity sows.

Post-weaning fertility failures occur more often in parity 1 (P1) sows due to high metabolic demands for lactation and their inability to meet energy requirements for maintenance, growth, and reproduction. We hypothesized that body condition loss occurs more frequently in P1 sows nursing a large litter, resulting in impairment of ovarian follicle development during lactation and post-weaning, which can negatively impact estrus and subsequent fertility. At 24 h post-farrowing, P1 sows (n = 123) were assigned to treatment (TRT) based on sow weight and the number of functional teats to receive a high number (HN, 15 to 16) or low number (LN, 12) of nursing piglets. At weaning, sows in each TRT were assigned to receive PG600 or None (Control). During lactation, sow body measures were obtained and ovarian follicles were assessed in mid-lactation and post-weaning. Lactation data were analyzed for the effects of TRT, and fertility data after weaning were assessed for TRT x PG600, but there were no interactions (P > 0.10). During lactation, 22.2 % of HN sows lost ≥ 4 piglets due to death or removal, and so these sows were excluded from further analysis. The HN sows were lighter (-6.2 kg), had less backfat (-1.0 mm), had lower body condition score (-0.4), and lost more nursing piglets (-1.2) than LN sows (P < 0.05). However, HN sows weaned more pigs (14.0) than LN sows (11.0). There was no effect of TRT on wean to estrus interval (4.2 d), but the interval was 0.5 days shorter for PG600 (P = 0.004) than control. There were no effects of TRT or PG600 on estrus within seven days after weaning (87.3 %), but PG600 induced smaller (P = 0.002) follicles at estrus (6.7 mm) than control (7.3 mm). In the subsequent parity, there were no effects of TRT or PG600 on farrowing rate (93.9%) and total born (13.2). Overall, HN sows lost more piglets and body condition but still weaned more pigs without any detrimental effects on subsequent reproductive performance.

Beneficial role of gut microbes in maintenance of pace-of-life traits in Phrynocephalus vlangalii

The pace-of-life syndrome theory suggests that species, populations, and individuals are positioned along a slow–fast pace-of-life continuum. However, whether and how individuals maintain a fast pace of life in a slow pace of life population remains unknown. In this study, the boldness and foraging behavior of Phrynocephalus vlangalii from Maduo (4250 m above sea level), a typical slow-paced population, were screened frequently. Both behaviors of P. vlangalii were significantly recurrent and linked with one another. Based on boldness and foraging behavior, the lizards were divided into positive and shy groups, and their gut microbial diversity were studied using 16S rRNA gene sequencing. No significant difference in α diversity was observed; however, a significant difference existed in the β diversity of gut microbes between the two groups. Principal coordinate analysis indicated that the gut microbes in the two groups were distinct. Linear discriminant analysis effect size determined that the shy group contained a more significant proportion of Rikenellaceae and Clostridia. In contrast, the positive group had a higher proportion of Verrucomicrobiota, Verrucomicrobiae, and Akkermansiaceae. Kyoto encyclopedia of genes and genomes pathway analysis revealed that biodegradation and metabolism, including lipid metabolism and glycan biosynthesis, were higher in the positive group; on the contrary, nucleotide metabolism and enzyme families were significantly higher in the shy group. The results showed that positive lizards had more beneficial intestinal microflora for lipid and glucose metabolism to satisfy their high metabolic energy demand, whereas shy lizards had more beneficial intestinal microflora for maintaining an elevated fasting blood glucose, a long life span, and a more stable metabolism to sustain their slow pace of life. In this study, we validate a strong relationship between the individual’s pace-of-life traits and intestinal microbiota in P. vlangalii. Further, we demonstrate that gut microorganisms are essential in sustaining the energy-intensive personality traits at high altitudes.

Cancer cell survival depends on collagen uptake into tumor-associated stroma

Collagen I, the most abundant protein in humans, is ubiquitous in solid tumors where it provides a rich source of exploitable metabolic fuel for cancer cells. While tumor cells were unable to exploit collagen directly, here we show they can usurp metabolic byproducts of collagen-consuming tumor-associated stroma. Using genetically engineered mouse models, we discovered that solid tumor growth depends upon collagen binding and uptake mediated by the TEM8/ANTXR1 cell surface protein in tumor-associated stroma. Tumor-associated stromal cells processed collagen into glutamine, which was then released and internalized by cancer cells. Under chronic nutrient starvation, a condition driven by the high metabolic demand of tumors, cancer cells exploited glutamine to survive, an effect that could be reversed by blocking collagen uptake with TEM8 neutralizing antibodies. These studies reveal that cancer cells exploit collagen-consuming stromal cells for survival, exposing an important vulnerability across solid tumors with implications for developing improved anticancer therapy.

Selective Activation of the Wnt-Signaling Pathway as a Novel Therapy for the Treatment of Diabetic Retinopathy and Other Retinal Vascular Diseases.

Retinal ischemia, often associated with various disorders such as diabetic retinopathy (DR), retinal vein occlusion, glaucoma, optic neuropathies, stroke, and other retinopathies, is a major cause of visual impairment and blindness worldwide. As proper blood supply to the retina is critical to maintain its high metabolic demand, any impediment to blood flow can lead to a decrease in oxygen supply, resulting in retinal ischemia. In the pathogenesis of DR, including diabetic macular edema (DME), elevated blood glucose leads to blood-retina barrier (BRB) disruptions, vascular leakage, and capillary occlusion and dropouts, causing insufficient delivery of oxygen to the retina, and ultimately resulting in visual impairment. Other potential causes of DR include neuronal dysfunction in the absence of vascular defect, genetic, and environmental factors. The exact disease progression remains unclear and varies from patient to patient. Vascular leakage leading to edema clearly links to visual impairment and remains an important target for therapy. Despite recent advances in the treatment of DME and DR with anti-VEGFs, effective therapies with new mechanisms of action to address current treatment limitations regarding vessel regeneration and reperfusion of ischemic retinal areas are still needed. The Wnt signaling pathway plays a critical role in proper vascular development and maintenance in the retina, and thus provides a novel therapeutic approach for the treatment of diabetic and other retinopathies. In this review, we summarize the potential of this pathway to address treatment gaps with current therapies, its promise as a novel and potentially disease modifying therapy for patients with DR and opportunities in other retinal vascular diseases.