Lactate Metabolism Research Articles

Monitoring live mitochondrial metabolism in real-time using NMR spectroscopy.

Investigation of mitochondrial metabolism is gaining increased interest owing to the growing recognition of the role of mitochondria in health and numerous diseases. Studies of isolated mitochondria promise novel insights into the metabolism devoid of confounding effects from other cellular organelles such as cytoplasm. This study describes the isolation of mitochondria from mouse skeletal myoblast cells (C2C12) and the investigation of live mitochondrial metabolism in real-time using isotope tracer-based NMR spectroscopy. [3-13 C1 ]pyruvate was used as the substrate to monitor the dynamic changes of the downstream metabolites in mitochondria. The results demonstrate an intriguing phenomenon, in which lactate is produced from pyruvate inside the mitochondria and the results were confirmed by treating mitochondria with an inhibitor of mitochondrial pyruvate carrier (UK5099). Lactate is associated with health and numerous diseases including cancer and, to date, it is known to occur only in the cytoplasm. The insight that lactate is also produced inside mitochondria opens avenues for exploring new pathways of lactate metabolism. Further, experiments performed using inhibitors of the mitochondrial respiratory chain, FCCP and rotenone, show that [2-13 C1 ]acetyl coenzyme A, which is produced from [3-13 C1 ]pyruvate and acts as a primary substrate for the tricarboxylic acid cycle in mitochondria, exhibits a remarkable sensitivity to the inhibitors. These results offer a direct approach to visualize mitochondrial respiration through altered levels of the associated metabolites.

The integrated single-cell analysis developed a lactate metabolism-driven signature to improve outcomes and immunotherapy in lung adenocarcinoma.

It has been suggested that lactate metabolism (LM) is crucial for the development of cancer. Using integrated single-cell RNA sequencing (scRNA-seq) analysis, we built predictive models based on LM-related genes (LMRGs) to propose novel targets for the treatment of LUAD patients. The most significant genes for LM were identified through the use of the AUCell algorithm and correlation analysis in conjunction with scRNA-seq analysis. To build risk models with superior predictive performance, cox- and lasso-regression were utilized, and these models were validated on multiple external independent datasets. We then explored the differences in the tumor microenvironment (TME), immunotherapy, mutation landscape, and enriched pathways between different risk groups. Finally, cell experiments were conducted to verify the impact of AHSA1 in LUAD. A total of 590 genes that regulate LM were identified for subsequent analysis. Using cox- and lasso-regression, we constructed a 5-gene signature that can predict the prognosis of patients with LUAD. Notably, we observed differences in TME, immune cell infiltration levels, immune checkpoint levels, and mutation landscapes between different risk groups, which could have important implications for the clinical treatment of LUAD patients. Based on LMRGs, we constructed a prognostic model that can predict the efficacy of immunotherapy and provide a new direction for treating LUAD.

Dietary Folate Deficiency Promotes Lactate Metabolic Disorders to Sensitize Lung Cancer Metastasis through MTOR-Signaling-Mediated Druggable Oncotargets

Lactate metabolism plays a pivotal role in cancers but is often overlooked in lung cancer (LC). Folate deficiency has been linked to lung cancer development, but its impact on lactate metabolism and cancer malignancy is unclear. To investigate this, mice were fed either a folate-deficient (FD) or control diet and intrapleurally implanted with lung cancer cells pre-exposed to FD growth medium. Results showed that FD promoted lactate over-production and the formation of tumor oncospheroids (LCSs) with increased metastatic, migration, and invasion potential. Mice implanted with these cells and fed an FD diet developed hyperlactatemia in blood and lungs. This coincided with increased expression of hexokinase 2 (HK2), lactate dehydrogenase (LDH), and decreased expression of pyruvate dehydrogenase (PDH). Pre-treatment of the FD-LCS-implanted mice with the mTORC1 inhibitor, rapamycin, and the anti-metabolic drug metformin abolished FD/LCS-activated mTORC1 and its targets including HIF1α, HK2, LDH, and monocarboxylate transporters (MCT1 and MCT4), which coincided with the reduction in lactate disorders and prevention of LC metastasis. The findings suggest that dietary FD promotes lactate metabolic disorders that sensitize lung cancer metastasis through mTOR-signaling-mediated targets.

The role of lactate metabolism-related LncRNAs in the prognosis, mutation, and tumor microenvironment of papillary thyroid cancer.

Lactate, a byproduct of glucose metabolism, is primarily utilized for gluconeogenesis and numerous cellular and organismal life processes. Interestingly, many studies have demonstrated a correlation between lactate metabolism and tumor development. However, the relationship between long non-coding RNAs (lncRNAs) and lactate metabolism in papillary thyroid cancer (PTC) remains to be explored. Lactate metabolism-related lncRNAs (LRLs) were obtained by differential expression and correlation analyses, and the risk model was further constructed by least absolute shrinkage and selection operator analysis (Lasso) and Cox analysis. Clinical, immune, tumor mutation, and enrichment analyses were performed based on the risk model. The expression level of six LRLs was tested using RT-PCR. This study found several lncRNAs linked to lactate metabolism in both The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Using Cox regression analysis, 303 lactate LRLs were found to be substantially associated with prognosis. Lasso was done on the TCGA cohort. Six LRLs were identified as independent predictive indicators for the development of a PTC prognostic risk model. The cohort was separated into two groups based on the median risk score (0.39717 -0.39771). Subsequently, Kaplan-Meier survival analysis and multivariate Cox regression analysis revealed that the high-risk group had a lower survival probability and that the risk score was an independent predictive factor of prognosis. In addition, a nomogram that can easily predict the 1-, 3-, and 5-year survival rates of PTC patients was established. Furthermore, the association between PTC prognostic factors and tumor microenvironment (TME), immune escape, as well as tumor somatic mutation status was investigated in high- and low-risk groups. Lastly, gene expression analysis was used to confirm the differential expression levels of the six LRLs. In conclusion, we have constructed a prognostic model that can predict the prognosis, mutation status, and TME of PTC patients. The model may have great clinical significance in the comprehensive evaluation of PTC patients.

In-vivo magnetic resonance spectroscopy of lactate as a non-invasive biomarker of dichloroacetate activity in cancer and non-cancer central nervous system disorders.

The adverse effects of lactic acidosis in the cancer microenvironment have been increasingly recognized. Dichloroacetate (DCA) is an orally bioavailable, blood brain barrier penetrable drug that has been extensively studied in the treatment of mitochondrial neurologic conditions to reduce lactate production. Due to its effect reversing aerobic glycolysis (i.e., Warburg-effect) and thus lactic acidosis, DCA became a drug of interest in cancer as well. Magnetic resonance spectroscopy (MRS) is a well-established, non-invasive technique that allows detection of prominent metabolic changes, such as shifts in lactate or glutamate levels. Thus, MRS is a potential radiographic biomarker to allow spatial and temporal mapping of DCA treatment. In this systematic literature review, we gathered the available evidence on the use of various MRS techniques to track metabolic changes after DCA administration in neurologic and oncologic disorders. We included in vitro, animal, and human studies. Evidence confirms that DCA has substantial effects on lactate and glutamate levels in neurologic and oncologic disease, which are detectable by both experimental and routine clinical MRS approaches. Data from mitochondrial diseases show slower lactate changes in the central nervous system (CNS) that correlate better with clinical function compared to blood. This difference is most striking in focal impairments of lactate metabolism suggesting that MRS might provide data not captured by solely monitoring blood. In summary, our findings corroborate the feasibility of MRS as a pharmacokinetic/pharmacodynamic biomarker of DCA delivery in the CNS, that is ready to be integrated into currently ongoing and future human clinical trials using DCA.

Lactate and Lactylation in the Brain: Current Progress and Perspectives.

As the final product of glycolysis, lactate features not only as an energy substrate, a metabolite, and a signaling molecule in a variety of diseases-such as cancer, inflammation, and sepsis-but also as a regulator of protein lactylation; this is a newly proposed epigenetic modification that is considered to be crucial for energy metabolism and signaling in brain tissues under both physiological and pathological conditions. In this review, evidence on lactylation from studies on lactate metabolism and disease has been summarized, revealing the function of lactate and its receptors in the regulation of brain function and summarizing the levels of lactylation expression in various brain diseases. Finally, the function of lactate and lactylation in the brain and the potential mechanisms of intervention in brain diseases are presented and discussed, providing optimal perspectives for future research on the role of lactylation in the brain.

Targeting cancer lactate metabolism with synergistic combinations of synthetic catalysts and monocarboxylate transporter inhibitors

Synthetic anticancer catalysts offer potential for low-dose therapy and the targeting of biochemical pathways in novel ways. Chiral organo-osmium complexes, for example, can catalyse the asymmetric transfer hydrogenation of pyruvate, a key substrate for energy generation, in cells. However, small-molecule synthetic catalysts are readily poisoned and there is a need to optimise their activity before this occurs, or to avoid this occurring. We show that the activity of the synthetic organometallic redox catalyst [Os(p-cymene)(TsDPEN)] (1), which can reduce pyruvate to un-natural d-lactate in MCF7 breast cancer cells using formate as a hydride source, is significantly increased in combination with the monocarboxylate transporter (MCT) inhibitor AZD3965. AZD3965, a drug currently in clinical trials, also significantly lowers the intracellular level of glutathione and increases mitochondrial metabolism. These synergistic mechanisms of reductive stress induced by 1, blockade of lactate efflux, and oxidative stress induced by AZD3965 provide a strategy for low-dose combination therapy with novel mechanisms of action.Graphical abstract

Investigating the Extracellular-Electron-Transfer Mechanisms and Kinetics of Shewanella decolorationis NTOU1 Reducing Graphene Oxide via Lactate Metabolism

Microbial graphene oxide reduction is a developing method that serves to reduce both production costs and environmental impact in the synthesis of graphene. This study demonstrates microbial graphene oxide reduction using Shewanella decolorationis NTOU1 under neutral and mild conditions (pH = 7, 35 °C, and 1 atm). Graphene oxide (GO) prepared via the modified Hummers' method is used as the sole solid electron acceptor, and the characteristics of reduced GO (rGO) are investigated. According to electron microscopic images, the surface structure of GO was clearly changed from smooth to wrinkled after reduction, and whole cells were observed to be wrapped by GO/rGO films. Distinctive appendages on the cells, similar to nanowires or flagella, were also observed. With regard to chemical-bonding changes, after a 24-h reaction of 1 mg mL-1, GO was reduced to rGO, the C/O increased from 1.4 to 3.0, and the oxygen-containing functional groups of rGO were significantly reduced. During the GO reduction process, the number of S. decolorationis NTOU1 cells decreased from 1.65 × 108 to 1.03 × 106 CFU mL-1, indicating the bactericide effects of GO/rGO. In experiments adding consistent concentrations of initial bacteria and lactate, it was shown that with the increase of GO additions (0.5-5.0 mg mL-1), the first-order reaction rate constants (k) of lactate metabolism and acetate production increased accordingly; in experiments adding consistent concentrations of initial bacteria and GO but different lactate levels (1 to 10 mM), the k values of lactate metabolism did not change significantly. The test results of adding different electron transfer mediators showed that riboflavin and potassium ferricyanide were able to boost GO reduction, whereas 2,6-dimethoxy-1,4-benzoquinone and 2,6-dimethyl benzoquinone completely eliminated bacterial activity.

Pyruvate dehydrogenase beta subunit (Pdhb) promotes peripheral axon regeneration by regulating energy supply and gene expression

Key metabolic enzymes not only regulate Glucose, lipid, amino acid metabolism to serve the cellular energy needs, but also modulate noncanonical or nonmetabolic signaling pathway such as gene expression, cell-cycle progression, DNA repair, apoptosis and cell proliferation in regulating the pathologic progression of disease. However, the role of glycometabolism in peripheral nerve axon regeneration is little known. In this study, we investigated the expression of Pyruvate dehydrogenase E1(PDH), a key enzyme linking glycolysis and the tricarboxylic acid (TCA) cycle, with qRT-PCR and found that pyruvate dehydrogenase beta subunit (Pdhb) is up-regulated at the early stage during peripheral nerve injury. The knockdown of Pdhb inhibits neurite outgrowth of primary DRG neurons in vitro and restrains axon regeneration of sciatic nerve after crush injury. Pdhb overexpression promoting axonal regeneration is reversed by knockdown of Monocarboxylate transporter 2(Mct2), a transporter involved in the transport and metabolism of lactate, indicating Pdhb promoting axon regeneration depends on lactate for energy supply. Given the nucleus-localization of Pdhb, further analysis revealed that Pdhb enhances the acetylation of H3K9 and affecting the expression of genes involved in arachidonic acid metabolism and Ras signaling pathway, such as Rsa-14-44 and Pla2g4a, thereby promoting axon regeneration. Collectively, our data indicates that Pdhb is a positive dual modulator of energy generation and gene expression in regulating peripheral axon regeneration.

Lactate transport and metabolism in rumen epithelial cells in SARA condition

Lactate, a main product of rumen microbial fermentation from dietary starch, has been recognised as an important mediator of rumen microbiota regulation in rumen acidosis. However, the mechanism of lactate transport and metabolism in the rumen remains unclear. This study aimed to evaluate the significance of the absorption, transport, and metabolism of lactic acid in the pH and LPS-induced subacute ruminal acidosis (SARA) model of rumen epithelial cells (RECs). In the current study, RECs were obtained from two adult Saanen goats (44.5 ± 4.6 kg BW) and using Lipopolysaccharide (LPS) and low pH to co-stimulate RECs to construct a microenvironment under SARA conditions, to further analyse the lactate transport and metabolism by RECs. The results showed that the LPS and low pH could significantly reduce cell viability by 29.36% (p < 0.05), induce inflammation in RECs, destroy tight junctions between RECs, and increase cell permeability. In addition, stimulation leads to changes in cellular metabolic activity and inhibits the expression of lactate transporters (p < 0.05), promoting an increased risk of lactate accumulation in the intracellular and intestinal lumen. This study hopefully provides a better understanding of lactate metabolic regulation and new perspectives for the nutritional prevention and treatment of SARA. HIGHLIGHTS Lactic acid is an important fermentation product in the rumen of ruminants, and its transport and metabolic regulation mechanisms are still unclear. To understand transport uptake in the rumen epithelium, a SARA model was therefore used. Low pH and high LPS trigger epithelial inflammation, increasing the risk of lactic acid entering the bloodstream.

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies.

The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.

A monocarboxylate transporter-dependent mechanism confers resistance to exercise-induced fatigue in a high-altitude hypoxic environment

The body is more prone to fatigue in a high-altitude hypoxic environment, in which fatigue occurs in both peripheral muscles and the central nervous system (CNS). The key factor determining the latter is the imbalance in brain energy metabolism. During strenuous exercise, lactate released from astrocytes is taken up by neurons via monocarboxylate transporters (MCTs) as a substrate for energy metabolism. The present study investigated the correlations among the adaptability to exercise-induced fatigue, brain lactate metabolism and neuronal hypoxia injury in a high-altitude hypoxic environment. Rats were subjected to exhaustive incremental load treadmill exercise under either normal pressure and normoxic conditions or simulated high-altitude, low-pressure and hypoxic conditions, with subsequent evaluation of the average exhaustive time as well as the expression of MCT2 and MCT4 in the cerebral motor cortex, the average neuronal density in the hippocampus, and the brain lactate content. The results illustrate that the average exhaustive time, neuronal density, MCT expression and brain lactate content were positively correlated with the altitude acclimatization time. These findings demonstrate that an MCT-dependent mechanism is involved in the adaptability of the body to central fatigue and provide a potential basis for medical intervention for exercise-induced fatigue in a high-altitude hypoxic environment.

Lactate in the tumor microenvironment: A rising star for targeted tumor therapy.

Metabolic reprogramming is one of fourteen hallmarks of tumor cells, among which aerobic glycolysis, often known as the "Warburg effect," is essential to the fast proliferation and aggressive metastasis of tumor cells. Lactate, on the other hand, as a ubiquitous molecule in the tumor microenvironment (TME), is generated primarily by tumor cells undergoing glycolysis. To prevent intracellular acidification, malignant cells often remove lactate along with H+, yet the acidification of TME is inevitable. Not only does the highly concentrated lactate within the TME serve as a substrate to supply energy to the malignant cells, but it also works as a signal to activate multiple pathways that enhance tumor metastasis and invasion, intratumoral angiogenesis, as well as immune escape. In this review, we aim to discuss the latest findings on lactate metabolism in tumor cells, particularly the capacity of extracellular lactate to influence cells in the tumor microenvironment. In addition, we examine current treatment techniques employing existing medications that target and interfere with lactate generation and transport in cancer therapy. New research shows that targeting lactate metabolism, lactate-regulated cells, and lactate action pathways are viable cancer therapy strategies.

Effects of Pyruvate Kinase M2 (PKM2) Gene Deletion on Astrocyte-Specific Glycolysis and Global Cerebral Ischemia-Induced Neuronal Death.

Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte-neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-CreERT2; PKM2f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke.

Monocarboxylate transporter-dependent mechanism is involved in the adaptability of the body to exercise-induced fatigue under high-altitude hypoxia environment

Under high-altitude hypoxia environment, the body is more prone to fatigue, which occurs in both peripheral muscles and the central nervous system (CNS). The key factor determining the latter is the imbalance of brain energy metabolism, which makes it difficult to maintain the central nervous system to send peripheral nerve impulse continuously. During strenuous exercise, lactate released from astrocytes is taken up by neurons stored for energy to maintain synaptic transmission, a process mediated by monocarboxylate transporters (MCTs) in CNS. The present study investigated the correlation among the adaptability to exercise-induced fatigue, brain lactate metabolism and neuronal hypoxia injury under high-altitude hypoxia environment. Rats were subjected to exhaustive incremental load treadmill exercise under either normal pressure and normoxic conditions or simulated high-altitude low pressure and hypoxic conditions, with subsequent evaluation of the average exhaustive time as well as the expression of monocarboxylate transporters 2 (MCT2), MCT4, the average neuronal density in the cerebral motor cortex, and the lactate content in rat brain. At the early stage of simulated high-altitude environment, the average exhaustive time and neuronal density of rats decreased rapidly, then gradually recovered to some extent with the extension of altitude acclimatization time. The expression of MCT2, MCT4 and the lactate content in rat brain also increased gradually with the extension of altitude acclimatization time. After the application of lactate transport inhibitor, the recovery of exercise capacity of rats after altitude acclimatization was quickly blocked, and the neuronal injury in the cerebral motor cortex of rats was also significantly aggravated. These findings demonstrate that MCT-dependent mechanism is involved in the adaptability of the body to central fatigue, and provide a potential basis for medical intervention for exercise-induced fatigue under high-altitude hypoxia environment.

Glutathione-responsive nanoplatform for intra/extracellular lactate exhaustion to enhance antitumor immunotherapy

Despite the critical breakthrough achieved by immune checkpoint blockade (ICB) therapies in the clinic, the antitumor effect is seriously restricted by the immunosuppressive tumor microenvironment (ITM). A variety of strategies to alleviate the ITM have been investigated. Direct regulation of lactate metabolism in the tumor microenvironment (TME) holds promise for ITM modulation. Herein, we fabricated a glutathione-responsive PEGylated hollow mesoporous organosilicon (HMOP), with monocarboxylate transporter 1/4 inhibitor (diclofenac, DC) and lactate oxidase (LOX) loaded in/onto the HMOP (denoted as DC-HMOP-LOX). DC-HMOP-LOX could spontaneously be biodegraded in the TME due to the disulfide bonds, and then DC/LOX could be released to exhaust intra/extracellular lactate. DC-HMOP-LOX hindered the transmission of lactate effectively and oxidized lactate directly. Therefore, DC-HMOP-LOX collaboratively depleted lactate in the TME, which induced an immunocompetent TME by activating immune-promoting cells (dendritic cell, T cells, natural killer cells, and M1-macrophage), inactivating immunosuppressive cells (M2-macrophage and bone marrow-derived suppressor cells), and regulating the levels of immune cytokines (IFN-γ, TNF-α, IL-10, and IL-12). The immunocompetent TME ultimately strengthened the antitumor effect of anti-PD1-based immunotherapy.

Unlocking the high-rate continuous performance of fermentative hydrogen bioproduction from fruit and vegetable residues by modulating hydraulic retention time

Harnessing fruit-vegetable waste (FVW) as a resource to produce hydrogen via dark fermentation (DF) embraces the circular economy concept. However, there is still a need to upgrade continuous FVW-DF bioprocessing to enhance hydrogen production rates (HPR). This study aims to investigate the influence of the hydraulic retention time (HRT) on the DF of FVW by mixed culture. A stirred tank reactor under continuous mesophilic conditions was operated for 47 days with HRT stepwise reductions from 24 to 6 h, leading to organic loading rates between 47 and 188 g volatile solids (VS)/L-d. The optimum HRT of 9 h resulted in an unprecedented HPR from FVW of 11.8 NL/L-d, with a hydrogen yield of 95.6 NmL/g VS fed. Based on an overarching inspection of hydrogen production in conjunction with organic acids and carbohydrates analyses, it was hypothesized that the high FVW-to-biohydrogen conversion rate achieved was powered by lactate metabolism.

Thyrotoxic periodic paralysis associated with lactic metabolic acidosis: Case report of an African man and review of literature

BackgroundThyrotoxic periodic paralysis (TPP) is a rare and most often acquired subtype of hypokalemic periodic paralysis. The association of varying degrees of muscle weakness, hyperthyroidism and hypokalemia characterizes it. The treatment requires potassium supplementation, control of hyperthyroidism and prevention measures. It is a frequent disease in Asian men, but much rare in Caucasian or African populations. This is the first report of TPP associated with lactic metabolic acidosis in an African man. Case presentationA 23 year-old African man, native from Morocco, with recurrent episodes of tetraparesis for eleven months, and abdominal pain, was referred for evaluation. Biochemical investigations showed severe hypokalemia associated with hyperthyroidism and lactic metabolic acidosis. His EKG showed signs of hypokalemia such as sinus tachycardia and U waves. After potassium supplementation, neurological recuperation was quick and complete. Thyroid ultrasound identified a hypoechogenic and hypervascularized goiter, associated with high levels of thyroid antibodies, in favor of Grave's disease. With antithyroid drugs and life-style changes, the patient did not have any other attack. Review of literatureIn addition to the case report, this article presents an extended review of literature, from the first large study reporting the diagnosis and incidence of TPP in 1957 to nowadays. Are reported here the latest information concerning epidemiology, clinical manifestations, complementary examinations, management and genetic finding. The lactic acidosis observed initially is exceptional, never described in TPP. TPP is a diagnostic and therapeutic emergency, requiring careful potassium supplementation, in order to avoid the risk of the onset of rebound hyperkalemia, to be maintained until the etiological treatment is effective. Paraclinical assessment with emergency EKG and electromyogram are essential to assess the impact. DiscussionIt is essential in the face of any hypokalaemic periodic paralysis, including in non-Asian subjects, to search hyperthyroidism. ConclusionsThis report demonstrates the importance of thyroid testing in case of acute muscle weakness, even in non-Asian patients in order to diagnose TPP. This is a rare but possible etiology, to be distinguished from the familial form of hypokalemic periodic paralysis. It also questions on the impact of TPP on energetic metabolism, in particular on lactic metabolism.

Genomic Plasticity of Acid-Tolerant Phenotypic Evolution in Acetobacter pasteurianus.

Acetic acid bacteria have a remarkable capacity to cope with elevated concentrations of cytotoxic acetic acid in their fermentation environment. In particular, the high-level acetate tolerance of Acetobacter pasteurianus that occurs in vinegar industrial settings must be constantly selected for. However, the improved acetic acid tolerance is rapidly lost without a selection pressure. To understand genetic and molecular biology of this acquired acetic acid tolerance in A. pasteurianus, we evolved three strains A. pasteurianus CICIM B7003, CICIM B7003-02, and ATCC 33,445 over 960 generations (4months) in two initial acetic acids of 20g·L-1 and 30g·L-1, respectively. An acetic acid-adapted strain M20 with significantly improved specific growth rate of 0.159h-1 and acid productivity of 1.61g·L-1·h-1 was obtained. Comparative genome analysis of six evolved strains revealed that the genetic variations of adaptation were mainly focused on lactate metabolism, membrane proteins, transcriptional regulators, transposases, replication, and repair system. Among of these, lactate dehydrogenase, acetolactate synthase, glycosyltransferase, ABC transporter ATP-binding protein, two-component regulatory systems, the type II toxin-antitoxin system (RelE/RelB/StbE), exodeoxyribonuclease III, type I restriction endonuclease, tRNA-uridine 2-sulfurtransferase, and transposase might collaboratively contribute to the improved acetic acid tolerance in A. pasteurianus strains. The balance between repair factors and transposition variations might be the basis for genomic plasticity of A. pasteurianus strains, allowing the survival of populations and their offspring in acetic acid stress fluctuations. These observations provide important insights into the nature of acquired acetic acid tolerance phenotype and lay a foundation for future genetic manipulation of these strains.

Admission lactate concentration has predictive value for death or severe complications within 30 days after admission in cattle with long-bone fractures.

To determine the prognostic value of lactate concentration measurements at admission in cattle with long-bone fractures. 43 cattle with long-bone fractures between July 2016 and Dec 2018. In this prospective cohort study, lactate concentration was measured in systemic venous blood and locally in capillary blood sampled from the fractured and contralateral limbs of cattle and assessed for outcome prediction. The cutoff value was determined by maximizing the Youden index from receiver-operating characteristic curves. Multivariable logistic regression was employed to verify whether higher lactate concentrations compared with the cutoff value were an independent risk factor for poor outcomes at 30 days or 3 years after admission. Poor outcome was associated with higher capillary lactate concentration in the fractured limb (P < .001) and greater difference with systemic blood (P = .005). A cutoff value of lactate difference ≥ 2.4 mmol/L (sensitivity = 0.80; specificity = 0.965) between capillary lactate in the fractured limb and systemic blood was the best predictor of death ≤ 30 days after admission (P < .001). Multivariable analysis revealed that this cutoff value was an independent risk factor for 30-day and 3-year outcomes (P < .001). Admission blood lactate concentration difference ≥ 2.4 mmol/L between the fractured limb and systemic blood was a robust and independent predictor of outcome for cattle of the present report. Lactate metabolism is locally impaired in fractured limbs of nonsurviving or at higher complication risk cattle, which may help identify patients at high risk for poor outcomes.