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MBio Nov 2023is an alpha-proteobacterium that is a promising platform for industrial scale production of biofuels due to its efficient ethanol fermentation and low biomass...
is an alpha-proteobacterium that is a promising platform for industrial scale production of biofuels due to its efficient ethanol fermentation and low biomass generation. is aerotolerant and encodes a complete respiratory electron transport chain, but the benefit of respiration for growth in oxic conditions has never been confirmed, despite decades of research. Growth and ethanol production of wild-type is poor in oxic conditions indicating that it does not benefit from oxidative phosphorylation. Additionally, in previous studies, aerobic growth improved significantly when respiratory genes were disrupted () or acquired point mutations ( and ), even if respiration was significantly reduced by these changes. Here, we obtained clean deletions of respiratory genes and , individually and in combination, and showed, for the first time, that deletion of completely inhibited O respiration and dramatically reduced growth in oxic conditions. Both respiration and aerobic growth were restored by expressing a heterologous, water-forming NADH oxidase, . Oxygen can have many negative effects, including formation of reactive oxygen species (ROS) or directly inactivating oxygen sensitive enzymes. Our results suggest that the effect of molecular oxygen on enzymes had a greater negative impact on than formation of ROS. This result shows that the main role of the electron transport chain in is reducing the intracellular concentration of molecular oxygen, helping to explain why it is beneficial for to use electron transport chain complexes that have little capacity to contribute to oxidative phosphorylation. IMPORTANCE A key to producing next-generation biofuels is to engineer microbes that efficiently convert non-food materials into drop-in fuels, and to engineer microbes effectively, we must understand their metabolism thoroughly. is a bacterium that is a promising candidate biofuel producer, but its metabolism remains poorly understood, especially its metabolism when exposed to oxygen. Although respires with oxygen, its aerobic growth is poor, and disruption of genes related to respiration counterintuitively improves aerobic growth. This unusual result has sparked decades of research and debate regarding the function of respiration in . Here, we used a new set of mutants to determine that respiration is essential for aerobic growth and likely protects the cells from damage caused by oxygen. We conclude that the respiratory pathway of should not be deleted from chassis strains for industrial production because this would yield a strain that is intolerant of oxygen, which is more difficult to manage in industrial settings.
PubMed: 37909744
DOI: 10.1128/mbio.02043-23 -
ESC Heart Failure Feb 2024Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF who have a suboptimal response or intolerance to beta-blockers. Degenerative mitral regurgitation (MR) is a valvular heart disease often associated with the development of HF and atrial fibrillation (AF). However, studies comparing the effects of ivabradine and beta-blockers on MR are lacking. Therefore, this study aimed to explore the potential therapeutic effects of ivabradine and carvedilol on MR using a rat model.
METHODS AND RESULTS
Using a novel echo-guided mini-invasive surgery, MR was created in 12-weeks-old Sprague-Dawley rats. After 2 weeks, the rats were randomized to receive either ivabradine or carvedilol for 4 weeks. Echocardiography was performed at baseline and at two-week intervals. Following haemodynamic studies, postmortem tissues were analysed. Notably, the MR-induced myocardial dysfunction did not improve considerably after treatment with ivabradine or carvedilol. However, in haemodynamic studies, pharmacological therapies, particularly carvedilol, mitigated MR-induced chamber dilatation (end-systolic volume and end-diastolic volume; MR vs. MR + Carvedilol; P < 0.05) and decreased compliance (end-systolic pressure-volume relationship; MR vs. MR + Carvedilol; P < 0.05). Compared with ivabradine, a shorter duration (MR vs. MR + Carvedilol; P < 0.05) and reduced inducibility (MR vs. MR + Carvedilol and MR vs. MR + Ivabradine; P < 0.05) of AF were observed in MR rats treated with carvedilol. Similarly, reduced cardiac fibrosis and apoptosis were observed in the MR rat model in the treatment groups, especially in those treated with carvedilol (MR vs. MR + Carvedilol; P < 0.01).
CONCLUSIONS
Although both ivabradine and carvedilol, at least in part, mitigated MR-induced chamber dilatation and decreased compliance, carvedilol had a better effect on reversing MR-induced cardiac fibrosis, apoptosis, and arrhythmogenesis than ivabradine. When compared with Ivabradine, MR rats treated with carvedilol exhibited a shorter duration and reduced inducibility of AF, thus providing more effective suppression of HCN4. Further investigations are required to validate our findings.
Topics: Humans; Rats; Animals; Carvedilol; Ivabradine; Mitral Valve Insufficiency; Rats, Sprague-Dawley; Adrenergic beta-Antagonists; Heart Failure; Atrial Fibrillation; Fibrosis
PubMed: 37963437
DOI: 10.1002/ehf2.14577 -
Biomedicines Jan 2024Ventricular tachycardia is a potentially life-threatening arrhythmia associated with an overall high morbi-mortality, particularly in patients with structural heart... (Review)
Review
Ventricular tachycardia is a potentially life-threatening arrhythmia associated with an overall high morbi-mortality, particularly in patients with structural heart disease. Despite their pivotal role in preventing sudden cardiac death, implantable cardioverter-defibrillators, although a guideline-based class I recommendation, are unable to prevent arrhythmic episodes and significantly alter the quality of life by delivering recurrent therapies. From open-heart surgical ablation to the currently widely used percutaneous approach, catheter ablation is a safe and effective procedure able to target the responsible re-entry myocardial circuit from both the endocardium and the epicardium. There are four main mapping strategies, activation, entrainment, pace, and substrate mapping, each of them with their own advantages and limitations. The contemporary guideline-based recommendations for VT ablation primarily apply to patients experiencing antiarrhythmic drug ineffectiveness or those intolerant to the pharmacological treatment. Although highly effective in most cases of scar-related VTs, the traditional approach may sometimes be insufficient, especially in patients with nonischemic cardiomyopathies, where circuits may be unmappable using the classic techniques. Alternative methods have been proposed, such as stereotactic arrhythmia radioablation or radiotherapy ablation, surgical ablation, needle ablation, transarterial coronary ethanol ablation, and retrograde coronary venous ethanol ablation, with promising results. Further studies are needed in order to prove the overall efficacy of these methods in comparison to standard radiofrequency delivery. Nevertheless, as the field of cardiac electrophysiology continues to evolve, it is important to acknowledge the role of artificial intelligence in both the pre-procedural planning and the intervention itself.
PubMed: 38397868
DOI: 10.3390/biomedicines12020266 -
The Journal of Clinical Investigation Jan 2024In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically,...
BACKGROUND
In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals.
METHODS
Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed.
RESULTS
Nine participants had low initial myocardial 18F-dopamine-derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) (P = 0.0009 by Fisher's exact test). Conversely, all 9 LBD+ participants had low 18F-dopamine-derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity (P < 0.0001 by Fisher's exact test).
CONCLUSION
Cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not.
CLINICALTRIALS
gov NCT00775853.
FUNDING
Division of Intramural Research, NIH, NINDS.
Topics: Humans; Dopamine; Prospective Studies; Lewy Bodies; Positron-Emission Tomography; Parkinson Disease; Norepinephrine
PubMed: 37883190
DOI: 10.1172/JCI172460 -
Italian Journal of Pediatrics Mar 2024Orthostatic intolerance, which includes vasovagal syncope and postural orthostatic tachycardia syndrome, is common in children and adolescents. Elevated plasma...
BACKGROUND
Orthostatic intolerance, which includes vasovagal syncope and postural orthostatic tachycardia syndrome, is common in children and adolescents. Elevated plasma homocysteine levels might participate in the pathogenesis of orthostatic intolerance. This study was designed to analyze the plasma metabolomic profile in orthostatic intolerance children with high levels of plasma homocysteine.
METHODS
Plasma samples from 34 orthostatic intolerance children with a plasma homocysteine concentration > 9 µmol/L and 10 healthy children were subjected to ultra-high-pressure liquid chromatography and quadrupole-time-of-flight mass spectrometry analysis.
RESULTS
A total of 875 metabolites were identified, 105 of which were significantly differential metabolites. Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, 1-(1Z-octadecenyl)-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine, histidine, isocitric acid, and DL-glutamic acid and its downstream metabolites were upregulated, whereas 1-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-sn-glycerol 3-phosphocholine, sphingomyelin (d18:1/18:0), betaine aldehyde, hydroxyproline, and gamma-aminobutyric acid were downregulated in the orthostatic intolerance group compared with the control group. All these metabolites were related to choline and glutamate. Heatmap analysis demonstrated a common metabolic pattern of higher choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid, and lower sphingomyelin (d18:1/18:0), 1-stearoyl-sn-glycerol 3-phosphocholine, and 1-palmitoyl-sn-glycero-3-phosphocholine in patients with certain notable metabolic changes (the special group) than in the other patients (the common group). The maximum upright heart rate, the change in heart rate from the supine to the upright position, and the rate of change in heart rate from the supine to the upright position of vasovagal syncope patients were significantly higher in the special group than in the common group (P < 0.05). Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid were positively correlated with the rate of change in heart rate from the supine to the upright position in vasovagal syncope patients (P < 0.05).
CONCLUSIONS
The levels of choline-related metabolites and glutamate-related metabolites changed significantly in orthostatic intolerance children with high levels of plasma homocysteine, and these changes were associated with the severity of illness. These results provided new light on the pathogenesis of orthostatic intolerance.
Topics: Adolescent; Child; Humans; Orthostatic Intolerance; Syncope, Vasovagal; Glutamic Acid; Glycerylphosphorylcholine; Phosphorylcholine; Sphingomyelins; Choline; Homocysteine; Glycerol
PubMed: 38486257
DOI: 10.1186/s13052-024-01601-4 -
Microbial Cell Factories Sep 2023Methanol, synthesized from CO, is a potentially sustainable one-carbon (C1) resource for biomanufacturing. The use of methanol as a feedstock to produce single cell...
BACKGROUND
Methanol, synthesized from CO, is a potentially sustainable one-carbon (C1) resource for biomanufacturing. The use of methanol as a feedstock to produce single cell protein (SCP) has been investigated for decades as an alternative to alleviate the high global demand for animal-derived proteins. The methylotrophic yeast Pichia pastoris is an ideal host for methanol-based SCP synthesis due to its natural methanol assimilation ability. However, improving methanol utilization, tolerance to higher temperature, and the protein content of P. pastoris are also current challenges, which are of great significance to the economical industrial application using methanol as a feedstock for SCP production.
RESULTS
In the present work, adaptive laboratory evolution (ALE) has been employed to overcome the low methanol utilization efficiency and intolerance to a higher temperature of 33 °C in P. pastoris, associated with reduced carbon loss due to the lessened detoxification of intracellular formaldehyde through the dissimilation pathway and cell wall rearrangement to temperature stress resistance following long-term evolution as revealed by transcriptomic and phenotypic analysis. By strengthening nitrogen metabolism and impairing cell wall synthesis, metabolic engineering further increased protein content. Finally, the engineered strain via multi-strategy produced high levels of SCP from methanol in a pilot-scale fed-batch culture at 33 °C with a biomass of 63.37 g DCW/L, methanol conversion rate of 0.43 g DCW/g, and protein content of 0.506 g/g DCW. SCP obtained from P. pastoris contains a higher percentage of protein compared to conventional foods like soy, fish, meat, whole milk, and is a source of essential amino acids, including methionine, lysine, and branched-chain amino acids (BCAAs: valine, isoleucine, leucine).
CONCLUSIONS
This study clarified the unique mechanism of P. pastoris for efficient methanol utilization, higher temperature resistance, and high protein synthesis, providing a P. pastoris cell factory for SCP production with environmental, economic, and nutritional benefits.
Topics: Animals; Methanol; Pichia; Carbon; Recombinant Proteins
PubMed: 37770920
DOI: 10.1186/s12934-023-02198-9 -
Heliyon Mar 2024(CT) improves energy metabolism. However, the role of CT in alleviating obesity-induced hyperglycemia by targeting the liver remains unknown. Therefore, this article...
(CT) improves energy metabolism. However, the role of CT in alleviating obesity-induced hyperglycemia by targeting the liver remains unknown. Therefore, this article aims to explore the mechanism by which CT improves energy metabolism and resists hyperglycemia. The water and ethanol extracts of CT were administered to high-fat diet-induced (HFD) obese C57BL/6J mice at a dose of 4 g/kg.bw (low-dose water extract, WL; low-dose ethanol extract, EL) or 10 g/kg.bw (high-dose water extract, WH; high-dose ethanol extract, EH). Mice that consumed a maintenance diet (LFD) were included as blank controls. Network pharmacology, liquid chromatography-mass spectrometry (LC-MS), L02 cell cultivation, and liver transcriptomics were used to examine the mechanism and functional components of CT against obesity-induced hyperglycemia. The results indicated that WL significantly (p < 0.05) alleviated glucose intolerance and insulin resistance in obesity-induced hyperglycemia. Kaempferol is the main active compound of CT, which demonstrated significant (p < 0.05) anti-hyperglycemic effects in obese mice and L02 cells. Finally, kaempferol significantly (p < 0.05; fold change >1.2) shifted the genes involved in carbon metabolism, glycolysis/gluconeogenesis, and the mitogen-activated protein kinase (MAPK) pathways toward the trend of LFD, indicating that it exerts an anti-hyperglycemic effect through these molecular mechanisms. Overall, oral intake of CT lowers blood glucose and improves insulin sensitivity in mice with obesity-induced hyperglycemia. Kaempferol is the primary functional component of CT.
PubMed: 38496841
DOI: 10.1016/j.heliyon.2024.e27449 -
Journal of Clinical Medicine Jul 2023Metabolic syndrome (MetS) can be resolved through active control. We aimed to examine the effect of changes in MetS status on colorectal cancer (CRC) risk. A total of...
Metabolic syndrome (MetS) can be resolved through active control. We aimed to examine the effect of changes in MetS status on colorectal cancer (CRC) risk. A total of 5,704,611 Korean national insurance beneficiaries that received two consecutive biennial mandatory health exams (2009-2011) were followed-up until 2017. MetS was determined as the presence of at least three of five components. Participants were categorized into four groups according to the change in MetS status; MetS-never, -resolved, -developed, or -persistent. A Cox proportional hazards model adjusted for age, sex, smoking, alcohol drinking, and physical exercise was used. Participants who recovered from MetS had a higher risk of CRC than those free of MetS but had a lower risk than those with persistent MetS (HR: 0.91, 95% CI: 0.86-0.95 vs. HR: 0.75, 95% CI: 0.73-0.78; reference: persistence group). Among the five MetS components, resolving high blood pressure, abdominal obesity, and blood sugar had a preventive effect on CRC prevention, while normalization of lipid profile did not reduce CRC risk independently. Resolving MetS could reduce CRC risk compared to having persistent MetS, indicating the necessity of considering control of MetS as a CRC prevention policy.
PubMed: 37568291
DOI: 10.3390/jcm12154889 -
Cureus Sep 2023Introduction Skin hydration is important for maintaining adequate skin barrier function. After delivery, the baby's skin faces the most difficult challenge as they are...
Introduction Skin hydration is important for maintaining adequate skin barrier function. After delivery, the baby's skin faces the most difficult challenge as they are exposed to the exterior world's environmental changes, friction, and microorganisms. The management is further complicated by the availability of a large range of infant skin-care products with varying claims. The first-ever Indian study on babies was done to analyze the test product (Venusia baby moisturizer; Dr. Reddy's Laboratories Ltd., Hyderabad, India) in order to bring scientific clarity to consumers. This product is devoid of parabens, alcohol, and animal origin (Dr. Reddy's Laboratories Ltd., Hyderabad, India) and is designed for skin hydration and in-use tolerance in babies with dry and/or normal skin. The endpoints were hydration and clinical evaluation of the skin, evaluated using a moisture meter scale (MMSC; Delfin Technologies Ltd., Kuopio, Finland) and parent self-assessment questionnaire, respectively. Material and methods A total of 136 healthy babies aged between six months to two years were enrolled in a four-group, monocentric, non-randomized, evaluator-blinded study: Group 1 (Venusia baby cream for dry skin), Group 2 (Venusia baby lotion for Dry Skin), Group 3 (Venusia baby cream for normal skin), and Group 4 (Venusia baby lotion for normal skin). The endpoints were hydration and clinical evaluation of the skin, evaluated using an MMSC and parent self-assessment questionnaire, respectively. Results In babies with dry skin, skin hydration was improved with Venusia baby cream (37.50%) and Venusia baby lotion (66.40%). Additionally, 66.66% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby cream; 76.47% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby lotion. In babies with normal skin, skin hydration was improved with Venusia baby cream (12.20%) and Venusia baby lotion (7.20%); 59.37% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby cream; and 84.84% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby lotion. Conclusion Significant improvement was seen in skin hydration using Venusia baby cream and Venusia baby lotion in babies with dry skin and normal skin. No skin intolerances and product-related adverse or serious adverse events were clinically observed or reported during the study duration. Venusia baby lotion had the highest effect (66.4%) on skin hydration in babies with dry skin, where there was a significant shift from dry skin to normal skin range.
PubMed: 37842370
DOI: 10.7759/cureus.45032 -
Cureus Dec 2023Post-acute sequelae of SARS-CoV-2 (PASC), or long COVID, is characterized by persistent symptoms after acute SARS-CoV-2 infection that can vary from patient to patient....
Post-acute sequelae of SARS-CoV-2 (PASC), or long COVID, is characterized by persistent symptoms after acute SARS-CoV-2 infection that can vary from patient to patient. Here, we present a case series of four patients with a history of SARS-CoV-2 infection referred to the Post-Acute COVID-19 Syndrome (PACS) Clinic at Stanford University for evaluation of persistent symptoms, who also experienced new-onset alcohol sensitivity. Alcohol reactions and sensitivity are not well characterized in the literature as it relates to post-viral illness. While there have been some anecdotal reports of new alcohol sensitivity in PASC patients in the media, there is a paucity of published data in the medical literature about this topic. During their medical consultation, the patients self-reported new changes in their symptoms or behaviors following the use of alcohol. A new onset of alcohol sensitivities should be assessed along with other post-COVID-19 symptoms and may provide novel avenues to explore the pathobiology of illness and potential interventions.
PubMed: 38288178
DOI: 10.7759/cureus.51286