Oxygen Supply Research Articles

The prognosis evaluation of guideline-directed medical therapy for type 2 acute myocardial infarction patients with acute respiratory failure

Abstract Backgrounds Type 2 myocardial infarction (T2MI) arises from an imbalance between myocardial oxygen supply and demand during acute illness such as tachyarrhythmia, hypoxia, or hypotension without acute atherothrombosis. The efficacy of guideline-directed medical therapy (GDMT) in T2MI complicated by acute respiratory failure remains uncertain. Purposes This study was aimed to assess the impact of GDMT (including dual antiplatelet therapy, statins and β-blockers) on the prognosis of patients with T2MI and acute respiratory failure. Methods The data for this study were derived from a retrospective cohort of patients admitted to and discharged from 72 secondary and tertiary hospitals between 2010 and 2023. Inclusion criteria included patients with a discharge diagnosis of T2MI and acute respiratory failure. GDMT was defined according to the ACC/AHA Class I recommendations. Patients were divided into GDMT and N-GDMT groups, with differences in clinical characteristics adjusted using propensity score matching (PSM). Primary outcome indicators were major adverse cardiac and cerebrovascular events (MACCE), while secondary outcome indicators included in-hospital mortality, cardiac mortality, non-lethal myocardial infarction, recurrent ischemic stroke, bleeding events and revascularization. Results This study comprised 898 patients in the GDMT group and 3,777 in the N-GDMT group, resulting in 888 matched pairs after PSM. Baseline data showed that patients in the GDMT group had a higher burden of pre-existing comorbidities. In terms of treatment, the GDMT group had a higher proportion of patients undergoing Percutaneous Coronary Intervention (PCI) (4.84% vs. 1.80%, p= 0.001). In-hospital mortality was significantly lower in the GDMT group (12.4% vs. 26.4%, p< 0.001).Over amedian follow-up of 1,304 days, the incidence of MACCE within 1 month was significantly lower in the GDMT group (23.1% vs. 41.3%, p< 0.001). Furthermore, the GDMT group exhibited lower all-cause mortality (52.4% vs. 60.1%, p＜0.01) and cardiac mortality (41.3% vs. 50.3%, p< 0.001) compared to the N-GDMT group, with higher rates of revascularization (3.15% vs. 1.24%, p＜0.01). There were no statistically significant differences in the incidence of bleeding BARC3 (0.45% vs. 0.45%, p=1), recurrent non-lethal myocardial infarction (0.23% vs. 0%, p =0.5) and recurrent stroke (1.46% vs. 0.79%, p =0.261). GDMT at discharge was associated with a lower risk of MACCE in unadjusted analysis (HR=0.51, 95%CI= 0.44-0.59, p＜0.01) and after adjusting for age, gender, Killip classification and comorbidities in multivariate Coxregression analysis (aHR = 0.49, 95%CI= 0.41-0.58). Conclusions Adherence to GDMT was associated with a lower incidence of MACCE during 1-month follow-up, suggesting the importance of GDMT in this patient population.Clinical characteristics of patients

Antiplatelet can improve the short-term prognosis of type 2 myocardial infarction caused by acute respiratory failure

Abstract Background Type 2 myocardial infarction (T2MI) is characterized by myocardial infarction resulting from an imbalance between myocardial oxygen supply and demand, without the rupture of acute atherosclerotic plaque. Antiplatelet therapy is the cornerstone of treatment for Type 1 myocardial infarction, however, its efficacy in T2MI remains unclear. Purpose This study aimed to explore the impacts of antiplatelets on prognosis in patients with T2MI caused by acute respiratory failure. Methods The data for this study were derived from the Health and Medical Big Data Superplatform, comprising a retrospective cohort of patients admitted to and discharged from 72 secondary and tertiary hospitals from 2010 to 2023. A total of 4708 patients with T2MI due to acute respiratory failure were included. Participants were divided into two groups: those receiving antiplatelet therapy and those not. T2MI caused by acute respiratory failure was defined as NSTEMI patients caused by respiratory failure without percutaneous coronary intervention (PCI). Propensity score matching (PSM) was used to balance covariates between the groups, followed by building a multivariable Cox regression model to further adjust for potential confounders. Covariates adjusted in multivariable Cox regression included antiplatelet, anticoagulant, and lipid-lowering drug use during hospitalization, age, sex, KILLIP classification, history of diabetes, hypertension, percutaneous coronary intervention, stroke, renal insufficiency, cerebral hemorrhage, and atrial fibrillation. One-to-one matching was performed based on propensity scores using the nearest available pair matching method with a caliper width of 0.01. The primary endpoint was Net Adverse Clinical Events (NACE) within 1 month, including myocardial infarction, cardiac death, stroke and Bleeding Academic Research Consortium (BARC) criteria type 3 or 5. Results Following 1:1 propensity score matching, a total of 1418 participants were enrolled in the final study sample, with 709 patients retained in each group. Patients using antiplatelet were more likely to use ACEI/ARB, CCB, and β-blockers during hospitalization, all p<0.05.Compared to non-antiplatelet therapy group, the use of antiplatelet was associated with a 0.69 times risk of 1-month NACE (aHR, 0.69; p<0.001), a 0.69 times risk of 1-month Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) (aHR, 0.69; p<0.001), a 0.70 times risk of 1-month cardiac death (aHR, 0.70; p<0.001), and a 0.70 times risk of 1-month all-cause mortality (aHR, 0.70; p<0.001); with no statistical significance for other clinical outcomes (p > 0.05) (Figure 1). Conclusions The present study suggested that patients receiving antiplatelet therapy had a lower incidence of one-month NACE, primarily due to a reduction in major cardiac death and MACCE at 1 month.

Triggers of type 2 myocardial infarction: implications for long-term prognosis

Abstract Background Type 2 myocardial infarction (T2MI) is characterized by a mismatch between myocardial oxygen supply and demand, unrelated to acute coronary thrombosis. This discrepancy arises from triggers, which may or may not be of cardiac origin. Common cardiac triggers include coronary artery spasm, coronary embolism, and arrhythmias, whereas non-cardiac triggers encompass factors such as anemia, hypertension/hypotension, sepsis, renal damage, and respiratory failure. However, identifying these triggers isn't always straightforward. Aim Our study aimed to identify, whenever possible, the triggers contributing to the oxygen supply-demand mismatch in T2MI cases, as defined by the Fourth Universal Definition of Myocardial Infarction. Additionally, we sought to explore the correlation between these triggers and patient prognosis. Methods We enrolled all consecutive patients diagnosed with non-ST-segment elevation myocardial infarction (NSTEMI) who met the criteria for T2MI and underwent coronary angiography within 72 hours of diagnosis. Patients were categorized into three groups based on the trigger causing T2MI: cardiac, non-cardiac, and unidentified. The primary endpoint was the occurrence of major adverse cardiovascular events (MACEs), including all-cause mortality, new myocardial infarction, hospitalization for heart failure, and ischemic stroke, during long-term follow-up. We estimated MACE-free survival using Kaplan-Meier curves and compared it among the three groups using the log-rank test. Multivariable logistic regression analysis was performed to identify independent predictors of MACE. Results The final cohort comprised 598 T2MI patients, with 308 having a cardiac trigger, 147 having a non-cardiac trigger, and 143 with an unidentified trigger. The mean age of the overall population was 69.6±13.1 years, with a median follow-up time of 25 (13-49) months. Kaplan-Meier curves demonstrated statistically significant differences in MACEs based on the trigger causing T2MI (p<0.001). Specifically, patients with an unidentified trigger exhibited a better prognosis, while those with a non-cardiac trigger had a worse prognosis during long-term follow-up. Multivariable logistic regression analysis confirmed that not having an identified trigger is an independent protective factor for MACEs (HR 0.63, 95% CI 0.45-0.89, p=0.009, unidentified trigger vs cardiac + non-cardiac trigger). Conclusions T2MI is prevalent in clinical practice, yet reliable outcome predictors remain elusive. Our findings indicate a relationship between the type of trigger precipitating T2MI and patient prognosis, notably demonstrating that the absence of a specific identifiable trigger is linked to a more favorable long-term outcome. Further studies are needed to better define the prognostic stratification of these patients.MACE-free survival Kaplan Meier

Research Progress on Acute Kidney Injury in Patients with Cardiogenic Shock Undergoing Venoarterial Extracorporeal Membrane Oxygenation

Cardiogenic shock (CS) is a life-threatening syndrome characterized by peripheral hypoperfusion and organ dysfunction caused by primary heart disease. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a temporary mechanical circulatory support device for CS, used in cases of profound shock, biventricular failure, respiratory failure, and cardiac arrest that require urgent maximal support. While VA-ECMO provides effective tissue perfusion and ensures oxygen supply to organs, it is also associated with severe complications, among which acute kidney injury (AKI) is one of the most common and serious. To date, no comprehensive review has been conducted on the pathophysiology, influencing factors, and treatment of AKI associated with VA-ECMO. This paper aims to elaborate on the pathophysiological mechanisms, influencing factors, and treatment options for AKI in patients with CS undergoing VA-ECMO, providing clinical and nursing references.

Three-Stage Solid-State Fermentation Technology for Distillers’ Grain Feed Protein Based on Different Microorganisms Considering Oxygen Requirements

The shortage of feed protein has plagued the development of the animal husbandry industry in China. In this study, a new three-stage fermentation technology for producing distillers’ grain feed protein was developed by introducing Aspergillus niger, yeast, and lactic acid bacteria. During the aerobic stage, there was a negative correlation between the reducing sugar content in the distillers’ grains and the amount of Aspergillus niger. The maximum reducing sugar concentration (36.89 mg g−1) was obtained when the oxygen supply was 30 mL min−1 and the fermentation time was two days. During the microaerophilic stage, the natural exchange of oxygen achieved optimal true protein enhancement (from 10.8% to 16.4%) among the three oxygen supply modes (natural exchange, forced ventilation, and filling supplement). During the anaerobic stage, lactic acid bacteria were inoculated for feed protein preservation and flavor enhancement. Our results provided insight and practical guidance for the high-value use of distillers’ grains.

Competing effects of wind and buoyancy forcing on ocean oxygen trends in recent decades

Ocean deoxygenation is becoming a major stressor for marine ecosystems due to anthropogenic climate change. Two major pathways through which climate change affects ocean oxygen are changes in wind fields and changes in air-sea heat and freshwater fluxes. Here, we use a global ocean biogeochemistry model run under historical atmospheric forcing to show that wind stress is the dominant driver of year-to-year oxygen variability in most ocean regions. Only in areas of water mass formation do air-sea heat and freshwater fluxes dominate year-to-year oxygen dynamics. The deoxygenation since the late 1960s has been driven mainly by changes in air-sea heat and freshwater fluxes. Part of this deoxygenation has been mitigated by wind-driven increases in ventilation and interior oxygen supply, mainly in the Southern Ocean. The predicted slowdown in wind stress intensification, combined with continued ocean warming, may therefore greatly accelerate ocean deoxygenation in the coming decades. The fact that the model used here, along with many state-of-the-art forced ocean models, underestimates recent ocean deoxygenation indicates the need to use forcing fields that better represent pre-industrial conditions during their spin-up.

Intraoperative Anesthesia-Related Critical Events in Low-Resource Hospitals During Short-Term Surgical Missions in Tanzania and Democratic Republic of the Congo: An Observational Study.

Critical incidents and mortality related to anesthesia are more frequently observed in low- and middle-income countries in comparison to high-income countries. The difficulties linked to anesthesia in rural areas of the Democratic Republic of the Congo (DRC) and Tanzania have limited documentation. The aim of this study was to comprehensively document anesthesia-related critical events that occurred during surgical missions organized by the nongovernmental organization 2nd Chance in hospitals in DRC and Tanzania. Data were collected during 6 surgical missions in 3 hospitals in the DRC and 1 in Tanzania. All scheduled surgery patients were included. Anesthesia was administered by a local Non-Physician Anesthesia Provider (NPAP), using local resources, under the supervision of an anesthesiologist from the association. The anesthesiologist reported critical events and collected data. Local teams managed critical events initially, with intervention by the anesthesiologist from 2nd Chance on the local team's request, according to preestablished protocol or if the situation was considered dangerous. Critical incidents associated with anesthesia, including bradycardia, hypoxemia, airway management failure, and equipment problems, were documented from induction of anesthesia until discharge from the recovery room. We recruited 201 patients, of whom 192 were evaluated, with 9 patients dropping out due to protocol noncompliance. All patients were American Society of Anesthesiologists (ASA) I (62%; n = 120) or ASA II (38%; n = 72). Among them, 104 individuals (54%) experienced at least 1 critical event, totaling 202 critical events. Hypoxemia emerged as the most common event, affecting 29% of the patients (n = 55) with at least 1 episode. Equipment problems (oxygen supply and/or anesthesia machine failure) occurred in 24% of cases (n = 46), airway management issues in 23% (n = 44), and bradycardia in 6% (n = 12). Hypotension and hypertension were not documented due to the lack of monitoring. The majority of these events (over 60%) required intervention by the anesthesiologist. The occurrence of critical events related to anesthesia appears to be high in this study. Due to numerous limitations, these results cannot be generalized to all hospitals in Tanzania and the DRC. However, this study underscores the challenges faced by anesthesia teams, encompassing inadequate resources, equipment deficiencies, and varying levels of expertise among anesthesia personnel. The research further stresses the significance of addressing these challenges to enhance patient safety.

Oxygenating respiratoid biosystem for therapeutic cell transplantation

In this study, we address the persistent challenge of providing adequate oxygen to transplanted cells by introducing a respiratoid biosystem. Central to our strategy is the chloroplast-transit-peptide (CTP), crucial for optimal oxygenation. Through conjugation of CTP with alginate, we achieve stabilization of chloroplast structure. Strategically anchored to the outer chloroplast membrane, CTP not only ensures structural integrity but also upregulates key photosynthesis-associated genes. This biosystem demonstrates exceptional efficacy in spontaneously generating oxygen, particularly under hypoxic conditions (~1% pO2). In an application, pancreatic islets encapsulated within the respiratoid biosystem and intraperitoneally implanted in diabetic mice maintain normal glucose levels effectively. Insulin secretion persists for 100 days post-xenotransplantation without the need for immunosuppressant administration, highlighting the reliance on the respiratoid biosystem’s oxygen supply and structural stability. Our study demonstrates the respiratoid biosystem as a platform in tissue engineering, offering a nature-inspired solution to the critical challenge of spontaneous oxygen supply.

Characteristics and outcomes of patients hospitalized for infection with Influenza A, SARS-CoV-2 or respiratory syncytial virus in the season 2023/2024 in a large German primary care centre

BackgroundIn addition to the persistence of SARS-CoV-2 infections, those with Influenza A/B and RSV have reappeared in 2022/23. To compare the development of prevalence, clinical outcomes and risk factors, we analysed data of the season 2023/24 from the same region/hospital as for 2022/23.MethodsPatients covering the whole age range with a positive polymerase chain reaction (PCR) test for SARS-CoV-2, Influenza A/B, RSV were included from the internal, neurological and paediatric units of the RoMed hospital Rosenheim, Germany/Bavaria, from August 1st 2023 to 29th February 2024.ResultsOf 932 patients included, 912 showed single infections with SARS-CoV-2, Influenza A or RSV (47.9% female, median age 68.0 years; 52.9% SARS-CoV-2, 23.2% Influenza A, 21.8% RSV). Co-infections (2.0%) and Influenza B (0.1%) were negligible. In patients of age ≥ 18 years (n = 628, 68.5% SARS-CoV-2, 26.0% Influenza A, 5.6% RSV), patients with Influenza A were younger compared to SARS-CoV-2 (p < 0.001), with RSV similar to SARS-CoV-2. Heart failure and asthma were the most prevalent comorbidities for RSV, immunosuppression for Influenza A. Admission to Intensive Care Unit (ICU) occurred in 111 patients (17.0% of SARS-CoV-2, 17.2% Influenza A, 28.6% RSV), and 59 patients died (8.8% SARS-CoV-2, 8.6% Influenza A, 20.0% RSV). Low-flow oxygen supplementation and non-invasive ventilation (NIV) were most frequent for RSV (68.6% and 20.0%, respectively), oxygen demand upon admission for Influenza A (39.3%), without differences in high-flow oxygen supply or length of hospital stay. Among patients aged < 18 years (n = 284, 21.4% SARS-CoV-2, 18.0% Influenza A, 57.1% RSV), 15 were admitted to ICU (4.8% SARS-CoV-2, 3.8% Influenza A, 6.0% RSV); none of them died. Oxygen supply via high-flow, low-flow or upon admission was highest for RSV (23.8%, 70.2%, 21.4%, respectively), as well as the length of hospital stay.ConclusionBetween 8/2023 to 2/2024, a large population of patients hospitalized due to respiratory tract infection, showed relative contributions of SARS-CoV-2, Influenza A or RSV similar to those in 2022/23. The findings underline that in both, adults and children, RSV posed a relatively higher clinical risk than Influenza A and SARS-CoV-2, though absolute numbers remained highest for SARS-CoV-2.

Strategies to reduce the culture medium costs for a high‐yield and high‐selectivity bio‐based 2,3‐butanediol production

AbstractBio‐based 2,3‐butanediol (2,3‐BDO) production on a large scale depends on critical factors, such as culture medium, oxygen supply, pH and biosafety. In this study, three strategies for reducing culture medium costs were investigated: carbon/nitrogen (C/N) ratio; low‐cost nitrogen sources (crude yeast extract, brewer's yeast extract, corn steep liquor, urea, sodium nitrate, ammonium chloride, ammonium sulfate and dibasic ammonium phosphate); and microbial pH autoregulation. Batch fermentations were performed in a microaerobic environment using wild‐type and safe Paenibacillus peoriae NRRL BD 62. The yield and selectivity of 2,3‐BDO were used as control variables. A ratio between 2,3‐BDO production and glucose consumption (YP/S) of almost 80% and an optical purity of 87% levo‐2,3‐BDO, with no acetoin accumulation, were achieved in an NH4Cl‐based medium at C/N = 8.5 g/g and without external pH control, considering an initial glucose of 10 g/L. Based on Free on Board prices, a 63% savings in culture medium costs was achieved by replacing commercial yeast extract at pH 5. Validation assays with higher initial glucose concentrations showed a YP/S of 0.40 g/g and an optical levo‐/meso‐2,3‐BDO ratio of 1:0.8, with negligible acetoin accumulation. Therefore, the NH4Cl‐based medium at C/N = 8.5 g/g and without pH control was considered economically promising for high‐yield and high‐selectivity bio‐based 2,3‐BDO production.

The Effectiveness of Deep Breathing Exercise Therapy on Oxygen Saturation among Patients with Ischemic Stroke

Ischemic stroke is an abnormality of central nervous system function in which blood flow decreases significantly, causing hypoxia. This systemic hypoxemia should be avoided; therefore oxygen saturation is monitored in the acute phase. One of the interventions that can be done in order to increase oxygen supply is by deep breathing exercise. The purpose of this study was to determine the effectiveness of deep breathing exercise therapy to increase oxygen saturation on patients with ischemic stroke. This study is a quasi-experimental study with one group pre-posttest design that has been implemented in the neural room of RSUP Dr. M. Djamil Padang with a sample of 16 patients with ischemic stroke who have fulfilled the inclusion criteria. Data was collected directly by measuring oxygen saturation of patients with ischemic stroke before and after a deep breathing exercise intervention. The data were processed by computer and analyzed as univariate and bivariate. Normality test results show the data is not normally distributed so that the analysis used is non-parametric test by using Wilcoxon test. The results showed that deep breathing exercise therapy was effective in increasing oxygen saturation level of patients with ischemic stroke with p = 0,000 so it can be recommended that this therapy can be used as one of the nursing interventions on patients with ischemic stroke to increase the oxygen saturation level.

Understanding Ischemic Stroke: Symptoms, Risks, and the Importance of Timely Intervention

An ischemic stroke transpires when a blood vessel supplying blood to the brain becomes obstructed or constricted, leading to decreased blood flow to a particular area of the brain. The absence of blood circulation restricts the supply of oxygen and nutrients to the brain cells, resulting in their demise or impairment. The obstruction typically arises from a thrombus or other debris that impedes the flow of blood in the artery. Globally, stroke is the second leading cause of death responsible for approximately 11% total deaths. In the United States, an estimated 795,000 people experience a new or recurrent stroke annually, and approximately 87% of these are ischemic strokes. A stroke can come on suddenly, and its effects can be devastating. If someone is suspected to be suffering from a stroke, it is important to call 911 or seek medical attention immediately. Time is of essence in the treatment of stroke.

Optimization of indoor thermal environment for high-altitude sentry buildings with attached ventilation based on proper orthogonal decomposition

The low-oxygen and severe cold climate characteristics of high-altitude regions significantly impact individuals' physiological health and thermal comfort inside buildings, especially for sentry buildings where the enclosure is fully exposed to the outdoors. This study aimed to optimize the indoor environment for high-altitude sentry buildings with attached ventilation. Firstly, the optimal location of exhaust outlets and oxygen sources in the heating mode of high-altitude sentry buildings was studied, and it showed high performance in terms of thermal comfort and energy efficiency. Additionally, the POD method and interpolation methods were applied to expand the sample dataset and identify the optimal combination of attached ventilation parameters and oxygen supply concentration, creating a comfortable, oxygen-enriched environment within the sentry buildings while also considering energy efficiency. The results indicate that when the optimization objective is weighted towards thermal comfort, the percentage of dissatisfied (PD) and the draught rate (DR) values under the optimal scheme are reduced by 82 % and 46.6 %, respectively, compared to previous studies. However, when the emphasis is on energy efficiency in environmental optimization, the air supply energy under the optimal scheme has a 64.4 % reduction compared to previous research results. When considering both optimization objectives simultaneously, the PD and DR values under the optimal scheme are reduced by 35.9 % and 96.9 %, respectively, compared to previous research results. These results demonstrate significant improvements in both thermal comfort and energy efficiency relative to our previous study.

Optimized Rhamnolipid Production by a Pseudomonas marginalis C9 Strain Isolated from a Biopurification System to Enhance Pesticide Solubilization

Biopurification systems designed for pesticide treatment are a source of diverse bacteria with environmental and biotechnological applications, including Pseudomonas marginalis C9, which has been reported as a biosurfactant-producing bacterium. The optimization of biosurfactant produced from P. marginalis C9 to enhance the solubility of a hydrophobic pesticide of environmental interest was investigated. The response surface methodology (RSM) was used to optimize the combined effect of the initial pH (5–9), agitation (100–300 rpm), and temperature (24–32 °C) on biosurfactant production. A DASbox® automated mini-bioreactor system was used to evaluate the critical factors in biosurfactant production using a full factorial design (FFD). The results showed that the optimal culture conditions using RSM were a pH of 8.5, a temperature of 25 °C, and agitation at 200 rpm. The extraction yield of the biosurfactant was 7.40 g L−1, the surface tension was reduced to 27.45 mN m−1, and the critical micelle concentration (CMC) was 48.9 mg L−1. The FFD analysis indicated that a high agitation rate (300 rpm) strongly influenced the biosurfactant activity, regardless of the inlet oxygen supply (0.5–1.5 vvm). The rhamnolipid increased the water solubility of chlorpyrifos by 11.2- and 21.7-fold at the CMC and twice the CMC, respectively.

Oxygenation Kinetics of Three Quadriceps Muscles During Squatting Exercise in Trained Men.

This study aimed to monitor the oxygenation and blood supply in three quadriceps muscles [the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF)] during squatting exercise to exhaustion. Eighteen young resistance-trained males performed five sets of 15 back squats in a Smith machine, with two warm-up sets [at 14% and 45% of the 15-repetition maximum (15RM)] and three main sets at 100% of the 15RM. Three near-infrared spectroscopy devices were attached to the VL, VM, and RF to record the muscle oxygen saturation (SmO2) and total hemoglobin (tHb, an index of muscle blood supply). The blood lactate concentration was measured after each set with a portable analyzer. The SmO2 and tHb data were analyzed by repeated-measures two-way ANOVA (muscle × set). Lactate data were analyzed by repeated-measures one-way ANOVA. The statistical significance was set at α = 0.05. The SmO2 dropped during each set (hitting zero in many instances) and was reinstated during recovery. The three main sets caused severe deoxygenation in the VL and VM, as opposed to moderate deoxygenation in the RF. From one set to the next, the initial value and the drop in the SmO2 increased, whereas the final SmO2 value decreased. The tHb increased in the VL, did not change considerably in the VM, and decreased in the RF during each set. The blood lactate concentration increased gradually from one set to the next, reaching about 10 mmol/L. These findings show pronounced differences in the physiological and metabolic responses of three quadriceps muscles to squatting exercise, thus highlighting the importance of studying such responses at multiple sites.

A growth-coupling strategy for improving the stability of terpenoid bioproduction in Escherichia coli

BackgroundAchieving cost-competitiveness remains challenging for industrial biomanufacturing. With whole-cell biocatalysis, inefficiency presents when individual cells vary in their production levels. The problem exacerbates when the basis for such production heterogeneity is heritable. Here, evolution selects for the low- and non-producers, as they have lowered/abolished the cost of bioproduction to fitness. With the scale of population expansion required for industrial bioproduction, the asymmetrical enrichment can be severe enough to compromise the performance, and hence commercial viability of the bioprocess. Clearly, addressing production heterogeneity is crucial, especially in improving the stability of bioproduction across the cell generations. In this respect, we designed a growth-coupling strategy for terpenoid bioproduction in Escherichia coli. By knocking out the native 1-deoxy-D-xylulose 5-phosphate reductoisomerase (dxr) gene and introducing the heterologous mevalonate pathway, we created a chassis that relies solely on the latter for synthesis of all terpenoids. We hypothesise that the need to sustain the biosynthesis of endogenous life-sustaining terpenoids will impose a minimum level of productivity, which concomitantly improves the bioproduction of our target terpenoid.ResultsFollowing the confirmation of lethality of a dxr knockout, we challenged the strains with a continuous plasmid-based bioproduction of linalool. The Δdxr strain achieved an improved productivity profile in the first three days post-inoculation when compared to the parental strain. Productivity of the Δdxr strain remained observable near the end of 12 days, and after a disruption in nutrient and oxygen supply in a separate run. Unlike the parental strain, the Δdxr strain did not evolve the same deleterious mutations in the mevalonate pathway, nor a viable subgroup that had lost its resistance to the antibiotic selection pressure (a plausible plasmid loss event). We believe that this divergence in the evolution trajectories is indicative of a successful growth-coupling.ConclusionWe have demonstrated a proof of concept of a growth-coupling strategy that improves the performance, and stability of terpenoid bioproduction across cell generations. The strategy is relatively broad in scope, and easy to implement in the background as a ‘fail-safe’ against a fall in productivity below the imposed minimum. We thus believe this work will find widespread utility in our collective effort towards industrial bioproduction.

Copper-Consuming Nanoplatform for Alleviating Hypoxia and Overcoming Resistance to Sonodynamic Therapy of Breast Cancer.

Sonodynamic therapy (SDT) is a promising treatment modality for breast cancer; however, its effectiveness is often impeded by the hypoxic tumor microenvironment owing to an insufficient oxygen supply in the solid tumors. To overcome this challenge, we elaborately developed a 4T1 tumor-targeted multifunctional nanoagent by integrating both dendrimer-structured copper chelating agents and organic sonosensitizers (IR820) into a biotin-modified nanoliposome via a microfluidic-assisted self-assembly. In particular, the aforementioned copper chelating agent was constructed by introducing multiple xanthate groups into a dendrimer polymer, which showed a significant selectivity for the consumption of the intracellular copper levels. Based on this, the nanoliposome-based therapeutic not only disrupted the activity of the mitochondrial complex IV to directly inhibit the tumor cell proliferation but also suppressed the resistance to the SDT via inhibition of the oxygen consumption for cellular respiration. Both in vitro and in vivo studies confirmed that the designed nanoagents exhibit a synergistic tumor inhibition effect of copper consumption and IR820-mediated SDT. Taken together, this approach establishes a proof-of-concept for the construction of a copper-ion-modulated nanomedicine to significantly enhance the efficiency of oxygen-dependent cancer treatments.

Coronary circulation enhances the aerobic performance of wild Pacific salmon.

Female Pacific salmon often experience higher mortality than males during their once-in-a-lifetime up-river spawning migration, particularly when exposed to secondary stressors (e.g. high temperatures). However, the underlying mechanisms remain unknown. One hypothesis is that female Pacific salmon hearts are more oxygen-limited than those of males and are less able to supply oxygen to the body's tissues during this demanding migration. Notably, female hearts have higher coronary blood flow, which could indicate a greater reliance on this oxygen source. Oxygen limitations can develop from naturally occurring coronary blockages (i.e. coronary arteriosclerosis) found in mature salmon hearts. If female hearts rely more heavily on coronary blood flow but experience similar arteriosclerosis levels as males, they will have disproportionately impaired aerobic performance. To test this hypothesis, we measured resting (RMR) and maximum metabolic rate (MMR), aerobic scope (AS) and acute upper thermal tolerance in coho salmon (Oncorhynchus kisutch) with an intact or artificially blocked coronary oxygen supply. We also assessed venous blood oxygen and chemistry (cortisol, ions and metabolite concentrations) at different time intervals during recovery from exhaustive exercise. We found that coronary blockage impaired MMR, AS and the partial pressure of oxygen in venous blood (PvO2) during exercise recovery but did not differ between sexes. Coronary ligation lowered acute upper thermal tolerance by 1.1°C. Although we did not find evidence of enhanced female reliance on coronary supply, our findings highlight the importance of coronary blood supply for mature wild salmon, where migration success may be linked to cardiac performance, particularly during warm water conditions.

Glomerular pressure and tubular oxygen supply: a critical dual target for renal protection.

The primary treatment goal of chronic kidney disease (CKD) is preserving renal function and preventing its progression to end-stage renal disease. Glomerular hypertension and tubular hypoxia are critical risk factors in CKD progression. However, the renal hemodynamics make it difficult to avoid both factors due to the existence of peritubular capillaries that supply oxygen to the renal tubules downstream from the glomerulus through the efferent arteriole. In the treatment strategies for balancing glomerular pressure and tubular oxygen supply, afferent and efferent arterioles of the glomerulus determine glomerular filtration rate and blood flow to the peritubular capillaries. Therefore, sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors as well as classical renin-angiotensin system inhibitors, which can change the diameter of afferent and/or efferent arterioles, are promising options for balancing this dual target and achieving renal protection. This review focuses on the clinical importance of glomerular pressure and tubular oxygen supply and proposes an effective treatment modality for this dual target.

Demand Ischemia due to Gastrointestinal Bleeding Secondary to Ticagrelor

Ticagrelor, an orally consumed antiplatelet medication, acts as an antagonist on the P2Y12 receptor preventing adenosine diphosphate-induced platelet aggregation. Gastrointestinal bleeding triggered by ticagrelor can lead to demand ischemia, as the demand for oxygen by the tissues surpasses the oxygen supply available following acute blood loss. A male patient in his 80s had his antiplatelet medication switched from clopidogrel to ticagrelor following a cardiac stent. He presented to the emergency department a few months later due to black stools and fatigue. The patient had a critically elevated initial troponin level of 780 ng/L which increased to 892 ng/L two hours later. Hemoglobin was low at 8.5 g/dL. The patient suspended usage of ticagrelor and switched back to clopidogrel. Three weeks later, he had an endoscopy, which demonstrated no active bleeding sources.