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Assessment of fluid responsiveness relies on dynamic echocardiographic parameters that have not yet been compared in large cohorts. To determine the diagnostic accuracy of dynamic parameters used to predict fluid responsiveness in ventilated patients with a circulatory failure of any cause. In this multicenter prospective study, respiratory variations of superior vena cava diameter (∆SVC) measured using transesophageal echocardiography, of inferior vena cava diameter (∆IVC) measured using transthoracic echocardiography, of the maximal Doppler velocity in left ventricular outflow tract (∆VmaxAo) measured using either approach, and pulse pressure variations (∆PP) were recorded with the patient in the semirecumbent position. In each patient, a passive leg raise was performed and an increase of aortic velocity time integral greater than or equal to 10% defined fluid responsiveness. Among 540 patients (379 men; age, 65 ± 13 yr; Simplified Acute Physiological Score II, 59 ± 18; Sequential Organ Failure Assessment, 10 ± 3), 229 exhibited fluid responsiveness (42%). ∆PP, ∆VmaxAo, ∆SVC, and ∆IVC could be measured in 78.5%, 78.0%, 99.6%, and 78.1% of cases, respectively. ∆SVC greater than or equal to 21%, ∆VmaxAo greater than or equal to 10%, and ∆IVC greater than or equal to 8% had a sensitivity of 61% (95% confidence interval, 57-66%), 79% (75-83%), and 55% (50-59%), respectively, and a specificity of 84% (81-87%), 64% (59-69%), and 70% (66-75%), respectively. The area under the receiver operating characteristic curve of ∆SVC was significantly greater than that of ∆IVC (P = 0.02) and ∆PP (P = 0.01). ∆VmaxAo had the best sensitivity and ∆SVC the best specificity in predicting fluid responsiveness. ∆SVC had a greater diagnostic accuracy than ∆IVC and ∆PP, but its measurement requires transesophageal echocardiography.

During biosynthesis by multi-modular trans -AT polyketide synthases, polyketide structural space can be expanded by conversion of initially-formed electrophilic β-ketones into β-alkyl groups. These multi-step transformations are catalysed by 3-hydroxy-3-methylgluratryl synthase cassettes of enzymes. While mechanistic aspects of these reactions have been delineated, little information is available concerning how the cassettes select the specific polyketide intermediate(s) to target. Here we use integrative structural biology to identify the basis for substrate choice in module 5 of the virginiamycin M trans -AT polyketide synthase. Additionally, we show in vitro that module 7, at minimum, is a potential additional site for β-methylation. Indeed, analysis by HPLC-MS coupled with isotopic labelling and pathway inactivation identifies a metabolite bearing a second β-methyl at the expected position. Collectively, our results demonstrate that several control mechanisms acting in concert underpin β-branching programming. Furthermore, variations in this control – whether natural or by design – open up avenues for diversifying polyketide structures towards high-value derivatives. Biosynthesis of complex polyketides by polyketide synthases often relies on trans-acting enzymes to modify the intermediates. Here, the authors elucidate how β-methylation enzymes identify their substrates. The recognition is imperfect, resulting in a doubly β-methylated virginiamycin derivative.

Abstract The modular organization of the type I polyketide synthases (PKSs) would seem propitious for rational engineering of desirable analogous. However, despite decades of efforts, such experiments remain largely inefficient. Here, we combine multiple, state-of-the-art approaches to reprogram the stambomycin PKS by deleting seven internal modules. One system produces the target 37-membered mini-stambomycin metabolites − a reduction in chain length of 14 carbons relative to the 51-membered parental compounds − but also substantial quantities of shunt metabolites. Our data also support an unprecedented off-loading mechanism of such stalled intermediates involving the C-terminal thioesterase domain of the PKS. The mini-stambomycin yields are reduced relative to wild type, likely reflecting the poor tolerance of the modules downstream of the modified interfaces to the non-native substrates. Overall, we identify factors contributing to the productivity of engineered whole assembly lines, but our findings also highlight the need for further research to increase production titers.

Abstract This review focuses on recent evidence that identifies potential extracellular and cellular mechanisms that may be involved in the tolerance of ectomycorrhizal fungi to excess metals in their environment. It appears likely that mechanisms described in the nonmycorrhizal fungal species are used in the ectomycorrhizal fungi as well. These include mechanisms that reduce uptake of metals into the cytosol by extracellular chelation through extruded ligands and binding onto cell-wall components. Intracellular chelation of metals in the cytosol by a range of ligands (glutathione, metallothioneins), or increased efflux from the cytosol out of the cell or into sequestering compartments are also key mechanisms conferring tolerance. Free-radical scavenging capacities through the activity of superoxide dismutase or production of glutathione add another line of defence against the toxic effect of metals.

Acquisition of new catalytic activity is a relatively rare evolutionary event. A striking example appears in the pathway to the antibiotic lankacidin, as a monoamine oxidase (MAO) family member, LkcE, catalyzes both an unusual amide oxidation, and a subsequent intramolecular Mannich reaction to form the polyketide macrocycle. We report evidence here for the molecular basis for this dual activity. The reaction sequence involves several essential active site residues and a conformational change likely comprising an interdomain hinge movement. These features, which have not previously been described in the MAO family, both depend on a unique dimerization mode relative to all structurally characterized members. Taken together, these data add weight to the idea that designing new multifunctional enzymes may require changes in both architecture and catalytic machinery. Encouragingly, however, our data also show LkcE to bind alternative substrates, supporting its potential utility as a general cyclization catalyst in synthetic biology. The monoamine oxidase family member LkcE is an enzyme from the lankacidin polyketide biosynthetic pathway, where it catalyzes an amide oxidation followed by an intramolecular Mannich reaction, yielding the polyketide macrocycle. Here the authors characterize LkcE and present several of its crystal structures, which explains the unusual dual activity of LkcE.

Background In the perioperative setting, the most accurate way to continuously measure arterial blood pressure (ABP) is using an arterial catheter. Surrogate methods such as finger cuff have been developed to allow non-invasive measurements and are increasingly used, but need further evaluation. The aim of this study is to evaluate the accuracy and clinical concordance between two devices for the measurement of ABP during neuroradiological procedure. Methods This is a prospective, monocentric, observational study. All consecutive patients undergoing a neuroradiological procedure were eligible. Patients who needed arterial catheter for blood pressure measurement were included. During neuroradiological procedure, ABP (systolic, mean and diatolic blood pressure) was measured with two different technologies: radial artery catheter and Nexfin. Bland-Altman and error grid analyses were performed to evaluate the accuracy and clinical concordance between devices. Results From March 2022 to November 2022, we included 50 patients, mostly ASA 3 (60%) and required a cerebral embolization (94%) under general anaesthesia (96%). Error grid analysis showed that 99% of non-invasive ABP measures obtained with the Nexfin were located in the risk zone A or B. However, 65.7% of hypertension events and 41% of hypotensive events were respectively not detected by Nexfin. Compared to the artery catheter, a significant relationship was found for SAP ( r 2  = 0.78) and MAP ( r 2  = 0.80) with the Nexfin ( p  < 0.001). Bias and limits of agreement (LOA) were respectively 9.6 mmHg (− 15.6 to 34.8 mmHg) and − 0.8 mmHg (− 17.2 to 15.6 mmHg), for SAP and MAP. Conclusions Nexfin is not strictly interchangeable with artery catheter for ABP measuring. Further studies are needed to define its clinical use during neuroradiological procedure. Trial registration Clinicaltrials.gov, registration number: NCT05283824.

IntroductionThe aim of this study was to compare bone mineral density (BMD) and geometric indices of hip bone strength in a group of obese sarcopenic premenopausal women (n = 27) and a group of obese premenopausal women with normal appendicular lean mass (ALM)/body mass index ratio (BMI) (n = 26).Materials and methodsThe ALM/BMI criterion of The Foundation for the National Institute of Health was used; women with an ALM/BMI ratio < 0.512 m2 were considered obese sarcopenic. Body composition and bone variables were measured by DXA. DXA measurements were completed for the whole body (WB), lumbar spine (L1–L4), total hip (TH) and femoral neck (FN). Hip geometry parameters including cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), section modulus (Z), strength index (SI) and buckling ratio (BR) were derived by DXA.ResultsAge, weight and BMI were not significantly different between the two groups. Height, lean mass, skeletal muscle mass index, ALM and the ratio ALM/BMI were significantly higher in obese women with normal ALM/BMI ratio compared to obese sarcopenic women. Fat mass percentage was significantly higher in obese sarcopenic women compared to obese women with normal ALM/BMI ratio. WB BMC, TH BMD, FN BMD, CSA, CSMI and Z were significantly higher in obese women with normal ALM/BMI ratio compared to obese sarcopenic women. In the whole population (n = 53), ALM and the ratio ALM/BMI were positively correlated to WB BMC, CSA, CSMI and Z.ConclusionThe present study suggests that sarcopenia negatively influences bone mineral density and hip geometry parameters before menopause in eumenorrheic obese women.

Background Information about airborne pollen concentrations is required by a range of end users, particularly from the health sector who use both observations and forecasts to diagnose and treat allergic patients. Manual methods are the standard for such measurements but, despite the range of pollen taxa that can be identified, these techniques suffer from a range of drawbacks. This includes being available at low temporal resolution (usually daily averages) and with a delay (usually 3–9 days from the measurement). Recent technological developments have made possible automatic pollen measurements, which are available at high temporal resolution and in real time, although currently only scattered in a few locations across Europe. Materials & Methods To promote the development of an extensive network across Europe and to ensure that this network will respond to end user needs, a stakeholder workshop was organised under the auspices of the EUMETNET AutoPollen Programme. Participants discussed requirements for the groups they represented, ranging from the need for information at various spatial scales, at high temporal resolution, and for targeted services to be developed. Results The provision of real‐time information is likely to lead to a notable decrease in the direct and indirect health costs associated with allergy in Europe, currently estimated between €50–150 billion/year.1 Discussion & Conclusion A European measurement network to meet end user requirements would thus more than pay for itself in terms of potential annual savings and provide significant impetus to research across a range of disciplines from climate science and public health to agriculture and environmental management.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.