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Objective: To evaluate the central venous-to-arterial carbon dioxide difference combined with arterial-to-venous oxygen content difference (∆Pv-aCO2/∆Ca-vO2 ratio) as a predictor of mortality in patients with COVID-19-related severe acute respiratory distress syndrome (ARDS)., Methods: Patients admitted to the intensive care unit with severe ARDS secondary to SARS-CoV-2, and invasive mechanical ventilation were included in this single-center and retrospective cohort study performed between April 18, 2020, and January 18, 2022. The tissue perfusion indexes (lactate, central venous oxygen saturation [ScvO2], and venous-to-arterial carbon dioxide pressure difference [∆Pv-aCO2]), anaerobic metabolism index (∆Pv-aCO2/∆Ca-vO2 ratio), and severity index (Simplified Acute Physiology Score II [SAPSII]) were evaluated to determine its association with the mortality through Cox regression analysis, Kaplan-Meier curve and receiver operating characteristic (ROC) curve., Results: One hundred fifteen patients were included in the study and classified into two groups, the survivor group (n = 54) and the non-survivor group (n = 61). The lactate, ScvO2, ∆Pv-aCO2, and ∆Pv-aCO2/∆Ca-vO2 ratio medians were 1.6 mEq/L, 75%, 5 mmHg, and 1.56 mmHg/mL, respectively. The ∆Pv-aCO2/∆Ca-vO2 ratio (Hazard Ratio (HR) = 1.17, 95% confidence interval (CI) = 1.06-1.29, p = 0.001) was identified as a mortality biomarker for patients with COVID-19-related severe ARDS. The area under the curve for ∆Pv-aCO2/∆Ca-vO2 ratio was 0.691 (95% CI 0.598-0.774, p = 0.0001). The best cut-off point for ∆Pv-aCO2/∆Ca-vO2 ratio was >2.14 mmHg/mL, with a sensitivity of 49.18%, specificity of 85.19%, a positive likelihood of 3.32, and a negative likelihood of 0.6. The Kaplan-Meier curve showed that survival rates were significantly worse in patients with values greater than this cut-off point., Conclusions: The ∆Pv-aCO2/∆Ca-vO2 ratio could be used as a predictor of mortality in patients with severe ARDS secondary to SARS-CoV-2., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sánchez Díaz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Measurement of end-tidal CO2 (ETCO2) can help to monitor circulation during cardiopulmonary resuscitation (CPR). However, early detection of restoration of spontaneous circulation (ROSC) during CPR using waveform capnography remains a challenge. The aim of the study was to investigate if the assessment of ETCO2 variation during chest compression pauses could allow for ROSC detection. We hypothesized that a decay in ETCO2 during a compression pause indicates no ROSC while a constant or increasing ETCO2 indicates ROSC., Methods: We conducted a retrospective analysis of adult out-of-hospital cardiac arrest (OHCA) episodes treated by the advanced life support (ALS). Continuous chest compressions and ventilations were provided manually. Segments of capnography signal during pauses in chest compressions were selected, including at least three ventilations and with durations less than 20 s. Segments were classified as ROSC or non-ROSC according to case chart annotation and examination of the ECG and transthoracic impedance signals. The percentage variation of ETCO2 between consecutive ventilations was computed and its average value, ΔETavg, was used as a single feature to discriminate between ROSC and non-ROSC segments., Results: A total of 384 segments (130 ROSC, 254 non-ROSC) from 205 OHCA patients (30.7% female, median age 66) were analyzed. Median (IQR) duration was 16.3 (12.9,18.1) s. ΔETavg was 0.0 (-0.7, 0.9)% for ROSC segments and -11.0 (-14.1, -8.0)% for non-ROSC segments (p < 0.0001). Best performance for ROSC detection yielded a sensitivity of 95.4% (95% CI: 90.1%, 98.1%) and a specificity of 94.9% (91.4%, 97.1%) for all ventilations in the segment. For the first 2 ventilations, duration was 7.7 (6.0, 10.2) s, and sensitivity and specificity were 90.0% (83.5%, 94.2%) and 89.4 (84.9%, 92.6%), respectively. Our method allowed for ROSC detection during the first compression pause in 95.4% of the patients., Conclusion: Average percent variation of ETCO2 during pauses in chest compressions allowed for ROSC discrimination. This metric could help confirm ROSC during compression pauses in ALS settings., Competing Interests: Author DMGO is employed by Bexen Cardio, a Spanish medical device manufacturer. Bexen Cardio had no additional role in study funding, or study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors declare that no competing interests exist.

Aim: High-quality chest compressions is challenging for bystanders and first responders to out-of-hospital cardiac arrest (OHCA). Long compression pauses and compression rates higher than recommended are common and detrimental to survival. Our aim was to design a simple and low computational cost algorithm for feedback on compression rate using the transthoracic impedance (TI) acquired by automated external defibrillators (AEDs)., Methods: ECG and TI signals from AED recordings of 242 OHCA patients treated by basic life support (BLS) ambulances were retrospectively analyzed. Beginning and end of chest compression series and each individual compression were annotated. The algorithm computed a biased estimate of the autocorrelation of the TI signal in consecutive non-overlapping 2-s analysis windows to detect the presence of chest compressions and estimate compression rate., Results: A total of 237 episodes were included in the study, with a median (IQR) duration of 10 (6-16) min. The algorithm performed with a global sensitivity in the detection of chest compressions of 98.7%, positive predictive value of 98.7%, specificity of 97.1%, and negative predictive value of 97.1% (validation subset including 207 episodes). The unsigned error in the estimation of compression rate was 1.7 (1.3-2.9) compressions per minute., Conclusion: Our algorithm is accurate and robust for real-time guidance on chest compression rate using AEDs. The algorithm is simple and easy to implement with minimal software modifications. Deployment of AEDs with this capability could potentially contribute to enhancing the quality of chest compressions in the first minutes from collapse., Competing Interests: Author Digna María González-Otero is employed by Bexen Cardio, a Spanish medical device manufacturer. Bexen Cardio had no additional role in study funding, or study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: Current resuscitation guidelines recommend waveform capnography as an indirect indicator of perfusion during cardiopulmonary resuscitation (CPR). Chest compressions (CCs) and ventilations during CPR have opposing effects on the exhaled carbon dioxide (CO2) concentration, which need to be better characterized. The purpose of this study was to model the impact of ventilations in the exhaled CO2 measured from capnograms collected during out-of-hospital cardiac arrest (OHCA) resuscitation., Methods: We retrospectively analyzed OHCA monitor-defibrillator files with concurrent capnogram, compression depth, transthoracic impedance and ECG signals. Segments with CC pauses, two or more ventilations, and with no pulse-generating rhythm were selected. Thus, only ventilations should have caused the decrease in CO2 concentration. The variation in the exhaled CO2 concentration with each ventilation was modeled with an exponential decay function using non-linear-least-squares curve fitting., Results: Out of the original 1002 OHCA dataset (one per patient), 377 episodes had the required signals, and 196 segments from 96 patients met the inclusion criteria. Airway type was endotracheal tube in 64.8% of the segments, supraglottic King LT-D™ in 30.1%, and unknown in 5.1%. Median (IQR) decay factor of the exhaled CO2 concentration was 10.0% (7.8 - 12.9) with R2 = 0.98(0.95 - 0.99). Differences in decay factor with airway type were not statistically significant (p = 0.17). From these results, we propose a model for estimating the contribution of CCs to the end-tidal CO2 level between consecutive ventilations and for estimating the end-tidal CO2 variation as a function of ventilation rate., Conclusion: We have modeled the decrease in exhaled CO2 concentration with ventilations during chest compression pauses in CPR. This finding allowed us to hypothesize a mathematical model for explaining the effect of chest compressions on ETCO2 compensating for the influence of ventilation rate during CPR. However, further work is required to confirm the validity of this model during ongoing chest compressions., Competing Interests: Author Digna María González-Otero is employed by Bexen Cardio, a Spanish medical device manufacturer. Bexen Cardio had no additional role in study funding, or study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Global warming is increasingly affecting our biosphere. However, in addition to global warming, a panoply of local stressors caused by human activities is having a profound impact on our environment. The risk that these local stressors could modify the response of organisms to global warming has attracted interest and fostered research on their combined effect, especially with a view to identifying potential synergies. In coastal areas, where human activities are heavily concentrated, this scenario is particularly worrying, especially for foundation species such as seagrasses. In this study we explore these potential interactions in the seagrass Posidonia oceanica. This species is endemic to the Mediterranean Sea. It is well known that the Mediterranean is already experiencing the effects of global warming, especially in the form of heat waves, whose frequency and intensity are expected to increase in the coming decades. Moreover, this species is especially sensitive to stress and plays a key role as a foundation species. The aim of this work is thus to evaluate plant responses (in terms of photosynthetic efficiency and growth) to the combined effects of short-term temperature increases and ammonium additions.To achieve this, we conducted a mesocosm experiment in which plants were exposed to three thermal treatments (20°C, 30°C and 35°C) and three ammonium concentrations (ambient, 30 μM and 120 μM) in a full factorial experiment. We assessed plant performance by measuring chlorophyll fluorescence variables (maximum quantum yield (Fv/Fm), effective quantum yield of photosystem II (ΔF/Fm'), maximum electron transport rate (ETRmax) and non-photochemical quenching (NPQ)), shoot growth rate and leaf necrosis incidence. At ambient ammonium concentrations, P. oceanica tolerates short-term temperature increases up to 30°C. However, at 35°C, the plant loses functionality as indicated by a decrease in photosynthetic performance, an inhibition of plant growth and an increase of the necrosis incidence in leaves. On the other hand, ammonium additions at control temperatures showed only a minor effect on seagrass performance. However, the combined effects of warming and ammonium were much worse than those of each stressor in isolation, given that photosynthetic parameters and, above all, leaf growth were affected. This serves as a warning that the impact of global warming could be even worse than expected (based on temperature-only approaches) in environments that are already subject to eutrophication, especially in persistent seagrass species living in oligotrophic environments., Competing Interests: The authors have declared that no competing interests exist.

Background: During cardiopulmonary resuscitation (CPR), there is a high incidence of capnograms distorted by chest compression artifact. This phenomenon adversely affects the reliability of automated ventilation detection based on the analysis of the capnography waveform. This study explored the feasibility of several filtering techniques for suppressing the artifact to improve the accuracy of ventilation detection., Materials and Methods: We gathered a database of 232 out-of-hospital cardiac arrest defibrillator recordings containing concurrent capnograms, compression depth and transthoracic impedance signals. Capnograms were classified as non-distorted or distorted by chest compression artifact. All chest compression and ventilation instances were also annotated. Three filtering techniques were explored: a fixed-coefficient (FC) filter, an open-loop (OL) adaptive filter, and a closed-loop (CL) adaptive filter. The improvement in ventilation detection was assessed by comparing the performance of a capnogram-based ventilation detection algorithm with original and filtered capnograms., Results: Sensitivity and positive predictive value of the ventilation algorithm improved from 91.9%/89.5% to 97.7%/96.5% (FC filter), 97.6%/96.7% (OL), and 97.0%/97.1% (CL) for the distorted capnograms (42% of the whole set). The highest improvement was obtained for the artifact named type III, for which performance improved from 77.8%/74.5% to values above 95.5%/94.5%. In addition, errors in the measurement of ventilation rate decreased and accuracy in the detection of over-ventilation increased with filtered capnograms., Conclusions: Capnogram-based ventilation detection during CPR was enhanced after suppressing the artifact caused by chest compressions. All filtering approaches performed similarly, so the simplicity of fixed-coefficient filters would take advantage for a practical implementation., Competing Interests: The authors have declared that no competing interests exist.

Many studies have reported that hydraulic properties vary considerably between tree species, but little is known about their intraspecific variation and, therefore, their capacity to adapt to a warmer and drier climate. Here, we quantify phenotypic divergence and clinal variation for embolism resistance, hydraulic conductivity and branch growth, in four tree species, two angiosperms (Betula pendula, Populus tremula) and two conifers (Picea abies, Pinus sylvestris), across their latitudinal distribution in Europe. Growth and hydraulic efficiency varied widely within species and between populations. The variability of embolism resistance was in general weaker than that of growth and hydraulic efficiency, and very low for all species but Populus tremula. In addition, no and weak support for a safety vs. efficiency trade-off was observed for the angiosperm and conifer species, respectively. The limited variability of embolism resistance observed here for all species except Populus tremula, suggests that forest populations will unlikely be able to adapt hydraulically to drier conditions through the evolution of embolism resistance.

Background: The use of real-time feedback systems to guide rescuers during cardiopulmonary resuscitation (CPR) significantly contributes to improve adherence to published resuscitation guidelines. Recently, we designed a novel method for computing depth and rate of chest compressions relying solely on the spectral analysis of chest acceleration. That method was extensively tested in a simulated manikin scenario. The purpose of this study is to report the results of this method as tested in human out-of-hospital cardiac arrest (OHCA) cases., Materials and Methods: The algorithm was evaluated retrospectively with seventy five OHCA episodes recorded by monitor-defibrillators equipped with a CPR feedback device. The acceleration signal and the compression signal computed by the CPR feedback device were stored in each episode. The algorithm was continuously applied to the acceleration signals. The depth and rate values estimated every 2-s from the acceleration data were compared to the reference values obtained from the compression signal. The performance of the algorithm was assesed in terms of the sensitivity and positive predictive value (PPV) for detecting compressions and in terms of its accuracy through the analysis of measurement error., Results: The algorithm reported a global sensitivity and PPV of 99.98% and 99.79%, respectively. The median (P75) unsigned error in depth and rate was 0.9 (1.7) mm and 1.0 (1.7) cpm, respectively. In 95% of the analyzed 2-s windows the error was below 3.5 mm and 3.1 cpm, respectively., Conclusions: The CPR feedback algorithm proved to be reliable and accurate when tested retrospectively with human OHCA episodes. A new CPR feedback device based on this algorithm could be helpful in the resuscitation field.

Parkinson's disease (PD) patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA), a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT) availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36), intermediate (I, n = 22), and tremor-dominant (TD, n = 17) subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001) and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25%) and I (45%) patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype.

The relationship between the denaturation temperatures of proteins (Tm values) and the living temperatures of their host organisms (environmental temperatures: TENV values) is poorly understood. Since different proteins in the same organism may show widely different Tm's, no simple universal relationship between Tm and TENV should hold, other than Tm≥TENV. Yet, when analyzing a set of homologous proteins from different hosts, Tm's are oftentimes found to correlate with TENV's but this correlation is shifted upward on the Tm axis. Supporting this trend, we recently reported Tm's for resurrected Precambrian thioredoxins that mirror a proposed environmental cooling over long geological time, while remaining a shocking ~50°C above the proposed ancestral ocean temperatures. Here, we show that natural selection for protein kinetic stability (denaturation rate) can produce a Tm↔TENV correlation with a large upward shift in Tm. A model for protein stability evolution suggests a link between the Tm shift and the in vivo lifetime of a protein and, more specifically, allows us to estimate ancestral environmental temperatures from experimental denaturation rates for resurrected Precambrian thioredoxins. The TENV values thus obtained match the proposed ancestral ocean cooling, support comparatively high Archaean temperatures, and are consistent with a recent proposal for the environmental temperature (above 75°C) that hosted the last universal common ancestor. More generally, this work provides a framework for understanding how features of protein stability reflect the environmental temperatures of the host organisms.

The Paleoproterozoic Era witnessed crucial steps in the evolution of Earth's surface environments following the first appreciable rise of free atmospheric oxygen concentrations ∼2.3 to 2.1 Ga ago, and concomitant shallow ocean oxygenation. While most sedimentary successions deposited during this time interval have experienced thermal overprinting from burial diagenesis and metamorphism, the ca. 2.1 Ga black shales of the Francevillian B Formation (FB2) cropping out in southeastern Gabon have not. The Francevillian Formation contains centimeter-sized structures interpreted as organized and spatially discrete populations of colonial organisms living in an oxygenated marine ecosystem. Here, new material from the FB2 black shales is presented and analyzed to further explore its biogenicity and taphonomy. Our extended record comprises variably sized, shaped, and structured pyritized macrofossils of lobate, elongated, and rod-shaped morphologies as well as abundant non-pyritized disk-shaped macrofossils and organic-walled acritarchs. Combined microtomography, geochemistry, and sedimentary analysis suggest a biota fossilized during early diagenesis. The emergence of this biota follows a rise in atmospheric oxygen, which is consistent with the idea that surface oxygenation allowed the evolution and ecological expansion of complex megascopic life.

The impact of disulfide bonds on protein stability goes beyond simple equilibrium thermodynamics effects associated with the conformational entropy of the unfolded state. Indeed, disulfide crosslinks may play a role in the prevention of dysfunctional association and strongly affect the rates of irreversible enzyme inactivation, highly relevant in biotechnological applications. While these kinetic-stability effects remain poorly understood, by analogy with proposed mechanisms for processes of protein aggregation and fibrillogenesis, we propose that they may be determined by the properties of sparsely-populated, partially-unfolded intermediates. Here we report the successful design, on the basis of high temperature molecular-dynamics simulations, of six thermodynamically and kinetically stabilized variants of phytase from Citrobacter braakii (a biotechnologically important enzyme) with one, two or three engineered disulfides. Activity measurements and 3D crystal structure determination demonstrate that the engineered crosslinks do not cause dramatic alterations in the native structure. The inactivation kinetics for all the variants displays a strongly non-Arrhenius temperature dependence, with the time-scale for the irreversible denaturation process reaching a minimum at a given temperature within the range of the denaturation transition. We show this striking feature to be a signature of a key role played by a partially unfolded, intermediate state/ensemble. Energetic and mutational analyses confirm that the intermediate is highly unfolded (akin to a proposed critical intermediate in the misfolding of the prion protein), a result that explains the observed kinetic stabilization. Our results provide a rationale for the kinetic-stability consequences of disulfide-crosslink engineering and an experimental methodology to arrive at energetic/structural descriptions of the sparsely populated and elusive intermediates that play key roles in irreversible protein denaturation.

Dispersal has received growing attention in marine ecology, particularly since evidence obtained with up-to-date techniques challenged the traditional view. The dogwhelk Nucella lapillus L., a sedentary gastropod with direct development, is a good example: dispersal was traditionally assumed to be limited until studies with microsatellites disputed this idea. To shed some light on this controversy, the genetic structure of dogwhelk populations in northwest Spain was investigated with highly polymorphic AFLP markers giving special attention to the influence of hydrodynamic stress. In agreement with the expectations for a poor disperser, our results show a significant genetic structure at regional (<200 km) and areal scales (<15 km). However, the spatial genetic structure varied with wave-exposure in the present case study: IBD was evident under sheltered conditions but absent from the exposed area where genetic differentiation was stronger. Our results provide evidence that differences in wave-exposure can exert a detectable influence on the genetic structure of coastal organisms, even in species without a planktonic larva.

Mammalian 14-3-3 protein scaffolds include seven conserved isoforms that bind numerous phosphorylated protein partners and regulate many cellular processes. Some 14-3-3-isoforms, notably γ, have elevated affinity for membranes, which might contribute to modulate the subcellular localization of the partners and substantiate the importance of investigating molecular mechanisms of membrane interaction. By applying surface plasmon resonance we here show that the binding to phospholipid bilayers is stimulated when 14-3-3γ is complexed with its partner, a peptide corresponding to the Ser19-phosphorylated N-terminal region of tyrosine hydroxylase. Moreover, membrane interaction is dependent on salts of kosmotropic ions, which also stabilize 14-3-3γ. Electrostatic analysis of available crystal structures of γ and of the non-membrane-binding ζ-isoform, complemented with molecular dynamics simulations, indicate that the electrostatic potential distribution of phosphopeptide-bound 14-3-3γ is optimal for interaction with the membrane through amphipathic helices at the N-terminal dimerization region. In addition, His158, and especially His195, both specific to 14-3-3γ and located at the convex lateral side, appeared to be pivotal for the ligand induced membrane interaction, as corroborated by site-directed mutagenesis. The participation of these histidine residues might be associated to their increased protonation upon membrane binding. Overall, these results reveal membrane-targeting motifs and give insights on mechanisms that furnish the 14-3-3γ scaffold with the capacity for tuned shuffling from soluble to membrane-bound states.

Despite several careful experimental analyses, it is not yet clear whether protein cold-denaturation is just a "mirror image" of heat denaturation or whether it shows unique structural and energetic features. Here we report that, for a well-characterized small protein, heat denaturation and cold denaturation show dramatically different experimental energetic patterns. Specifically, while heat denaturation is endothermic, the cold transition (studied in the folding direction) occurs with negligible heat effect, in a manner seemingly akin to a gradual, second-order-like transition. We show that this highly anomalous energetics is actually an apparent effect associated to a large folding/unfolding free energy barrier and that it ultimately reflects kinetic stability, a naturally-selected trait in many protein systems. Kinetics thus emerges as an important factor linked to differential features of cold denaturation. We speculate that kinetic stabilization against cold denaturation may play a role in cold adaptation of psychrophilic organisms. Furthermore, we suggest that folding-unfolding kinetics should be taken into account when analyzing in vitro cold-denaturation experiments, in particular those carried out in the absence of destabilizing conditions.