Regional genetic structure in the Magellanic penguin (Spheniscus magellanicus) suggests metapopulation dynamics

Using microsatellite markers and mitochondrial DNA (mtDNA) sequences (cytochrome oxidase 1 gene), we estimated levels of genetic structuring among nine Magellanic Penguin (Spheniscus magellanicus) colonies distributed throughout three major reproductive regions of the South Atlantic Ocean. Overall, breeding colonies showed relatively high levels of genetic diversity at both nuclear and mtDNA markers (mean heteorzygosity: He = 0.598; mean allelic diversity: A = 7.11; mtDNA haplotype diversity: h = 0.812). A hierarchical analysis of molecular variance based on microsatellite data showed limited genetic structuring of breeding colonies, with 99% of the variation explained by differences among individuals and 0.7–1.0% attributed to differences among the three regions. The mtDNA analysis revealed higher levels of genetic structuring, with 3.43% of the variation explained by regions and 2.24% explained by colonies within the regions. Furthermore, a Mantel test revealed a significant association between geographic and genetic distances among colonies. The limited genetic structuring we detected is likely a result of (1) population intermixing through natal dispersal and (2) the large effective sizes of the reproductive colonies, both of which prevent genetic differentiation at neutral markers, balanced with (3) the regional association of breeding colonies to distinct feeding grounds and (4) a recent expansion of the population. Our results suggest that the demographic dynamics of breeding colonies of Magellanic Penguins may be framed under a metapopulation model, in which colonies with large numbers of breeding pairs could be considered source populations for maintaining the overall abundance of this species in the Atlantic Ocean

Cerebral Microdialysis Monitoring to Improve Individualized Neurointensive Care Therapy: An Update of Recent Clinical Data.

Cerebral microdialysis (CMD) allows bedside semicontinuous monitoring of patient brain extracellular fluid. Clinical indications of CMD monitoring are focused on the management of secondary cerebral and systemic insults in acute brain injury (ABI) patients [mainly, traumatic brain injury (TBI), subarachnoid hemorrhage, and intracerebral hemorrhage (ICH)], specifically to tailor several routine interventions-such as optimization of cerebral perfusion pressure, blood transfusion, glycemic control and oxygen therapy-in the individual patient. Using CMD as clinical research tool has greatly contributed to identify and better understand important post-injury mechanisms-such as energy dysfunction, posttraumatic glycolysis, post-aneurysmal early brain injury, cortical spreading depressions, and subclinical seizures. Main CMD metabolites (namely, lactate/pyruvate ratio, and glucose) can be used to monitor the brain response to specific interventions, to assess the extent of injury, and to inform about prognosis. Recent consensus statements have provided guidelines and recommendations for CMD monitoring in neurocritical care. Here, we summarize recent clinical investigation conducted in ABI patients, specifically focusing on the role of CMD to guide individualized intensive care therapy and to improve our understanding of the complex disease mechanisms occurring in the immediate phase following ABI. Promising brain biomarkers will also be described

Improvement of Neuroenergetics by Hypertonic Lactate Therapy in Patients with Traumatic Brain Injury Is Dependent on Baseline Cerebral Lactate/Pyruvate Ratio.

Energy dysfunction is associated with worse prognosis after traumatic brain injury (TBI). Recent data suggest that hypertonic sodium lactate infusion (HL) improves energy metabolism after TBI. Here, we specifically examined whether the efficacy of HL (3h infusion, 30-40 μmol/kg/min) in improving brain energetics (using cerebral microdialysis [CMD] glucose as a main therapeutic end-point) was dependent on baseline cerebral metabolic state (assessed by CMD lactate/pyruvate ratio [LPR]) and cerebral blood flow (CBF, measured with perfusion computed tomography [PCT]). Using a prospective cohort of 24 severe TBI patients, we found CMD glucose increase during HL was significant only in the subgroup of patients with elevated CMD LPR >25 (n = 13; +0.13 [95% confidence interval (CI) 0.08-0.19] mmol/L, p < 0.001; vs. +0.04 [-0.05-0.13] in those with normal LPR, p = 0.33, mixed-effects model). In contrast, CMD glucose increase was independent from baseline CBF (coefficient +0.13 [0.04-0.21] mmol/L when global CBF was <32.5 mL/100 g/min vs. +0.09 [0.04-0.14] mmol/L at normal CBF, both p < 0.005) and systemic glucose. Our data suggest that improvement of brain energetics upon HL seems predominantly dependent on baseline cerebral metabolic state and support the concept that CMD LPR - rather than CBF - could be used as a diagnostic indication for systemic lactate supplementation following TBI

Data and methods to calculate cut-off values for serum potassium and core temperature at hospital admission for extracorporeal rewarming of avalanche victims in cardiac arrest.

The data and estimation methods presented in this article are associated with the research article, "Cut-off values of serum potassium and core temperature at hospital admission for extracorporeal rewarming of avalanche victims in cardiac arrest: a retrospective multi-centre study" [1]. In this article we estimate recommended cut-off values for in-hospital triage with respect to extracorporeal rewarming. With only 6 survivors of 103 patients collected over a period of 20 years the ability to estimate reliable threshold values is limited. In addition, because the number of avalanche victims is also limited, a significantly larger dataset is unlikely to be obtained. We have therefore adapted two non-parametric estimation methods (bootstrapping and exact binomial distribution) to our specific needs and performed a simulations to confirm validity and reliability

Limit cycle induced by multiplicative noise in a system of coupled Brownian motors

We study a model consisting of $N$ nonlinear oscillators with {\em global periodic} coupling and {\em local multiplicative} and additive noises. The model was shown to undergo a nonequilibrium phase transition towards a broken-symmetry phase exhibiting noise-induced "ratchet" behavior. A previous study \cite{[7]} focused on the relationship between the character of thehysteresis loop, the number of ``homogeneous'' mean-field solutions and the shape of the stationary mean-field probability distribution function. Here we show --as suggested by the absence of stable solutions when the load force is beyond a critical value-- the existence of a limit cycle induced by both:multiplicative noise and {\em global periodic} coupling.Comment: Submitted to Phys. Rev. E, RevTex, 18 pgs, 5 figure

Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure

The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coordinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hepcidin synthesis by inhibiting hepatic BMP/SMAD signaling, evidence for the role of ERFE in humans is limited. To investigate the role of ERFE as a physiological erythroid regulator in humans, we conducted two studies: first, 24 males received six injections of saline (placebo), recombinant Epo (rhEpo) 20 UI kg-1 (micro-dose) or 50 UI kg-1 (low-dose). Second, we quantified ERFE in 22 subjects exposed to high altitude (3800 m) for 15 hours. In the first study, total hemoglobin mass (Hbmass) increased after low- but not after micro-dose injections, when compared to placebo. Serum ERFE levels were enhanced by rhEpo, remaining higher than after placebo for 48 (micro-dose) or 72 hours (low-dose) post-injections. Conversely, hepcidin levels decreased when Epo and ERFE arose, before any changes in serum iron parameters occurred. In the second study, serum Epo and ERFE increased at high altitude. The present results demonstrate that in healthy humans ERFE responds to slightly increased Epo levels not associated with Hbmass expansion and down-regulates hepcidin in an apparently iron-independent way. Notably, ERFE flags micro-dose Epo, thus holding promise as novel anti-doping biomarker

Association of Early Norepinephrine Administration With 24-Hour Mortality Among Patients With Blunt Trauma and Hemorrhagic Shock.

Hemorrhagic shock is a common cause of preventable death after injury. Vasopressor administration for patients with blunt trauma and hemorrhagic shock is often discouraged. To evaluate the association of early norepinephrine administration with 24-hour mortality among patients with blunt trauma and hemorrhagic shock. This retrospective, multicenter, observational cohort study used data from 3 registries in the US and France on all consecutive patients with blunt trauma from January 1, 2013, to December 31, 2018. Patients were alive on admission with hemorrhagic shock, defined by prehospital or admission systolic blood pressure less than 100 mm Hg and evidence of hemorrhage (ie, prehospital or resuscitation room transfusion of packed red blood cells, receipt of emergency treatment for hemorrhage control, transfusion of >10 units of packed red blood cells in the first 24 hours, or death from hemorrhage). Blunt trauma was defined as any exposure to nonpenetrating kinetic energy, collision, or deceleration. Statistical analysis was performed from January 15, 2021, to February 22, 2022. Continuous administration of norepinephrine in the prehospital environment or resuscitation room prior to hemorrhage control, according to European guidelines. The primary outcome was 24-hour mortality, and the secondary outcome was in-hospital mortality. The average treatment effect (ATE) of early norepinephrine administration on 24-hour mortality was estimated according to the Rubin causal model. Inverse propensity score weighting and the doubly robust approach with 5 distinct analytical strategies were used to determine the ATE. A total of 52 568 patients were screened for inclusion, and 2164 patients (1508 men [70%]; mean [SD] age, 46 [19] years; median Injury Severity Score, 29 [IQR, 17-36]) presented with acute hemorrhage and were included. A total of 1497 patients (69.1%) required emergency hemorrhage control, 128 (5.9%) received a prehospital transfusion of packed red blood cells, and 543 (25.0%) received a massive transfusion. Norepinephrine was administered to 1498 patients (69.2%). The 24-hour mortality rate was 17.8% (385 of 2164), and the in-hospital mortality rate was 35.6% (770 of 2164). None of the 5 analytical strategies suggested any statistically significant association between norepinephrine administration and 24-hour mortality, with ATEs ranging from -4.6 (95% CI, -11.9 to 2.7) to 2.1 (95% CI, -2.1 to 6.3), or between norepinephrine administration and in-hospital mortality, with ATEs ranging from -1.3 (95% CI, -9.5 to 6.9) to 5.3 (95% CI, -2.1 to 12.8). The findings of this study suggest that early norepinephrine infusion was not associated with 24-hour or in-hospital mortality among patients with blunt trauma and hemorrhagic shock. Randomized clinical trials that study the effect of early norepinephrine administration among patients with trauma and hypotension are warranted to further assess whether norepinephrine is safe for patients with hemorrhagic shock

Enhancement of Stochastic Resonance in distributed systems due to a selective coupling

Recent massive numerical simulations have shown that the response of a "stochastic resonator" is enhanced as a consequence of spatial coupling. Similar results have been analytically obtained in a reaction-diffusion model, using "nonequilibrium potential" techniques. We now consider a field-dependent diffusivity and show that the "selectivity" of the coupling is more efficient for achieving stochastic-resonance enhancement than its overall value in the constant-diffusivity case.Comment: 10 pgs (RevTex), 4 figures, submitted to Phys.Rev.Let

Signal Transduction Pathways in the Pentameric Ligand-Gated Ion Channels

The mechanisms of allosteric action within pentameric ligand-gated ion channels (pLGICs) remain to be determined. Using crystallography, site-directed mutagenesis, and two-electrode voltage clamp measurements, we identified two functionally relevant sites in the extracellular (EC) domain of the bacterial pLGIC from Gloeobacter violaceus (GLIC). One site is at the C-loop region, where the NQN mutation (D91N, E177Q, and D178N) eliminated inter-subunit salt bridges in the open-channel GLIC structure and thereby shifted the channel activation to a higher agonist concentration. The other site is below the C-loop, where binding of the anesthetic ketamine inhibited GLIC currents in a concentration dependent manner. To understand how a perturbation signal in the EC domain, either resulting from the NQN mutation or ketamine binding, is transduced to the channel gate, we have used the Perturbation-based Markovian Transmission (PMT) model to determine dynamic responses of the GLIC channel and signaling pathways upon initial perturbations in the EC domain of GLIC. Despite the existence of many possible routes for the initial perturbation signal to reach the channel gate, the PMT model in combination with Yen's algorithm revealed that perturbation signals with the highest probability flow travel either via the β1-β2 loop or through pre-TM1. The β1-β2 loop occurs in either intra- or inter-subunit pathways, while pre-TM1 occurs exclusively in inter-subunit pathways. Residues involved in both types of pathways are well supported by previous experimental data on nAChR. The direct coupling between pre-TM1 and TM2 of the adjacent subunit adds new insight into the allosteric signaling mechanism in pLGICs. © 2013 Mowrey et al