Mitochondria are complex organelles that play a central role in metabolism. Dynamic membrane-associated processes regulate mitochondrial morphology and bioenergetics in response to cellular demand. ...In tumor cells, metabolic reprogramming requires active mitochondrial metabolism for providing key metabolites and building blocks for tumor growth and rapid proliferation. To counter this, the mitochondrial serine beta-lactamase-like protein (LACTB) alters mitochondrial lipid metabolism and potently inhibits the proliferation of a variety of tumor cells. Mammalian LACTB is localized in the mitochondrial intermembrane space (IMS), where it assembles into filaments to regulate the efficiency of essential metabolic processes. However, the structural basis of LACTB polymerization and regulation remains incompletely understood. Here, we describe how human LACTB self-assembles into micron-scale filaments that increase their catalytic activity. The electron cryo-microscopy (cryoEM) structure defines the mechanism of assembly and reveals how highly ordered filament bundles stabilize the active state of the enzyme. We identify and characterize residues that are located at the filament-forming interface and further show that mutations that disrupt filamentation reduce enzyme activity. Furthermore, our results provide evidence that LACTB filaments can bind lipid membranes. These data reveal the detailed molecular organization and polymerization-based regulation of human LACTB and provide new insights into the mechanism of mitochondrial membrane organization that modulates lipid metabolism.
Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate
. The mechanochemical GTPase optic atrophy 1 (OPA1) ...influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane
. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.
Suspended particles in rivers can act as carriers of potentially bioavailable metal species and are thus an emerging area of interest in river system monitoring. The delineation of bulk metals ...concentrations in river water into dissolved and particulate components is also important for risk assessment. Linear relationships between bulk metal concentrations in water (CW,tot) and total suspended solids (TSS) in water can be used to easily evaluate dissolved (CW, intercept) and particle-bound metal fluxes (CSUS, slope) in streams (CW,tot = CW + CSUS TSS). In this study, we apply this principle to catchments in Iran (Haraz) and Germany (Ammer, Goldersbach, and Steinlach) that show differences in geology, geochemistry, land use and hydrological characteristics. For each catchment, particle-bound and dissolved concentrations for a suite of metals in water were calculated based on linear regressions of total suspended solids and total metal concentrations. Results were replicable across sampling campaigns in different years and seasons (between 2013 and 2016) and could be reproduced in a laboratory sedimentation experiment. CSUS values generally showed little variability in different catchments and agree well with soil background values for some metals (e.g. lead and nickel) while other metals (e.g. copper) indicate anthropogenic influences. CW was elevated in the Haraz (Iran) catchment, indicating higher bioavailability and potential human and ecological health concerns (where higher values of CSUS/CW are considered as a risk indicator).
This study determines the aspects of river bathymetry that have the greatest influence on the predictive biases when simulating hyporheic exchange. To investigate this, we build a highly ...parameterized HydroGeoSphere model of the Steinlach River Test Site in southwest Germany as a reference. This model is then modified with simpler bathymetries, evaluating the changes to hyporheic exchange fluxes and transit time distributions. Results indicate that simulating hyporheic exchange with a high‐resolution detailed bathymetry using a three‐dimensional fully coupled model leads to nested multiscale hyporheic exchange systems. A poorly resolved bathymetry will underestimate the small‐scale hyporheic exchange, biasing the simulated hyporheic exchange towards larger scales, thus leading to overestimates of hyporheic exchange residence times. This can lead to gross biases in the estimation of a catchment's capacity to attenuate pollutants when extrapolated to account for all meanders along an entire river within a watershed. The detailed river slope alone is not enough to accurately simulate the locations and magnitudes of losing and gaining river reaches. Thus, local bedforms in terms of bathymetric highs and lows within the river are required. Bathymetry surveying campaigns can be more effective by prioritizing bathymetry measurements along the thalweg and gegenweg of a meandering channel. We define the gegenweg as the line that connects the shallowest points in successive cross‐sections along a river opposite to the thalweg under average flow conditions. Incorporating local bedforms will likely capture the nested nature of hyporheic exchange, leading to more physically meaningful simulations of hyporheic exchange fluxes and transit times.
Article impact statement: Three‐dimensional fully coupled surface water‐groundwater models with detailed river bathymetry contrasts lead to nested multiscale hyporheic exchange systems.
Objective Inspired by the limited facility of the Penn classification, the authors aimed to determine a rapid and optimal preoperative assessment tool to predict surgical mortality after acute ...Stanford type-A aortic dissection (AAAD) repair. Design Patients who underwent an attempted surgical repair of AAAD were determined using a de-identified single institution database. The charts of 144 patients were reviewed retrospectively for preoperative demographics and surrogates for disease severity and malperfusion. Bivariate analysis was used to determine significant (p≤0.05) predictors of in-hospital and 1-year mortality, the primary endpoints. Receiver operating characteristic curve generation was used to define optimal cut-off values for continuous predictors. Setting Single center, level 1 trauma, university teaching hospital. Participants The study included 144 cardiac surgical patients with acute type-A aortic dissection presenting for surgical correction. Interventions Surgical repair of aortic dissection with preoperative laboratory samples drawn before patient transfer to the operating room or immediately after arterial catheter placement intraoperatively. Measurements and Main Results The study cohort comprised 144 patients. In-hospital mortality was 9%, and the 1-year mortality rate was 17%. Variables that demonstrated a correlation with in-hospital mortality included an elevated serum lactic acid level (odds ratio OR 1.5 1.3-1.9, p<0.001), a depressed ejection fraction (OR 0.91 0.86-0.96, p = .001), effusion (OR 4.8 1.02-22.5, p = 0.04), neurologic change (OR 5.3 1.6-17.4, p = 0.006), severe aortic regurgitation (OR 8.2 2.0-33.9, p = 0.006), and cardiopulmonary resuscitation (OR 6.8 1.7-26.9, p = 0.01). Only an increased serum lactic acid level demonstrated a trend with 1-year mortality using univariate Cox regression (hazard ratio 1.1 1.0-1.1, p = 0.006). Receiver operating characteristic analysis revealed optimal cut-off lactic acid levels of 6.0 mmol/L and 6.9 mmol/L for in-hospital and 1-year mortality, respectively. Conclusion Lactic acidosis, ostensibly as a surrogate for systemic malperfusion, represents a novel, accurate, and easily obtainable preoperative predictor of short-term mortality after attempted AAAD repair. These data may improve identification of patients who would not benefit from surgery.
The spatial variability of hydraulic conductivity is known to have a strong impact on solute spreading and mixing. In most investigations, its local anisotropy has been neglected. Recent studies have ...shown that spatially varying orientation in sedimentary anisotropy can lead to twisting flow enhancing transverse mixing, but most of these studies used geologically implausible geometries. We use an object‐based approach to generate stacked scour‐pool structures with either isotropic or anisotropic filling which are typically reported in glacial outwash deposits. We analyze how spatially variable isotropic conductivity and variation of internal anisotropy in these features impacts transverse plume deformation and both longitudinal and transverse spreading and mixing. In five test cases, either the scalar values of conductivity or the spatial orientation of its anisotropy is varied between the scour‐pool structures. Based on 100 random configurations, we compare the variability of velocity components, stretching and folding metrics, advective travel‐time distributions, one and two‐particle statistics in advective‐dispersive transport, and the flux‐related dilution indices for steady state advective‐dispersive transport among the five test cases. Variation in the orientation of internal anisotropy causes strong variability in the lateral velocity components, which leads to deformation in transverse directions and enhances transverse mixing, whereas it hardly affects the variability of the longitudinal velocity component and thus longitudinal spreading and mixing. The latter is controlled by the spatial variability in the scalar values of hydraulic conductivity. Our results demonstrate that sedimentary anisotropy is important for transverse mixing, whereas it may be neglected when considering longitudinal spreading and mixing.
Plain Language Summary
When sediments are deposited in stream channels they retain the “imprint” of the stream flow that deposited them. Groundwater flows more easily along the path of this streamflow imprint than against it—this is called anisotropy. Many groundwater systems are made up of deposits from many different streams and so will have many different imprints, even when the deposits are close to each other. We found that this can cause groundwater to flow along complicated and tangled paths. These tangled groundwater paths can change the way that compounds move through the system, especially at right angles to the main groundwater flow direction. This is important because groundwater scientists often do not think about the imprint, or anisotropy, of the sediments in their studies, and perhaps they should.
Key Points
Internal anisotropy in realistic glacial outwash deposits causes complex three‐dimensional groundwater flow patterns
Dilution of steady state plumes in anisotropic test cases is not adequately characterized by two‐particle statistics
Sedimentary anisotropy is of critical importance when considering contaminant plumes controlled by transverse mixing
The spatial distribution of hydraulic properties in the subsurface controls groundwater flow and solute transport. However, many approaches to modeling these distributions do not produce geologically ...realistic results and/or do not model the anisotropy of hydraulic conductivity caused by bedding structures in sedimentary deposits. We have developed a flexible object‐based package for simulating hydraulic properties in the subsurface—the Hydrogeological Virtual Realities (HyVR) simulation package. This implements a hierarchical modeling framework that takes into account geological rules about stratigraphic bounding surfaces and the geometry of specific sedimentary structures to generate realistic aquifer models, including full hydraulic‐conductivity tensors. The HyVR simulation package can create outputs suitable for standard groundwater modeling tools (e.g., MODFLOW), is written in Python, an open‐source programming language, and is openly available at an online repository. This paper presents an overview of the underlying modeling principles and computational methods, as well as an example simulation based on the Macrodispersion Experiment site in Columbus, Mississippi. Our simulation package can currently simulate porous media that mimic geological conceptual models in fluvial depositional environments, and that include fine‐scale heterogeneity in distributed hydraulic parameter fields. The simulation results allow qualitative geological conceptual models to be converted into digital subsurface models that can be used in quantitative numerical flow‐and‐transport simulations, with the aim of improving our understanding of the influence of geological realism on groundwater flow and solute transport.
Article impact statement: Generate hydrogeological virtual realities and analyze three‐dimensional conceptual models using a flexible open‐source Python package.
Abstract Study Objective To propose a set of recommendations for the perioperative management of patients with Eisenmenger syndrome and similar physiology, based on 20 years of experience at a single ...institution. Design Retrospective study of institutional outcomes of Eisenmenger syndrome patients and patients with balanced or fixed right-to-left intracardiac shunts with pulmonary hypertension undergoing noncardiac surgery. Setting Single center, university-affiliated hospital. Measurements Measurements included data from patients with Eisenmenger syndrome or similar physiology, shunt direction, right ventricular systolic pressure, congestive heart failure classification, noncardiac surgery, type of anesthesia, echocardiographic and catheterization data, mortality within 30 days of surgery, choice of monitoring, and vasopressor use. Main Results 33 patients with Eisenmenger syndrome or similar physiology undergoing 53 general, regional and/or monitored anesthetic procedures were identified. Significant systemic arterial hypotension occurred in 14 individuals (26%) and oxygen desaturation in 9 (17%) patients. Administration of an intravenous (IV) vasopressor agent during induction significantly decreased the incidence of hypotension. The type of IV induction agent did not influence hemodynamic alterations, though patients who received propofol experienced a trend towards increased hypotension (83% of pts) when a vasopressor was not used. Inhalational induction, regardless of vasopressor use, was more likely to result in hypotension (60% of pts). The 30-day mortality was 3.8% (two pts). Both patients had minor elective procedures with monitored anesthesia care (MAC). Conclusions Hypotension is more common in patients with Eisenmenger syndrome and similar physiology when a vasopressor is not used during the peri-induction period, regardless of induction agent. Etomidate tended to have better hemodynamic stability than other induction agents. The use of a vasopressor is recommended. We present general recommendations for anesthesiologists and strongly recommend use of a vasopressor before or during induction to reduce hypotension along with complete avoidance of inhalational induction. Further, MAC anesthesia has been associated with perioperative and 30-day mortality.
Atrial fibrillation is a very common arrhythmia whose prevalence is expected to increase significantly as the population ages. The associated stroke risk is a major cause of morbidity and mortality. ...Stroke prevention by anticoagulation carries its own risks, leading to the search for alternative strategies. Multiple techniques have been developed to exclude the left atrial appendage (the main source of thromboembolism in atrial fibrillation) from the circulation. Such techniques offer the hope of stroke prevention without the risks of anticoagulation. This article describes the percutaneous approaches being currently performed in the United States. Particular emphasis is placed on the use of transesophageal echocardiography to guide these procedures.
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