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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 1 – 3 . The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane 4 , 5 . 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. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain, and OPA1 oligomerization through multiple assembly interfaces promotes the helical assembly of a flexible OPA1 lattice on the membrane, driving mitochondrial fusion in cells.

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).

Premise Robust standards to evaluate quality and completeness are lacking in eukaryotic structural genome annotation, as genome annotation software is developed using model organisms and typically lacks benchmarking to comprehensively evaluate the quality and accuracy of the final predictions. The annotation of plant genomes is particularly challenging due to their large sizes, abundant transposable elements, and variable ploidies. This study investigates the impact of genome quality, complexity, sequence read input, and method on protein‐coding gene predictions. Methods The impact of repeat masking, long‐read and short‐read inputs, and de novo and genome‐guided protein evidence was examined in the context of the popular BRAKER and MAKER workflows for five plant genomes. The annotations were benchmarked for structural traits and sequence similarity. Results Benchmarks that reflect gene structures, reciprocal similarity search alignments, and mono‐exonic/multi‐exonic gene counts provide a more complete view of annotation accuracy. Transcripts derived from RNA‐read alignments alone are not sufficient for genome annotation. Gene prediction workflows that combine evidence‐based and ab initio approaches are recommended, and a combination of short and long reads can improve genome annotation. Adding protein evidence from de novo assemblies, genome‐guided transcriptome assemblies, or full‐length proteins from OrthoDB generates more putative false positives as implemented in the current workflows. Post‐processing with functional and structural filters is highly recommended. Discussion While the annotation of non‐model plant genomes remains complex, this study provides recommendations for inputs and methodological approaches. We discuss a set of best practices to generate an optimal plant genome annotation and present a more robust set of metrics to evaluate the resulting predictions.

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. 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. Single center, university-affiliated hospital. 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. 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). 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.

Premise An informatics approach was used for the construction of an Axiom genotyping array from heterogeneous, high‐throughput sequence data to assess the complex genome of loblolly pine (Pinus taeda). Methods High‐throughput sequence data, sourced from exome capture and whole genome reduced‐representation approaches from 2698 trees across five sequence populations, were analyzed with the improved genome assembly and annotation for the loblolly pine. A variant detection, filtering, and probe design pipeline was developed to detect true variants across and within populations. From 8.27 million variants, a total of 642,275 were evaluated and 423,695 of those were screened across a range‐wide population. Results The final informatics and screening approach delivered an Axiom array representing 46,439 high‐confidence variants to the forest tree breeding and genetics community. Based on the annotated reference genome, 34% were located in or directly upstream or downstream of genic regions. Discussion The Pita50K array represents a genome‐wide resource developed from sequence data for an economically important conifer, loblolly pine. It uniquely integrates independent projects that assessed trees sampled across the native range. The challenges associated with the large and repetitive genome are addressed in the development of this resource.

Background Anesthesiologists administer excess supplemental oxygen (hyper-oxygenation) to patients during surgery to avoid hypoxia. Hyper-oxygenation, however, may increase the generation of reactive oxygen species and cause oxidative damage. In cardiac surgery, increased oxidative damage has been associated with postoperative kidney and brain injury. We hypothesize that maintenance of normoxia during cardiac surgery (physiologic oxygenation) decreases kidney injury and oxidative damage compared to hyper-oxygenation. Methods/design The Risk of Oxygen during Cardiac Surgery (ROCS) trial will randomly assign 200 cardiac surgery patients to receive physiologic oxygenation, defined as the lowest fraction of inspired oxygen (FIO 2 ) necessary to maintain an arterial hemoglobin saturation of 95 to 97%, or hyper-oxygenation (FIO 2  = 1.0) during surgery. The primary clinical endpoint is serum creatinine change from baseline to postoperative day 2, and the primary mechanism endpoint is change in plasma concentrations of F 2 -isoprostanes and isofurans. Secondary endpoints include superoxide production, clinical delirium, myocardial injury, and length of stay. An endothelial function substudy will examine the effects of oxygen treatment and oxidative stress on endothelial function, measured using flow mediated dilation, peripheral arterial tonometry, and wire tension myography of epicardial fat arterioles. Discussion The ROCS trial will test the hypothesis that intraoperative physiologic oxygenation decreases oxidative damage and organ injury compared to hyper-oxygenation in patients undergoing cardiac surgery. Trial registration ClinicalTrials.gov, ID: NCT02361944 . Registered on the 30th of January 2015.

Acute pulmonary embolism is a major cause of morbidity and mortality in patients presenting for emergent cardiac surgery with overall mortality ranging from 6% to as high as 85%. While the initial focus of treatment is nonsurgical or percutaneous interventions, surgical treatment continues to be a treatment for patients with refractory thrombus burden or cardiogenic shock. Our institution regularly performs surgical pulmonary embolectomy with improved outcomes compared to current reports. We thus performed a retrospective analysis of outcomes of pulmonary embolectomy patients and anesthetic management. A retrospective review of 40 patients undergoing emergent pulmonary embolectomy over a 4 year period (2008-2012) at our institution was performed to assess for a 2nd period of critical instability. The study was conducted at a tertiary, level 1, trauma university medical center. The study was performed through chart review of patient hospital records. No interventions were performed. Anesthetic records were reviewed along with echocardiographic records and surgical reports to assess cardiac function, need for emergent cardiopulmonary bypass, and degree of patient morbidity. A total of 40 patients were studied. Hemodynamic instability occurred in 12.5% of patients at time of induction requiring emergent cardiopulmonary bypass. Another 17% of patients who remained stable following induction developed subsequent instability requiring emergent cardiopulmonary bypass during pericardial opening or manipulation which has not been previously reported. One patient died during hospitalization. Patients who required emergent bypass following induction of general anesthesia tended to receive higher doses of induction drugs than the other groups. In patients who needed emergent bypass during pericardial manipulation there were no identifiable factors suggesting that these patients remain at risk despite a stable post-induction course.

Supraglottic airway (SGA) is an alternative to endotracheal intubation, however endotracheal intubation is often essential. One method to convert from an SGA to an endotracheal tube (ETT) is utilizing the SGA as a conduit for fiberoptic-guided advancement of an Aintree catheter (airway exchange catheter), and exchange of the SGA for an ETT. In this prospective randomized study, we compared two SGA devices in facilitating this exchange. Subjects were randomized to receive either the i-gel® or LMA® Supreme™ SGA. The SGA was placed and an Aintree intubation catheter was inserted through the SGA over a fiberoptic bronchoscope. Next, the SGA was removed, leaving the Aintree within the trachea, and an ETT was placed over the Aintree catheter and advanced into the trachea. The i-gel group exhibited shorter time to successful intubation (median, 191 vs. 434 seconds; = .002). The i-gel group also had fewer study subjects requiring more than one attempt for successful Aintree placement (33% vs. 75%, = .02). The i-gel group showed superior laryngeal view score (LVS) (6 vs. 4; = .003). The i-gel SGA achieved a faster time to successful intubation, higher rate of first attempt Aintree placement, and superior LVS.

The following thesis is a series of observations and explorations documenting my experiences as both an artistic collaborator and contributor of the Davis Performing Arts Center at Georgetown University’s production of Here I Am. The production opened April 15th, 2021 as a virtual live performance streamed through YouTube. Here I Am was an original performance by Mélisande (Meli) Short-Colomb with direction by Derek Goldman and Nikkole Salter, music composition and vocal performance by Somi Kakoma, multimedia design by Jared Mezzocchi, sound design by Andre Pluess and lighting design by Alberto Segarra.