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"Eckmann, Christian"
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Iron from Tutankhamun's tomb
\"\"A century after Howard Carter and Lord Carnarvon's sensational discovery in 1922 of the virtually intact tomb of Tutankhamun in the Valley of the Kings, the boy-king and his treasures continue to fascinate people all over the world. Although nearly 5,400 objects accompanied the young pharaoh on his journey to the afterlife, many of them have not been investigated in detail. Iron from Tutankhamun's Tomb analyzes nineteen iron artifacts from the tomb in depth for the first time. This group consists of sixteen small iron chisels set into wooden handles, an Eye of Horus amulet, a miniature headrest, and the blade of a richly decorated golden dagger. The most important of these were placed in close proximity to the king's mummy, emphasizing the high value attributed to this rare material in late Bronze Age Egypt-a time when iron smelting was not yet known in the land of the Nile. Written by a research team of archaeologists, scientists, and conservators, this comprehensive study explores in fascinating detail the context and meaning of these artifacts, while establishing for the first time that Tutankhamun's iron came from meteorites. They complete their examination with the results of chemical analyses, offering in the process a rich overall understanding of iron and its significance in ancient Egypt.\"\"-- Provided by publisher.
Book
disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics
P granules and other RNA/protein bodies are membrane-less organelles that may assemble by intracellular phase separation, similar to the condensation of water vapor into droplets. However, the molecular driving forces and the nature of the condensed phases remain poorly understood. Here, we show that the Caenorhabditis elegans protein LAF-1, a DDX3 RNA helicase found in P granules, phase separates into P granule-like droplets in vitro. We adapt a microrheology technique to precisely measure the viscoelasticity of micrometer-sized LAF-1 droplets, revealing purely viscous properties highly tunable by salt and RNA concentration. RNA decreases viscosity and increases molecular dynamics within the droplet. Single molecule FRET assays suggest that this RNA fluidization results from highly dynamic RNA–protein interactions that emerge close to the droplet phase boundary. We demonstrate than an N-terminal, arginine/glycine rich, intrinsically disordered protein (IDP) domain of LAF-1 is necessary and sufficient for both phase separation and RNA–protein interactions. In vivo, RNAi knockdown of LAF-1 results in the dissolution of P granules in the early embryo, with an apparent submicromolar phase boundary comparable to that measured in vitro. Together, these findings demonstrate that LAF-1 is important for promoting P granule assembly and provide insight into the mechanism by which IDP-driven molecular interactions give rise to liquid phase organelles with tunable properties.
Significance Phase transitions have recently emerged as a key mechanism for intracellular organization. However, the underlying molecular interactions and nature of the resulting condensed phases are poorly understood. Here, we identify a role for LAF-1 in the liquid phase separation of P granules—RNA/protein assemblies implicated in germ-line maintenance. We adapt microrheology techniques to measure precise viscoelastic properties of LAF-1 liquid droplets. Our experiments reveal that electrostatic disordered protein interactions give rise to droplets with tunable material properties. RNA can fluidize protein droplets by decreasing the viscosity and increasing internal molecular dynamics. Our results provide insight into the mechanism by which molecular level interactions can give rise to liquid phase organelles with tunable material properties, potentially underlying biologically adaptable functions.
Journal Article
Iron from Tutankhamun's tomb
\"\"A century after Howard Carter and Lord Carnarvon's sensational discovery in 1922 of the virtually intact tomb of Tutankhamun in the Valley of the Kings, the boy-king and his treasures continue to fascinate people all over the world. Although nearly 5,400 objects accompanied the young pharaoh on his journey to the afterlife, many of them have not been investigated in detail. Iron from Tutankhamun's Tomb analyzes nineteen iron artifacts from the tomb in depth for the first time. This group consists of sixteen small iron chisels set into wooden handles, an Eye of Horus amulet, a miniature headrest, and the blade of a richly decorated golden dagger. The most important of these were placed in close proximity to the king's mummy, emphasizing the high value attributed to this rare material in late Bronze Age Egypt-a time when iron smelting was not yet known in the land of the Nile. Written by a research team of archaeologists, scientists, and conservators, this comprehensive study explores in fascinating detail the context and meaning of these artifacts, while establishing for the first time that Tutankhamun's iron came from meteorites. They complete their examination with the results of chemical analyses, offering in the process a rich overall understanding of iron and its significance in ancient Egypt.
Book
Mouse HORMAD1 and HORMAD2, Two Conserved Meiotic Chromosomal Proteins, Are Depleted from Synapsed Chromosome Axes with the Help of TRIP13 AAA-ATPase
Meiotic crossovers are produced when programmed double-strand breaks (DSBs) are repaired by recombination from homologous chromosomes (homologues). In a wide variety of organisms, meiotic HORMA-domain proteins are required to direct DSB repair towards homologues. This inter-homologue bias is required for efficient homology search, homologue alignment, and crossover formation. HORMA-domain proteins are also implicated in other processes related to crossover formation, including DSB formation, inhibition of promiscuous formation of the synaptonemal complex (SC), and the meiotic prophase checkpoint that monitors both DSB processing and SCs. We examined the behavior of two previously uncharacterized meiosis-specific mouse HORMA-domain proteins--HORMAD1 and HORMAD2--in wild-type mice and in mutants defective in DSB processing or SC formation. HORMADs are preferentially associated with unsynapsed chromosome axes throughout meiotic prophase. We observe a strong negative correlation between SC formation and presence of HORMADs on axes, and a positive correlation between the presumptive sites of high checkpoint-kinase ATR activity and hyper-accumulation of HORMADs on axes. HORMADs are not depleted from chromosomes in mutants that lack SCs. In contrast, DSB formation and DSB repair are not absolutely required for depletion of HORMADs from synapsed axes. A simple interpretation of these findings is that SC formation directly or indirectly promotes depletion of HORMADs from chromosome axes. We also find that TRIP13 protein is required for reciprocal distribution of HORMADs and the SYCP1/SC-component along chromosome axes. Similarities in mouse and budding yeast meiosis suggest that TRIP13/Pch2 proteins have a conserved role in establishing mutually exclusive HORMAD-rich and synapsed chromatin domains in both mouse and yeast. Taken together, our observations raise the possibility that involvement of meiotic HORMA-domain proteins in the regulation of homologue interactions is conserved in mammals.
Journal Article
GLD-4-Mediated Translational Activation Regulates the Size of the Proliferative Germ Cell Pool in the Adult C. elegans Germ Line
To avoid organ dysfunction as a consequence of tissue diminution or tumorous growth, a tight balance between cell proliferation and differentiation is maintained in metazoans. However, cell-intrinsic gene expression mechanisms controlling adult tissue homeostasis remain poorly understood. By focusing on the adult Caenorhabditis elegans reproductive tissue, we show that translational activation of mRNAs is a fundamental mechanism to maintain tissue homeostasis. Our genetic experiments identified the Trf4/5-type cytoplasmic poly(A) polymerase (cytoPAP) GLD-4 and its enzymatic activator GLS-1 to perform a dual role in regulating the size of the proliferative zone. Consistent with a ubiquitous expression of GLD-4 cytoPAP in proliferative germ cells, its genetic activity is required to maintain a robust proliferative adult germ cell pool, presumably by regulating many mRNA targets encoding proliferation-promoting factors. Based on translational reporters and endogenous protein expression analyses, we found that gld-4 activity promotes GLP-1/Notch receptor expression, an essential factor of continued germ cell proliferation. RNA-protein interaction assays documented also a physical association of the GLD-4/GLS-1 cytoPAP complex with glp-1 mRNA, and ribosomal fractionation studies established that GLD-4 cytoPAP activity facilitates translational efficiency of glp-1 mRNA. Moreover, we found that in proliferative cells the differentiation-promoting factor, GLD-2 cytoPAP, is translationally repressed by the stem cell factor and PUF-type RNA-binding protein, FBF. This suggests that cytoPAP-mediated translational activation of proliferation-promoting factors, paired with PUF-mediated translational repression of differentiation factors, forms a translational control circuit that expands the proliferative germ cell pool. Our additional genetic experiments uncovered that the GLD-4/GLS-1 cytoPAP complex promotes also differentiation, forming a redundant translational circuit with GLD-2 cytoPAP and the translational repressor GLD-1 to restrict proliferation. Together with previous findings, our combined data reveals two interconnected translational activation/repression circuitries of broadly conserved RNA regulators that maintain the balance between adult germ cell proliferation and differentiation.
Journal Article
Structural basis for the activation of the C. elegans noncanonical cytoplasmic poly(A)-polymerase GLD-2 by GLD-3
The Caenorhabditis elegans germ-line development defective (GLD)-2âGLD-3 complex up-regulates the expression of genes required for meiotic progression. GLD-2âGLD-3 acts by extending the short poly(A) tail of germ-lineâspecific mRNAs, switching them from a dormant state into a translationally active state. GLD-2 is a cytoplasmic noncanonical poly(A) polymerase that lacks the RNA-binding domain typical of the canonical nuclear poly(A)-polymerase Pap1. The activity of C. elegans GLD-2 in vivo and in vitro depends on its association with the multi-K homology (KH) domain-containing protein, GLD-3, a homolog of Bicaudal-C. We have identified a minimal polyadenylation complex that includes the conserved nucleotidyl-transferase core of GLD-2 and the N-terminal domain of GLD-3, and determined its structure at 2.3-AÌ resolution. The structure shows that the N-terminal domain of GLD-3 does not fold into the predicted KH domain but wraps around the catalytic domain of GLD-2. The picture that emerges from the structural and biochemical data are that GLD-3 activates GLD-2 both indirectly by stabilizing the enzyme and directly by contributing positively charged residues near the RNA-binding cleft. The RNA-binding cleft of GLD-2 has distinct structural features compared with the poly(A)-polymerases Pap1 and Trf4. Consistently, GLD-2 has distinct biochemical properties: It displays unusual specificity in vitro for single-stranded RNAs with at least one adenosine at the 3â² end. GLD-2 thus appears to have evolved specialized nucleotidyl-transferase properties that match the 3â² end features of dormant cytoplasmic mRNAs.
The efficient translation of the vast majority of eukaryotic mRNAs requires the presence of a poly(A) tail. Although the poly(A) tail was originally thought of as a stable modification, it is now clear that it is much more dynamic. Poly(A) tails can be shortened by deadenylases, leading to mRNA decay or translational repression. The short poly(A) tails of translationally inactive mRNAs can also be reextended by cytoplasmic noncanonical poly(A) polymerases, activating their translation. This mechanism of translational control is found predominantly in metazoan oocytes and neurons and is mediated by germ-line development defective (GLD)-2. Here, we report the molecular mechanism with which Caenorhabditis elegans GLD-2 is activated by GLD-3, a homologue of Bicaudal-C, and identify the unusual substrate specificity of this class of noncanonical poly(A) polymerases.
Journal Article
MAPK signaling couples SCF-mediated degradation of translational regulators to oocyte meiotic progression
RNA-binding proteins (RBPs) are important regulators of gene expression programs, especially during gametogenesis. How the abundance of particular RBPs is restricted to defined stages of meiosis remains largely elusive. Here, we report a molecular pathway that subjects two nonrelated but broadly evolutionarily conserved translational regulators (CPB-3/CPEB and GLD-1/STAR) to proteosomal degradation in Caenorhabditis elegans germ cells at the transition from pachytene to diplotene of meiotic prophase. Both RBPs are recognized by the same ubiquitin ligase complex, containing the molecular scaffold Cullin-1 and the tumor suppressor SEL-10/FBXW7 as its substrate recognition subunit. Destabilization of either RBP through this Skp, Cullin, F-box–containing complex (SCF) ubiquitin ligase appears to loosen its negative control over established target mRNAs, and presumably depends on a prior phosphorylation of CPB-3 and GLD-1 by MAPK (MPK-1), whose activity increases in mid- to late pachytene to promote meiotic progression and oocyte differentiation. Thus, we propose that the orchestrated degradation of RBPs via MAPK-signaling cascades during germ cell development may act to synchronize meiotic with sexual differentiation gene expression changes.
Journal Article
Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI)
Background. Increasing antimicrobial resistance among pathogens causing complicated intra-abdominal infections (cIAIs) supports the development of new antimicrobials. Ceftolozane/tazobactam, a novel antimicrobial therapy, is active against multidrug-resistant Pseudomonas aeruginosa and most extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae. Methods. ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours or meropenem (1 g) every 8 hours intravenously for 4–14 days. The prospectively defined objectives were to demonstrate statistical noninferiority in clinical cure rates at the test-of-cure visit (24–32 days from start of therapy) in the microbiological intent-to-treat (primary) and microbiologically evaluable (secondary) populations using a noninferiority margin of 10%. Microbiological outcomes and safety were also evaluated. Results. Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, −4.2%; 95% confidence interval [CI], −8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, −1.0%; 95% CI, −4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea. Conclusions. Treatment with ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in adult patients with cIAI, including infections caused by multidrug-resistant pathogens.
Journal Article
Post-operative abdominal infections: epidemiology, operational definitions, and outcomes
Postoperative abdominal infections are an important and heterogeneous health challenge in intensive care units (ICU) and encompass postoperative infectious processes developing within the abdominal cavity that may be caused by either bacterial or fungal pathogens. In this narrative review, we discuss postoperative bacterial and fungal abdominal infections, covering also multidrug-resistant (MDR) pathogens. We also cover clinically preeminent aspects such as the definition of postoperative abdominal infections, which still remains difficult owing to their heterogeneity in patient characteristics, clinical presentation, ecology and antimicrobial treatment. With regard to treatment, modifiable factors such as source control and antimicrobial therapy play a key role in influencing the prognosis of postoperative abdominal infections, but several conditions may hamper their correct application; thus efforts should necessarily be devoted towards improving their appropriateness and timing. Hot topics regarding the characteristics and management of postoperative abdominal infections are discussed in this narrative review.
Journal Article
Clinical and economic burden of surgical site infections in inpatient care in Germany: A retrospective, cross-sectional analysis from 79 hospitals
Surgical site infections (SSI) present a substantial burden to patients and healthcare systems. This study aimed to elucidate the prevalence of SSIs in German hospitals and to quantify their clinical and economic burden based on German hospital reimbursement data (G-DRG).
This retrospective, cross-sectional study used a 2010-2016 G-DRG dataset to determine the prevalence of SSIs in hospital, using ICD-10-GM codes, after surgical procedures. The captured economic and clinical outcomes were used to quantify and compare resource use, reimbursement and clinical parameters for patients who had or did not have an SSI.
Of the 4,830,083 patients from 79 hospitals, 221,113 were eligible. The overall SSI prevalence for the study period was 4.9%. After propensity-score matching, procedure type, immunosuppression and BMI ≥30 were found to significantly affect the risk of SSI (p<0.001). Mortality and length of stay (LOS) were significantly higher in patients who had an SSI (mortality: 9.3% compared with 4.5% [p<0.001]; LOS (median [interquartile range, IQR]): 28 [27] days compared with 12 [8] days [p<0.001]). Case costs were significantly higher for the SSI group (median [IQR]) €19,008 [25,162] compared with € 9,040 [7,376] [p<0.001]). A median underfunding of SSI was identified at €1,534 per patient.
The dataset offers robust information about the \"real-world\" clinical and economic burden of SSI in hospitals in Germany. The significantly increased mortality of patients with SSI, and their underfunding, calls for a maximization of efforts to prevent SSI through the use of evidence-based SSI-reduction care bundles.
Journal Article