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Background: Although rapid response teams have been widely promoted as a strategy to reduce unexpected hospital deaths, most studies of rapid response teams have not adjusted for secular trends in mortality before their implementation. We examined whether implementation of a rapid response team was associated with a reduction in hospital mortality after accounting for preimplementation mortality trends. Methods: Among 56 hospitals in Get With The Guidelines-Resuscitation linked to Medicare, we calculated the annual rates of case mix–adjusted mortality for each hospital during 2000 to 2014. We constructed a hierarchical log-binomial regression model of mortality over time (calendar-year), incorporating terms to capture the effect of rapid response teams, to determine whether implementation of rapid response teams was associated with reduction in hospital mortality that was larger than expected based on preimplementation trends, while adjusting for hospital case mix index. Results: The median annual number of Medicare admissions was 5214 (range, 408–18 398). The median duration of preimplementation and postimplementation period was 7.6 years (≈2.5 million admissions) and 7.2 years (≈2.6 million admissions), respectively. Hospital mortality was decreasing by 2.7% annually during the preimplementation period. Implementation of rapid response teams was not associated with a change in mortality during the initial year (relative risk for model intercept, 0.98 [95% CI, 0.94–1.02]; P =0.30) or in the mortality trend (relative risk for model slope, 1.01 per year [95% CI, 0.99–1.02]; P =0.30). Among individual hospitals, implementation of a rapid response team was associated with a lower-than-expected mortality at only 4 (7.1%) and higher-than-expected mortality at 2 (3.7%) hospitals. Conclusions: Among a large and diverse sample of US hospitals, we did not find implementation of rapid response teams to be associated with reduction in hospital mortality. Studies are needed to understand best practices for rapid response team implementation, to ensure that hospital investment in these teams improves patient outcomes.

Seven new polyketides, termed veramycins, were isolated from a Streptomyces sp. from the Sanofi microbial strain collection along with their known congeners NFAT-133 and TM-123. Veramycin A, an α-pyrone congener of TM-123 and NFAT-133 showed an increased baseline deoxy-glucose uptake in the absence of insulin in a modified L6 rat skeletal muscle cell line (L6 GLUT4 AS160-like cells). In addition, both compounds slightly increased the sensitivity to insulin in this cell line. Total syntheses of NFAT-133, TM-123 and veramycin A were accomplished starting from a central building block, which bears the three contiguous stereogenic centers of this polyketide family. Our approach enables an efficient, selective and flexible access to all possible isomers of the stereotriad for further exploration of this series as a potential anti-diabetic lead structure as exemplified by the synthesis of an NFAT-133 epimer. Finally, the corresponding biosynthetic gene cluster (BGC) was identified by genome sequencing and gene inactivation. Based on feeding experiments, a biosynthetic pathway was proposed, which enabled access to new veramycin A analogs by precursor-directed biosynthesis.

A morpholine-based nucleotide analog was developed as a building block for hepatic siRNA targeting and stabilization. Attachment of an asialoglycoprotein-binding GalNAc ligand at the morpholine nitrogen was realized with different linkers. The obtained morpholino GalNAc scaffolds were coupled to the sense strand of a transthyretin-targeting siRNA and tested for their knockdown potency in vitro and in vivo. A clear structure-activity relationship was developed with regard to the linker type and length as well as the attachment site of the morpholino GalNAc moieties at the siRNA sense strand. Further, simple alkylation of the morpholine nitrogen led to a nucleotide analog, which increased siRNA stability, when used as a double 3'-overhang at the sense strand sequence. Combination of the best morpholino GalNAc building blocks as targeting nucleotides with an optimized stabilizing alkyl-substituted morpholine as 3'-overhangs resulted in siRNAs without any phosphorothioate stabilization in the sense strand and clearly improved the duration of action in vivo.

Herein, we describe the myxobacterial natural product Corramycin isolated from Corallococcus coralloides. The linear peptide structure contains an unprecedented (2R,3S)-γ-N-methyl-β-hydroxy-histidine moiety. Corramycin exhibits anti-Gram-negative activity against Escherichia coli (E. coli) and is taken up via two transporter systems, SbmA and YejABEF. Furthermore, the Corramycin biosynthetic gene cluster (BGC) was identified and a biosynthesis model was proposed involving a 12-modular non-ribosomal peptide synthetase/polyketide synthase. Bioinformatic analysis of the BGC combined with the development of a total synthesis route allowed for the elucidation of the molecule's absolute configuration. Importantly, intravenous administration of 20 mg kg

Herein, we describe the myxobacterial natural product Corramycin (1) isolated from Corallococcus coralloides (C. coralloides). Corramycin is a linear peptide containing an unprecedented (2R,3S)  N-methyl-β-hydroxy histidine moiety and exhibiting anti-Gram-negative activity against Escherichia coli. Moreover, we describe the Corramycin biosynthetic gene cluster (BGC) and propose a biosynthesis model involving a 12-modular non-ribosomal peptide synthetase (NRPS)/polyketide synthase (PKS). Bioinformatic analysis of the BGC combined with the development of a total synthesis route allowed for the elucidation of the molecule’s absolute configuration. Furthermore, we show that the uptake of Corramycin in E. coli depends on two transporter systems, SbmA and YejABEF. Importantly, intravenous administration of 30 mg kg 1 of Corramycin in an E. coli mouse infection model resulted in significantly reduced colony forming units (CFU) and in 60 % survival of animals, with no toxic effects observed in vitro or in vivo. Corramycin is thus an intriguing innovative starting point to develop a potent antibacterial drug against hospital acquired infections.

Elaborate fragments of the proposed stereostructure of the complex polyketide antibiotic vancoresmycin have been synthesized in a stereoselective fashion based on a modular and convergent approach. Significant nuclear magnetic resonance differences in one of these subunits compared with the natural product question the proposed stereoconfiguration. Consequently, an extensive bioinformatics analysis of the biosynthetic gene cluster was carried out, leading to a revised stereoconfigurational proposal for this highly potent antibiotic.

A novel class of nucleotide analogues with a dioxane ring as central scaffold has been developed. Synthetic routes in two diastereomeric series were realized, and the final thymidine analogues were synthesized with common functionalities for the automated oligonucleotide synthesis. The chemical space of the initially derived nucleotides was expanded by changing the central dioxane to analogous morpholine derivatives. This opens up the possibility for further derivatization by attaching different substituents at the morpholine nitrogen. The novel nucleotide building blocks were incorporated into double-stranded RNA sequences, and their hybridization properties investigated by melting-temperature analysis. Both scaffolds, dioxanes and morpholines, had an equal impact on double-strand stability, but Tm values differed depending on the chirality in the six-membered ring.

Increasingly sensitive analytical instruments and robust downstream data processing tools have revolutionized natural product research over the past decade. A molecular networking-guided survey led...

Termites live in a dynamic environment where colony health is strongly influenced by surrounding microbes. However, little is known about the mycobiomes of lower termites and their nests, and how these change in response to disease. Here we compared the individual and nest mycobiomes of a healthy subterranean termite colony (Coptotermes testaceus) to one infected and ultimately eradicated by a fungal pathogen. We identified Trichoderma species in the materials of both nests, but they were also abundant in the infected termites. Methanolic extracts of Trichoderma sp. FHG000531, isolated from the infected nest, were screened for secondary metabolites by UHPLC-HR MS/MS-guided molecular networking. We identified many bioactive compounds with potential roles in the eradication of the infected colony, as well as a cluster of six unknown peptides. The novel peptide FE011 was isolated and characterized by NMR spectroscopy. The function of this novel peptide family as well as the role of Trichoderma species in dying termite colonies therefore requires further investigation.

Protease inhibitors represent a promising therapeutic option for the treatment of parasitic diseases such as malaria and human African trypanosomiasis. Falcitidin was the first member of a new class of inhibitors of falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum. Using a metabolomics dataset of 25 Chitinophaga strains for molecular networking enabled identification of over 30 natural analogues of falcitidin. Based on MS/MS spectra, they vary in their amino acid chain length, sequence, acyl residue, and C-terminal functionalization; therefore, they were grouped into the four falcitidin peptide families A-D. The isolation, characterization, and absolute structure elucidation of two falcitidin-related pentapeptide aldehyde analogues by extensive MS/MS spectrometry and NMR spectroscopy in combination with advanced Marfey’s analysis was in agreement with the in silico analysis of the corresponding biosynthetic gene cluster. Total synthesis of chosen pentapeptide analogues followed by in vitro testing against a panel of proteases revealed selective parasitic cysteine protease inhibition and, additionally, low-micromolar inhibition of α-chymotrypsin. The pentapeptides investigated here showed superior inhibitory activity compared to falcitidin.

Tuberculosis represents one of the ten most common courses of death worldwide and the emergence of multidrug-resistant M. tuberculosis makes the discovery of novel anti-tuberculosis active structures an urgent priority. Here, we show that (+)-floyocidin B representing the first example of a novel dihydroisoquinoline class of fungus-derived natural products, displays promising antitubercular hit properties. (+)-Floyocidin B was identified by activity-guided extract screening and its structure was unambiguously determined by total synthesis. The absolute configuration was deduced from a key synthesis intermediate by single crystal X-ray diffraction analysis. A hit series was generated by the isolation of further natural congeners and the synthesis of analogs of (+)-floyocidin B. Extensive biological and physicochemical profiling of this series revealed first structure-activity relationships and set the basis for further optimization and development of this novel antitubercular scaffold.

Protease inhibitors represent a promising therapeutic option for the treatment of parasitic diseases such as malaria and human African trypanosomiasis. Falcitidin was the first member of a new class of inhibitors of falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum. Using a metabolomics dataset of 25 Chitinophaga strains for molecular networking enabled identification of over 30 natural analogs of falcitidin. Based on MS/MS spectra, they vary in their amino acid chain length, sequence, acyl residue, and C-terminal functionalization; therefore, they were grouped into the four falcitidin peptide families A-D. The isolation, characterization and absolute structure elucidation of two falcitidin-related pentapeptide aldehyde analogs by extensive MS/MS spectrometry and NMR spectroscopy in combination with advanced Marfey’s analysis was in agreement with the in silico analysis of the corresponding biosynthetic gene cluster. Total synthesis of chosen pentapeptide analogs followed by in vitro testing against a panel of proteases revealed selective parasitic cysteine protease inhibition and additionally low-micromolar inhibition of α-chymotrypsin. The pentapeptides investigated here showed superior inhibitory activity compared to falcitidin.

The therapeutic success of peptidic GLP-1 receptor agonists for treatment of type 2 diabetes mellitus (T2DM) motivated our search for orally bioavailable small molecules that can activate the GLP-1 receptor (GLP-1R) as a well-validated target for T2DM. Here, the discovery and characterization of a potent and selective positive allosteric modulator (PAM) for GLP-1R based on a 3,4,5,6-tetrahydro-1H-1,5-epiminoazocino[4,5-b]indole scaffold is reported. Optimization of this series from HTS was supported by a GLP-1R ligand binding model. Biological in vitro testing revealed favorable ADME and pharmacological profiles for the best compound 19. Characterization by in vivo pharmacokinetic and pharmacological studies demonstrated that 19 activates GLP-1R as positive allosteric modulator (PAM) in the presence of the much less active endogenous degradation product GLP1(9-36)NH2 of the potent endogenous ligand GLP-1(7-36)NH2. While these data suggest the potential of small molecule GLP-1R PAMs for T2DM treatment, further optimization is still required towards a clinical candidate.

Zusammenfassung. Zusammenfassungen: Die Makrohämaturie sollte als Symptom immer abgeklärt werden, unabhängig davon, ob eine Antikoagulation besteht oder nicht. Die häufigsten Ursachen sind die hämorrhagische Zystitis und bei Männern die Prostatahyperplasie. Die wichtigsten weiteren Differenzialdiagnosen sind das Urothelkarzinom und die Urolithiasis. Zur Primärdiagnostik gehören ein Urinschnelltest, eine Urinkultur und die Sonografie des Harntrakts. Die vollständige Abklärung erfolgt mittels Zystoskopie und Computertomografie. Die Gerinnung sollte immer kontrolliert werden. Leichte Blutungen können ambulant urologisch abgeklärt werden, während Patienten mit hämodynamisch relevanten und/oder tamponierenden Hämorrhagien immer stationär aufgenommen werden sollten. Antikoagulierte, blutende Patienten erfordern auch wegen der internistischen Grunderkrankungen die volle Aufmerksamkeit von Urologen, Internisten und Anästhesisten.

With progress in genome sequencing and data sharing, 1000s of bacterial genomes are publicly available. Genome mining – using bioinformatics tools in terms of biosynthetic gene cluster (BGC) identification, analysis and rating – has become a key technology to explore the capabilities for natural product (NP) biosynthesis. Comprehensively, analyzing the genetic potential of the phylum Bacteroidetes revealed Chitinophaga as the most talented genus in terms of BGC abundance and diversity. Guided by the computational predictions, we conducted a metabolomics and bioactivity driven NP discovery program on 25 Chitinophaga strains. High numbers of peerless strain-specific metabolite buckets confirmed the upfront predicted biosynthetic potential and revealed a tremendous uncharted chemical space. Sourcing this dataset, we isolated the new iron chelating nonribosomally-synthesized cyclic tetradeca- and pentadecalipodepsipeptide antibiotics chitinopeptins with activity against Candida, produced by C. eiseniae DSM 22224 and C. flava KCTC 62435, respectively.TeaserCombination of omics-technologies revealed taxonomical hotspots for specialized metabolites within Bacteroidetes.

Increasingly sensitive analytical instruments and robust downstream data processing tools have revolutionized natural product research over the past decade. A molecular networking-guided survey led to the identification of 33 new cyclic lipopeptides (CLPs) from the culture broth of the proteobacterium

The two isotopomers of teriflunomide were synthesized starting from isotopically stable-labeled stocks of [13 C]potassium cyanide and [1-13 C]ethyl bromoacetate. The two 13 C-labeled compounds 1a, b were applied in several NMR studies to study the E/Z ratio in different matrices. In a solution, such as dimethyl sulfoxide (DMSO), a dynamic equilibrium between E/Z-isomers (ratio of 8:92) was determined by initial 13 C-carbon NMR experiments. To get insights into the E/Z ratio of teriflunomide under in vivo conditions, advanced heteronuclear NMR (heteronuclear Overhauser effect spectroscopy [HOESY]) in D2 O and mixtures of D2 O/plasma were performed. Whereas NMR experiments in mixtures of water and plasma failed owing to extreme line broadening, NMR spectra in water at pH 7.4 showed only the Z-isomer.

Novel peptidic dual agonists of the glucagon-like peptide 1 (GLP-1) and glucagon receptor are reported to have enhanced efficacy over pure GLP-1 receptor agonists with regard to treatment of obesity and diabetes. We describe novel exendin-4 based dual agonists designed with an activity ratio favoring the GLP-1 versus the glucagon receptor. As result of an iterative optimization procedure that included molecular modeling, structural biological studies (X-ray, NMR), peptide design and synthesis, experimental activity, and solubility profiling, a candidate molecule was identified. Novel SAR points are reported that allowed us to fine-tune the desired receptor activity ratio and increased solubility in the presence of antimicrobial preservatives, findings that can be of general applicability for any peptide discovery project. The peptide was evaluated in chronic in vivo studies in obese diabetic monkeys as translational model for the human situation and demonstrated favorable blood glucose and body weight lowering effects.

Background Women have higher utilization of “do not attempt resuscitation” ( DNAR ) orders during treatment for critical illness. Occurrence of sex differences in the establishment of DNAR orders after resuscitation from in‐hospital cardiac arrest is unknown. Whether differences in DNAR use by sex lead to disparities in survival remains unclear. Methods and Results We identified 71 820 patients with return of spontaneous circulation ( ROSC ) after in‐hospital cardiac arrest from the Get With The Guidelines–Resuscitation registry. Multivariable models evaluated the association between de novo DNAR (anytime after ROSC , within 12 hours of ROSC , or within 72 hours of ROSC ) by sex and the association between sex and survival to discharge accounting for DNAR . All models accounted for clustering of patients within hospital and adjusted for demographic and cardiac arrest characteristics. The cohort included 30 454 (42.4%) women, who were slightly more likely than male participants to establish DNAR orders anytime after ROSC (45.0% versus 43.5%; adjusted relative risk: 1.15 [95% CI , 1.10–1.20]; P DNAR status within the first 12 hours (51.8% versus 46.5%; adjusted relative risk: 1.40 [95% CI, 1.30–1.52]; P ROSC (75.9% versus 70.9%; adjusted relative risk: 1.35 [95% CI, 1.26–1.45]; P CI , 0.99–1.02]; P =0.74) was appreciated. Conclusions In patients successfully resuscitated from in‐hospital cardiac arrest, there was no survival difference between men and women while accounting for DNAR . However, women had a higher rate of DNAR status early after resuscitation (

Background: G protein–coupled receptors are important regulators of contractility and differentiation in vascular smooth muscle cells (SMCs), but the specific function of SMC-expressed orphan G protein–coupled receptor class C group 5 member B (GPRC5B) is unclear. Methods: We studied the role of GPRC5B in the regulation of contractility and dedifferentiation in human and murine SMCs in vitro and in iSM- Gprc5b -KO (tamoxifen-inducible, SMC-specific knockout) mice under conditions of arterial hypertension and atherosclerosis in vivo. Results: Mesenteric arteries from SMC-specific Gprc5b -KOs showed ex vivo significantly enhanced prostacyclin receptor (IP)–dependent relaxation, whereas responses to other relaxant or contractile factors were normal. In vitro, knockdown of GPRC5B in human aortic SMCs resulted in increased IP-dependent cAMP production and consecutive facilitation of SMC relaxation. In line with this facilitation of IP-mediated relaxation, iSM- Gprc5b -KO mice were protected from arterial hypertension, and this protective effect was abrogated by IP antagonists. Mechanistically, we show that knockdown of GPRC5B increased the membrane localization of IP both in vitro and in vivo and that GPRC5B, but not other G protein–coupled receptors, physically interacts with IP. Last, we show that enhanced IP signaling in GPRC5B-deficient SMCs not only facilitates relaxation but also prevents dedifferentiation during atherosclerosis development, resulting in reduced plaque load and increased differentiation of SMCs in the fibrous cap. Conclusions: Taken together, our data show that GPRC5B regulates vascular SMC tone and differentiation by negatively regulating IP signaling.

Dual glucagon-like peptide-1/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed, for example, by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain lengths in terms of apparent molecular mass and hydrodynamic radius (R-S). We use NMR spectroscopy to gain an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of the fatty acid chain length using circular dichroism and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4-derived dual agonist peptides is essentially driven by hydrophobic interactions involving the conjugated acyl chains. The fatty acid chain length affects assembly equilibria and the assembly stability, although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether, our study contributes to a thorough understanding of the association characteristics and the tendency toward self-assembly in response to lipidation. This is important not only to achieve the desired bioavailability but also with respect to the physical stability of peptide solutions.

Macrohaematuria in Anticoagulated Patients Abstract. Macrohaematuria should always be clarified as a symptom, regardless of whether anticoagulation exists. The most common causes are haemorrhagic cystitis and in men prostate hyperplasia. The most important other differential diagnoses are urothelial carcinoma and urolithiasis. Primary diagnostics include a rapid urine test, urine culture and sonography of the urinary tract. The complete examination is performed by cystoscopy and computer tomography. Coagulation should always be checked. Light bleeding can be clarified urologically on an outpatient basis, while patients with haemodynamically relevant and/or tamponing haemorrhages should always be admitted on an inpatient basis. Anticoagulated, bleeding patients also require the full attention of urologists, internists and anaesthetists due to the underlying internal diseases.Zusammenfassung. Zusammenfassungen: Die Makrohämaturie sollte als Symptom immer abgeklärt werden, unabhängig davon, ob eine Antikoagulation besteht oder nicht. Die häufigsten Ursachen sind die hämorrhagische Zystitis und bei Männern die Prostatahyperplasie. Die wichtigsten weiteren Differenzialdiagnosen sind das Urothelkarzinom und die Urolithiasis. Zur Primärdiagnostik gehören ein Urinschnelltest, eine Urinkultur und die Sonografie des Harntrakts. Die vollständige Abklärung erfolgt mittels Zystoskopie und Computertomografie. Die Gerinnung sollte immer kontrolliert werden. Leichte Blutungen können ambulant urologisch abgeklärt werden, während Patienten mit hämodynamisch relevanten und/oder tamponierenden Hämorrhagien immer stationär aufgenommen werden sollten. Antikoagulierte, blutende Patienten erfordern auch wegen der internistischen Grunderkrankungen die volle Aufmerksamkeit von Urologen, Internisten und Anästhesisten.

Following the 2008 financial crisis, policy makers considered regulations that restrict banks’ activities which were motivated by concerns that banks use central bank borrowing, government guarantees, or subsidies to fund securities trading instead of lending to the real economy. Using a global sample of 132 major banks from 2003 to 2016, we find that banks’ securities trading is indeed associated with decreased loan supply. Effects are stronger for domestic lending markets, during crisis periods, and in countries with deeper financial markets. However, corporate capital expenditures and employment growth are unaffected, suggesting that policy makers’ concerns are only partly justified.

In order to cope with the challenges of an increased demand for flexibility, quality and availability of production, maintenance measures provide a major competiveness factor for manufacturing companies. Yet, interdependencies between maintenance and production activities as well as differing target systems within the functional units of an enterprise, especially production and maintenance, raise needs for extended coordination efforts. This paper aims to develop an innovative approach for the coordination between maintenance and production activities for industrial production companies. To achieve this, the novel coordination mechanism is used. It helps to achieve maximised operational availability—for a maximised output of the production system at optimal costs. Based on the developed model, the present paper identifies findings regarding the impact of different maintenance strategies on the medium-term economic efficiency of the production system.

Background: Disability-adjusted life years (DALY) are a common public health metric used to consistently estimate and compare disease burden. The impact of bystander interventions on DALY following out-of-hospital cardiac arrest (OHCA) is unknown. Our objective was to estimate the effect of bystander CPR (B-CPR) and bystander AED (B-AED) application on DALY following OHCA in the United States (U.S.). Methods: DALY were calculated as the sum of years of life lost (YLL) and years lived with disability (YLD) using all adult non-traumatic EMS-treated OHCA from the national CARES database for 2016. A multivariable linear regression model was constructed for effect estimation with DALY values as the outcome and standard Utstein variables as independent variables. Marginal effect estimates for B-CPR and B-AED were derived in models that used all independent variables as main effects. A sensitivity analysis included interaction terms. The analysis for B-CPR was limited to bystander witnessed events. The B-AED analysis was limited to public OHCA events. The marginal effects on DALY were used to derive national estimates of life years saved. Results: A total of 19,324 OHCA cases met study inclusion criteria. The provision of B-CPR was associated with an absolute mean decrease of -0.36 DALY; 95% CI (-0.44, -0.27) per OHCA, when compared to cases without B-CPR (p Conclusion: Bystander interventions are associated with a decrease in DALY following adult OHCA. These results highlight the importance of national bystander CPR and AED education and surveillance.

Background and purpose The NaV 1.7 channel is highly expressed in dorsal root ganglia of the sensory nervous system and plays a central role in the pain signalling process. We investigated a library prepared from original venoms of 117 different animals to identify new selective inhibitors of this target. Experimental approach We used high throughput screening of a large venom collection using automated patch-clamp experiments on human voltage-gated sodium channel subtypes and then in vitro and in vivo electrophysiological experiments to characterize the active peptides that have been purified, sequenced, and chemically synthesized. Analgesic effects were evaluated in vivo in mice models. Key results We identified cyriotoxin-1a (CyrTx-1a), a novel peptide isolated from Cyriopagopus schioedtei spider venom, as a candidate for further characterization. This 33 amino acids toxin belongs to the inhibitor cystine knot structural family and inhibits hNaV 1.1-1.3 and 1.6-1.7 channels in the low nanomolar range, compared to the micromolar range for hNaV 1.4-1.5 and 1.8 channels. CyrTx-1a was 920 times more efficient at inhibiting tetrodotoxin (TTX)-sensitive than TTX-resistant sodium currents recorded from adult mouse dorsal root ganglia neurons and in vivo electrophysiological experiments showed that CyrTx-1a was approximately 170 times less efficient than huwentoxin-IV at altering mouse skeletal neuromuscular excitability properties. CyrTx-1a exhibited an analgesic effect in mice by increasing reaction time in the hot-plate assay. Conclusions and implications The pharmacological profile of CyrTx-1a paves the way for further molecular engineering aimed to optimize the potential antinociceptive properties of this peptide.

Background Maternal mortality has risen in the United States in the twenty-first century, yet large cohort data of maternal cardiac arrest (MCA) are limited. Objective We sought to describe contemporary characteristics and outcomes of in-hospital MCA. Methods We queried the American Heart Association’s Get with the Guidelines Resuscitation voluntary registry from 2000 to 2016 to identify cases of maternal cardiac arrest. All index cardiac arrests occurring in women aged 18–50 with a patient illness category designated as obstetric or location of arrest occurring in a delivery suite were included. Institutional review deemed that this research was exempt from ethical approval. Results A total of 462 index events met criteria for MCA, with a mean age of 31 ± 7 years and a racial distribution of: 49.4% White, 35.3% Black and 15.3% Other/Unknown. While 32% had no pre-existing conditions or physiologic disorders, respiratory insufficiency (36.1%) and hypotension/hypoperfusion (33.3%) were the most common antecedent conditions. In most cases, the first documented pulseless rhythm was non-shockable; pulseless electrical activity (50.8%) or asystole (25.6%). Only 11.7% presented with a shockable rhythm; ventricular fibrillation (6.5%) or pulseless ventricular tachycardia (5.2%) while the initial pulseless rhythm was unknown in 11.9% of cases. Return of spontaneous circulation occurred in 73.6% but 68 (14.7%) had more than one arrest. The rate of survival to discharge was 40.7% overall; 37.3% with non-shockable rhythms, 33% with shockable rhythms and 64.3% with unknown presenting rhythms. Conclusions Maternal survival at hospital discharge in this cohort was less than 50%, lower than rates reported in other epidemiological datasets. More research is required in maternal resuscitation science and translational medicine to continue to improve outcomes and understand maternal mortality.

Bengamide, aus marinen Schwammen stammende und als Inhibitoren der Methionin-Aminopeptidase (MetAP) charakterisierte Naturstoffe, wurden intensiv als Wirkstoffe gegen Krebs erforscht. In einem multidisziplinaren Forschungsprojekt haben wir die Bereitstellung von Bengamiden uber Fermentation des terrestrischen Myxobakteriums M. virescens, die Aufklarung ihrer Biosynthese und die Optimierung ihrer Eigenschaften als Arzneistoff-Leitstrukturen untersucht. Die Charakterisierung des Biosyntheseweges zeigte auf, dass bakterielle Resistenz gegenuber Bengamiden durch Leu154 des myxobakteriellen MetAP-Proteins vermittelt wird, und ermoglichte den Transfer des gesamten Biosynthesegenclusters in den geeigneteren Produktionsstamm M. xanthus DK1622. Eine Kombination aus Semisynthese mikrobiell gewonnener Bengamide und Totalsynthese fuhrte zum optimierten Derivat 8 a. Die nanomolare zellulare Wirksamkeit und die hohe metabolische Stabilitat waren mit einer verbesserten Halbwertszeit in Mausen sowie mit Antitumor-Effizienz in einem Melanom-Mausmodell verbunden.

The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model.

Telomycin (TEM) is a cyclic depsipeptide antibiotic active against Gram-positive bacteria. In this study, five new natural telomycin analogues produced by Streptomyces canus ATCC 12646 were identified. To understand the biosynthetic machinery of telomycin and to generate more analogues by pathway engineering, the TEM biosynthesis gene cluster has been characterized from S. canus ATCC 12646: it spans approximately 80.5 kb and consists of 34 genes encoding fatty acid ligase, nonribosomal peptide synthetases (NRPSs), regulators, transporters, and tailoring enzymes. The gene cluster was heterologously expressed in Streptomyces albus J1074 setting the stage for convenient biosynthetic engineering, mutasynthesis, and production optimization. Moreover, in-frame deletions of one hydroxylase and two P450 monooxygenase genes resulted in the production of novel telomycin derivatives, revealing these genes to be responsible for the specific modification by hydroxylation of three amino acids found in the TEM backbone. Surprisingly, natural lipopeptide telomycin precursors were identified when characterizing an unusual precursor deacylation mechanism during telomycin maturation. By in vivo gene inactivation and in vitro biochemical characterization of the recombinant enzyme Tem25, the maturation process was shown to involve the cleavage of previously unknown telomycin precursor-lipopeptides, to yield 6-methylheptanoic acid and telomycins. These lipopeptides were isolated from an inactivation mutant of tem25 encoding a (de)acylase, structurally elucidated, and then shown to be deacylated by recombinant Tem25. The TEM precursor and several semisynthetic lipopeptide TEM derivatives showed rapid bactericidal killing and were active against several multidrug-resistant (MDR) Gram-positive pathogens, opening the path to future chemical optimization of telomycin for pharmaceutical application.

New for old—TB drug development Tuberculosis (TB) is a global health threat for which there is only lengthy drug treatment. Patients need to consume multiple tablets over several months and frequently fail to complete their treatment. Consequently, drug-resistant strains of the pathogen have emerged, which add to the threat. Kling et al. revisited a natural product called griselimycin, extracted from the same organism that produced the prototype anti-TB drug, streptomycin. Unmodified griselimycin has poor pharmacological properties. However, one synthetic derivative had improved oral uptake and penetrated cells of the immune system that harbor the TB mycobacterium. In combination with other drugs, the griselimycin derivative showed high potency in mice with TB. Science , this issue p. 1106