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PURPOSE: 3-indoxyl sulfate (3-IS) is an indole metabolism byproduct produced by commensal gut bacteria and excreted in the urine; low urinary 3-IS has been associated with increased mortality in bone marrow transplant recipients. This study investigated urinary 3-IS and patient outcomes in the ICU. MATERIALS AND METHODS: Prospective study that collected urine samples, rectal swabs, and clinical data on 78 adult ICU patients at admission and again 72 hours later. Urine was analyzed for 3-IS by mass spectrometry. RESULTS: Median urinary 3-IS levels were 17.1 μmol/mmol creatinine (IQR 9.5 to 26.2) at admission and 15.6 (IQR 4.2 to 30.7) 72 hours later. 22% of patients had low 3-IS (≤6.9 μmol/mmol) on ICU admission and 28% after 72 hours. Low 3-IS at 72 hours was associated with fewer ICU-free days (22.5 low versus 26 high, p=0.03) and with death during one year of follow-up (36% low versus 9% high 3-IS, p

Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of a set of PRS ATP-site binders, initially designed for human indications, led to identification of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing a novel antimalarial scaffold. Evidence designates cytoplasmic PRS as the drug target. The frontrunner 1 and its active enantiomer 1- S exhibited low-double-digit nanomolar activity against resistant Plasmodium falciparum (Pf) laboratory strains and development of liver schizonts. No cross-resistance with strains resistant to other known antimalarials was noted. In addition, a similar level of growth inhibition was observed against clinical field isolates of Pf and P. vivax. The slow killing profile and the relative high propensity to develop resistance in vitro (minimum inoculum resistance of 8 × 105 parasites at a selection pressure of 3 × IC50) constitute unfavorable features for treatment of malaria. However, potent blood stage and antischizontal activity are compelling for causal prophylaxis which does not require fast onset of action. Achieving sufficient on-target selectivity appears to be particularly challenging and should be the primary focus during the next steps of optimization of this chemical series. Encouraging preliminary off-target profile and oral efficacy in a humanized murine model of Pf malaria allowed us to conclude that 1-(pyridin-4-yl)pyrrolidin-2-one derivatives represent a promising starting point for the identification of novel antimalarial prophylactic agents that selectively target Plasmodium PRS.

Gut microbial imbalance may contribute to endotoxemia, inflammation, and oxidative stress in heart failure (HF). Changes occurring in the intestinal microbiota and inflammatory/oxidative milieu during HF progression and following left ventricular assist device (LVAD) or heart transplantation (HT) are unknown. We aimed to investigate variation in gut microbiota and circulating biomarkers of endotoxemia, inflammation, and oxidative stress in patients with HF (New York Heart Association, Class I-IV), LVAD, and HT.We enrolled 452 patients. Biomarkers of endotoxemia (lipopolysaccharide and soluble [sCD14]), inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-α, and endothelin-1 adiponectin), and oxidative stress (isoprostane) were measured in 644 blood samples. A total of 304 stool samples were analyzed using 16S rRNA sequencing.Gut microbial community measures of alpha diversity were progressively lower across worsening HF class and were similarly reduced in patients with LVAD and HT (p0.05). Inflammation and oxidative stress were elevated in patients with Class IV HF vs all other groups (all p0.05). Lipopolysaccharide was elevated in patients with Class IV HF (vs Class I-III) as well as in patients with LVAD and HT (p0.05). sCD14 was elevated in patients with Class IV HF and LVAD (vs Class I-III, p0.05) but not in patients with HT.Reduced gut microbial diversity and increased endotoxemia, inflammation, and oxidative stress are present in patients with Class IV HF. Inflammation and oxidative stress are lower among patients with LVAD and HT relative to patients with Class IV HF, whereas reduced gut diversity and endotoxemia persist in LVAD and HT.

Biodegradable electronic devices based on non-toxic materials are an emerging field, in which the key characteristic is the complete dissolution of the devices within a determined period of time. Usually, these devices are built on polymer substrates or pure metals; however they present some disadvantages such as low degradation rate. The present study reports and compares the sustainable preparation of FeMn films via electrodeposition and magnetron co-sputtering as a possible alternative to the aforementioned materials. Morphological, chemical, structural and magnetic characterization of the obtained layers was carried out and the corrosion and biocompatibility characteristics were assessed by electrochemical studies and cell viability assays. Different ratios of Mn2+:Fe2+ ions in the electrolyte leaded to metallic and oxide based FeMn layers. The electrodeposited FeMn films showed different crystalline structure depending on their nature: a bcc-Fe crystal structure when they are metallic and fcc when they are oxidized. In addition, glycine was used as complexing agent in the electrolytic bath, which leaded to less-crack films and varied the Mn content in the films (9–24 wt%). The Mn content of the magnetron co-sputtered films varied between 10 and 70 wt%. Differently to the electrodeposited films, the sputtered revealed a well-defined bcc structure that lowers its symmetry when the Mn content increases. Regarding the magnetic behavior, all obtained films showed a soft magnetic behavior. Their corrosion behavior in NaCl solutions was evaluated by electrochemical studies, observing a shift to more negative corrosion potential values when Mn content increases. In vitro cytotoxicity tests revealed highly biocompatible characteristics with a cell viability of 85% even for the Mn-richest sputtered films (70 wt%) while electrodeposited films showed a clear indication of toxicity.

Background Outbreaks of MRSA occur in NICUs and may be difficult to control. We describe an outbreak of mupirocin-resistant MRSA, molecular epidemiology of isolates and control. Methods Medical record review of personnel contact with infants. MRSA isolates were analyzed by whole genome sequencing (WGS); single nucleotide polymorphisms (SNPs) were identified. Results A 31-month outbreak of MRSA infection occurred. Weekly colonization surveillance of infants was initiated; initial prevalence was 45%. Isolates exhibited high level mupirocin-resistance. There were 3 periods of increased colonization and new infections despite implementation of multiple infection prevention interventions. During the second period, an analysis identified a frontline staff member associated with newly colonized infants whose nasal culture grew the clonal MRSA. A marked reduction in colonization followed removal from patient contact. WGS of isolates from years 1-3 showed clonality with maximum SNP differences of 33. Importantly, the year 3 isolates were more closely related to the early year 1 isolates (15-20 SNP differences) than to the late year 1 or year 2 isolates (18-33 SNP differences). Discussion/Conclusions During a recrudescent MRSA outbreak due to a clonal strain, both contact with a colonized staff member and a putative environmental or personnel reservoir were associated with MRSA acquisition.

Background Staphylococcus aureus protein A (spa) typing can be used to expand characterization of the epidemiology of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in neonatal intensive care units (NICU). Methods From January 2017 to June 2018, twice-monthly surveillance for S. aureus was performed in an academically affiliated NICU. Decolonization of infants colonized with S. aureus included chlorhexidine gluconate bathing and/or mupirocin for those with mupirocin-susceptible strains. Spa typing and mupirocin-resistance testing were performed. Demographic and clinical characteristics were compared between infants colonized with MSSA vs MRSA and infants with and without the most common MSSA spa type, MSSA-t279. Results Overall, 14% and 2% of 1556 hospitalized infants had positive surveillance cultures for MSSA and MRSA, respectively. Thirty-six infants harbored unique MSSA spa types, 5 infants harbored unique MRSA spa types, and 30 MSSA and 6 MRSA spa types were identified in ≥2 infants. No outbreaks were identified during the study period. MSSA-t279 was isolated from 3% of infants and largely detected from infants hospitalized in one section of the NICU; 96% of t279 isolates were mupirocin resistant. Infection rates, length of hospitalization, and mortality were similar among infants initially colonized with t279 vs other MSSA spa types. Conclusions The MSSA colonization burden was 5-fold larger than that of MRSA. Numerous unique spa types were identified. The most common spa type, MSSA-t279, was not associated with increased morbidity or mortality but was mupirocin resistant and associated with clustered NICU beds. This suggests potential transmission from the environment, shared staff, and/or workflow issues requiring further study. Other decolonization strategies for S. aureus in the NICU are needed.

3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound 22 exhibited excellent antiplasmodial in vitro activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains of Plasmodium falciparum (with IC(50) values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells. In addition, 22 showed strong in vivo activity in the Plasmodium berghei mouse model with a cure rate of 66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test after once daily oral administration for 4 consecutive days. A quick onset of action was indicated by the fast drug absorption shown in mice. The new lead compound was also characterized by a high barrier to resistance and inhibited the heme detoxification machinery in P. falciparum.

Summary Multi-drug resistant (MDR) Klebsiella pneumoniae remains an urgent public health threat. While whole-genome sequencing has helped identify genetic changes underlying resistance, functional validation remains difficult due to a lack of genetic manipulation systems for MDR K. pneumoniae. CRISPR-Cas9 has revolutionized molecular biology, but its use was only recently adapted in bacteria by overcoming the lack of genetic repair systems. We describe a CRISPR-Cas9/lambda recombineering system utilizing a zeocin resistance cassette allowing efficient and versatile genetic manipulation of K. pneumoniae. For complete details on the use and execution of this protocol, please refer to McConville et al. (2020) .

Objectives: Staphylococcus aureus Smith strain is a historical strain widely used for research purposes in animal infection models for testing the therapeutic activity of antimicrobial agents. We found that it displayed higher sensitivity towards lysocin E, a menaquinone (MK) targeting antibiotic, compared to other S. aureus strains. Therefore, we further explored the mechanism of this hypersensitivity. Methods: MK production was analyzed by high-performance liquid chromatography and mass spectrometric analysis. S. aureus Smith genome sequence was completed using a hybrid assembly approach, and the MK biosynthetic genes were compared with other S. aureus strains. The hepT gene was cloned and introduced into S. aureus RN4220 strain using phage mediated recombination, and lysocin E sensitivity was analyzed by the measurement of minimum inhibitory concentration and colony-forming units. Results: We found that Smith strain produced MKs with the length of the side chain ranging between 8 – 10, as opposed to other S. aureus strains that produce MKs 7 – 9. We revealed that Smith strain possessed the classical pathway for MK biosynthesis like the other S. aureus. HepT, a polyprenyl diphosphate synthase involved in chain elongation of isoprenoid, in Smith strain harbored a Q25P substitution. Introduction of hepT from Smith to RN4220 led to the production of MK-10 and an increased sensitivity towards lysocin E. Conclusions: We found that HepT was responsible for the definition of isoprenoid chain length of MKs and antibiotic sensitivity.

Polymyxin resistance (PR) threatens the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. PR frequently arises through the chemical modification of the lipid-A portion of lipopolysaccharide. Various mutations have been implicated in PR, but few have been functionally validated. We therefore adapted a CRISPR-Cas9 system to CRKP to elucidate how mutations in clinical CRKP isolates lead to PR. Specifically we demonstrate that CrrB acts as a positive regulator of PR and common clinical mutations lead to the addition of both L-Ara4N and pEtN to lipid-A, inducing notably higher polymyxin minimum inhibitory concentrations than mgrB disruption; a validated cause of PR. Additionally, crrB mutations induce a significant bacterial virulence increase at a notable fitness cost; partially from the activation of the pentose phosphate pathway. Our data demonstrate the importance of CrrB in high-level PR and establish important differences across CrrB alleles in balancing resistance with fitness and virulence.

Staphylococcus aureus is a prominent human pathogen that readily adapts to host immune defenses. Here, we show that, in contrast to Gram-negative pathogens, S. aureus induces a distinct airway immunometabolic response dominated by the release of the electrophilic metabolite, itaconate. The itaconate synthetic enzyme, IRG1, is activated by host mitochondrial stress, which is induced by staphylococcal glycolysis. Itaconate inhibits S. aureus glycolysis and selects for strains that re-direct carbon flux to fuel extracellular polysaccharide (EPS) synthesis and biofilm formation. Itaconate-adapted strains, as illustrated by S. aureus isolates from chronic airway infection, exhibit decreased glycolytic activity, high EPS production, and proficient biofilm formation even before itaconate stimulation. S. aureus thus adapts to the itaconate-dominated immunometabolic response by producing biofilms, which are associated with chronic infection of the human airway., The authors show that the pathogen Staphylococcus aureus induces a distinct airway immunometabolic response, dominated by release of itaconate. This metabolite, in turn, potentiates extracellular polysaccharide synthesis and biofilm formation in S. aureus, which may facilitate chronic infection.

Protocols for anionic polymerization of vinylferrocenes in bulk ( b ) and solution ( s ) are reported. Polymerization of vinylferrocenes bearing one or multiple (2–4) vinyl groups yielded linear polyvinylferrocene PVF-1 ( b, s ) or cross-linked polyvinylferrocenes PVF-2 – PVF-4 ( b, s ), respectively. Furthermore, copolymerization of mono-with multifunctional vinylferrocenes produced cross-linked copolymers PVF-5 – PVF-7 ( b, s ). For anionic polymerization in bulk, a high monomer conversion and a relatively high dispersity was observed. A reversible redox behavior of the ferrocenyl group with cycle stability up to 100 cycles was found for PVF- ( 1s – 7s ). Li-ion battery cell tests demonstrated the applicability of the polyvinylferrocenes PVF-1b and PVF- ( 5b – 7b ) as electrode materials.

A test campaign was launched to determine the mechanical properties of the High Luminosity-Large Hadron Collider (HL-LHC) 11 T Nb3Sn magnet components. The results can be used to accurately represent the mechanical properties in finite element models that predict the stress and strain distribution in these magnets. Particular attention is paid to anisotropic mechanical behavior of the different magnet materials. Static and dynamic test methods have been applied for determining elastic materials’ behavior, and highly accurate Young's moduli are obtained with the nondestructive dynamic methods resonance and impulse excitation at ambient temperature and during in situ heat cycles.

We report on the facile synthesis of porous carbons based on a biopolymer lignin employing a two-step process which includes the activation by KOH in various amounts under an inert gas atmosphere. The resulting carbons are characterized with regard to their structural properties and their electrochemical performance as an active material in double-layer capacitors using for the first time an ionic liquid (EMIBF4) as the electrolyte for this type of carbon material to enhance storage ability. A capacitance of more than 200 F g–1 at 10 A g–1 is achieved for a carbon with a specific surface area of more than 1800 m2 g–1. One of the most crucial factors determining the electrochemical response of the active materials was found to be the strong surface functionalization by oxygen-containing groups. Furthermore, the sulfur content of the carbon precursor lignin does not result in a significant amount of sulfur-containing surface functionalities which might interact with the electrolyte.

Ethylene glycol-functionalized Co(II) carboxylates [Co(CO2CH2(OC2H4) n OMe)2] (2a, n = 1; 2b, n = 2), [Co(CO2CHPh(OC2H4)2OMe)2] (2c) and [Co(CO2CMe2(O–C2H4)2OMe)2] (2d) have been synthesized by the reaction of [Co(OAc)2·4H2O] with the corresponding acids MeO(C2H4O) n CRR′CO2H (n = 1, 2; R=H, R′=Me; R=H, R′=Ph). Based on the IR spectroscopic studies, the binding motif of the carboxylato ligands to cobalt is discussed. Thermogravimetry and mass spectrometry studies were carried out in order to investigate the thermal decomposition mechanism of 2a–2d in the solid state. Based on the result obtained, complex 2b was chosen as single-source precursor for the generation and stabilization of Co3O4 nanoparticles (NPs) by solid-state thermal decomposition in air. Depending on the decomposition time, NPs with different chemical composition (consisting of Co3O4, CoO and Co) and with crystallite sizes ranging from 9 to 18 nm were obtained. Furthermore, the preparation of cobalt oxide-based nanocomposites by twin polymerization of 2,2′-spirobi[4H-1,3,2-benzodioxasiline] (3) in the presence of 2b is reported. After treatment of the as-prepared hybrid material by either oxidation or etching, the respective mesoporous carbon/silica (IUPAC type IV isotherms) matrices were obtained. Quenched solid and nonlinear density functional theory calculations gave a surface area of 1040 cm2 g−1 for the respective carbon and 336 cm2 g−1 for the appropriate silica material. Powder X-ray diffraction measurements confirm the formation of Co3O4 NPs in both components. High-angle annular dark field scanning transmission electron microscopy revealed well-distributed particles within the silica matrix, whereas no particles were found in the carbon material. The electrochemical properties of the composite materials have been investigated by cyclic voltammetry. The respective silica material shows five reduction events (Co3O4 to CoO, CoO to Co), while no redox potentials occurred for the Co3O4 NPs embedded in the carbon matrix.

Background The enterosalivary nitrate‐nitrite‐nitric oxide pathway is an alternative pathway of nitric oxide generation, potentially linking the oral microbiome to insulin resistance and blood pressure (BP). We hypothesized that increased abundance of nitrate‐reducing oral bacteria would be associated with lower levels of cardiometabolic risk cross‐sectionally. Methods and Results ORIGINS (Oral Infections, Glucose Intolerance, and Insulin Resistance Study) enrolled 300 diabetes mellitus–free adults aged 20 to 55 years (mean=34±10 years) (78% women). Microbial DNA was extracted from subgingival dental plaque (n=281) and V3–V4 regions of the 16S rRNA gene were sequenced to measure the relative abundances of 20 a priori – selected taxa with nitrate‐reducing capacity. Standardized scores of each taxon's relative abundance were summed, producing a nitrate‐reducing taxa summary score ( NO 3 TSS ) for each participant. Natural log‐transformed homeostatic model assessment of insulin resistance, plasma glucose, systolic BP, and diastolic BP were regressed on NO 3 TSS in multivariable linear regressions; prediabetes mellitus and hypertension prevalence were regressed on NO 3 TSS using modified Poisson regression models. Nitrate‐reducing bacterial species represented 20±16% of all measured taxa. After multivariable adjustment, a 1‐ SD increase in NO 3 TSS , was associated with a −0.09 (95% CI , −0.15 to −0.03) and −1.03 mg/dL (95% CI , −1.903 to −0.16) lower natural log‐transformed homeostatic model assessment of insulin resistance and plasma glucose, respectively. NO 3 TSS was associated with systolic BP only among patients without hypertension; 1‐ SD increase in NO 3 TSS was associated with −1.53 (95% CI , −2.82 to −0.24) mm Hg lower mean systolic BP. No associations were observed with prediabetes mellitus and hypertension. Conclusions A higher relative abundance of oral nitrate‐reducing bacteria was associated with lower insulin resistance and plasma glucose in the full cohort and with mean systolic BP in participants with normotension.

SUMMARYSalinipostin A (Sal A) is a potent antimalarial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in thePlasmodium falciparumparasite. All of the identified proteins contain α/β serine hydrolase domains, and several are essential for parasite growth. One of the essential targets displays high homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism and produces disorganized and stalled schizonts similar to Sal A. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a protein linked to drug resistance inToxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.

Summary Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.

Salinipostin A (Sal A) is a potent antimalarial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays high homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism and produces disorganized and stalled schizonts similar to Sal A. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.

Peroxisome proliferator-activated receptors (PPARs) control the expression of genes involved in glucose homeostasis, lipid metabolism, inflammation, and cell differentiation. Here, we analyzed the effects of aleglitazar, a dual PPARα and PPARγ agonist with balanced affinity for either subtype, on subacute stroke outcome. Healthy young adult mice were subjected to transient 30 min middle cerebral artery occlusion (MCAo)/reperfusion. Daily treatment with aleglitazar was begun on the day of MCAo and continued until sacrifice. Blood glucose measurements and lipid profile did not differ between mice receiving aleglitazar and mice receiving vehicle after MCAo. Aleglitazar reduced the size of the ischemic lesion as assessed using NeuN immunohistochemistry on day 7. Sensorimotor performance on the rotarod was impaired during the first week after MCAo, an effect that was significantly attenuated by treatment with aleglitazar. Smaller lesion volume in mice treated with aleglitazar was accompanied by a decrease in mRNA transcription of IL-1β, Vcam-1, and Icam-1, suggesting that reduced proinflammatory signaling and reduced vascular inflammation in the ischemic hemisphere contribute to the beneficial effects of aleglitazar during the first week after stroke. Further experiments in primary murine microglia confirmed that aleglitazar reduces key aspects of microglia activation including NO production, release of proinflammatory cytokines, migration, and phagocytosis. In aggregate, a brief course of PPARα/γ agonist aleglitazar initiated post-event affords stroke protection and functional recovery in a model of mild brain ischemia. Our data underscores the theme of delayed injury processes such as neuroinflammation as promising therapeutic targets in stroke. Key messages PPARα/γ agonist aleglitazar improves stroke outcome after transient brain ischemia.Aleglitazar attenuates inflammatory responses in post-ischemic brain.Aleglitazar reduces microglia migration, phagocytosis, and release of cytokines.Beneficial effects of aleglitazar independent of glucose regulation.Aleglitazar provides extended window of opportunity for stroke treatment.

Background Tocilizumab, an interleukin-6 receptor blocker, has been used in the inflammatory phase of COVID-19, but its impact independent of corticosteroids remains unclear in patients with severe disease. Methods In this retrospective analysis of patients with COVID-19 admitted between March 2 and April 14, 2020 to a large academic medical center in New York City, we describe outcomes associated with tocilizumab 400 mg (without methylprednisolone) compared to a propensity-matched control. The primary endpoints were change in a 7-point ordinal scale of oxygenation and ventilator free survival, both at days 14 and 28. Secondary endpoints include incidence of bacterial superinfections and gastrointestinal perforation. Primary outcomes were evaluated using t-test. Results We identified 33 patients who received tocilizumab and matched 74 controls based on demographics and health measures upon admission. After adjusting for illness severity and baseline ordinal scale, we failed to find evidence of an improvement in hypoxemia based on an ordinal scale at hospital day 14 in the tocilizumab group (OR 2.2; 95% CI, 0.7–6.5; p = 0.157) or day 28 (OR 1.1; 95% CI, 0.4–3.6; p = 0.82). There also was no evidence of an improvement in ventilator-free survival at day 14 (OR 0.8; 95% CI, 0.18–3.5; p = 0.75) or day 28 (OR 1.1; 95% CI, 0.1–1.8; p = 0.23). There was no increase in secondary bacterial infection rates in the tocilizumab group compared to controls (OR 0.37; 95% CI, 0.09–1.53; p = 0.168). Conclusions There was no evidence to support an improvement in hypoxemia or ventilator-free survival with use of tocilizumab 400 mg in the absence of corticosteroids. No increase in secondary bacterial infections was observed in the group receiving tocilizumab.

Mixed copper and titanium hydride powder was hot-pressed and characterized by Carrier Gas Hot Extraction, X-Ray Diffraction, Thermal Gravimetric Analysis coupled with Mass Spectrometry, and Scanning Electron Microscopy. The hot-pressed and five conventional samples were applied for calibration of hydrogen in Glow Discharge Optical Emission and Mass Spectrometry. Up to the introduction of 15 ng/s hydrogen the emission yield model is useful in Glow Discharge Optical Emission Spectrometry. A correlation between saturation and even reversal of the emission yield of the spectral lines H121, H486 and H656 and low sputtering rates was found. Hydrogen effects exist for the spectral lines of Cu(II) 219 and Ti(I) 399. In Glow Discharge Mass Spectrometry, a linear dependency of the 1H ion current on the sputtered mass per time exists over the total range of hydrogen content investigated. Hydrogen effects also exist for the sensitivity of 48Ti and 63Cu. The sputtering rate of two-phase materials depends linearly on the sputtered mass per time of one phase, which allows the sputtering rate of two-phase materials with known composition to be predicted.

An electrochemical and in situ magnetic study is conducted to identify key parameters for room-temperature electrochemical (magneto-ionic) switching of magnetism by repeated oxidation and reduction of iron species in aqueous KOH. Potentiodynamic routines allow to distinguish the reaction potentials and, in contrast to measurements on bulk Fe electrodes, uncover the importance of dissolution processes in thin film geometry. The pH of the solution affects both dissolution and reduction to metallic iron. The magnetic properties strongly depend on the applied oxidation and reduction potentials. Large magnetic changes are obtained when switching between the potential of reduction to metallic iron and intermediate oxidation potentials, revealing an influence of the structure of the oxide layer. Keywords: Magnetoelectric effect, Magnetic films, Magnetoionic effect, Oxidation, Reduction, Iron

Beta-type Ti-40Nb with very low Young's modulus is a promising alloy for long-term bone implant applications but surface states must be tailored for optimum osseointegration. Different anodization methods for surface oxidation were evaluated and oxide layers with characteristic morphologies were obtained. Anodization in fluoride-containing solutions generates oxide nanotubes with higher aspect ratio than those grown on CP2-Ti. The electrolyte composition has some influence on the oxide morphology. Plasma electrolytic oxidation in strongly alkaline solution yields a two-layer oxide structure with a thin compact inner layer and a much thicker outer layer with micropores and microchannels. Inductively coupled RF oxygen plasma anodization causes the formation of microstructured oxides on the Ti-40Nb surface. With increasing processing temperature a transition from random structured to patterned oxides was observed which is opposite to the trend for CP2-Ti. For all three techniques the oxide layer growth on the Ti-40Nb alloy follows the principal mechanisms that are established for Ti. Nb species are involved in the oxidation processes which causes significantly enhanced layer thickness growth, morphological changes and mixed oxides (Ti x Nb 1 − x )O 2 , more specific (Ti 0.75 Nb 0.25 )O 2 . All obtained oxide types appear to be promising as coatings of beta-type implants with appropriate bioactivity to stimulate bone growth.

We report on the successful application of porous hollow carbon nanospheres consisting of graphitic shells with a hierarchical porosity that were obtained by carbonizing an iron-containing commercially available metal-organic framework, as active material for supercapacitors. The influence of basic key parameters, such as the degree of graphitization and the accessible surface area of the carbons obtained at different temperatures, on the electrochemical performance is discussed in-depth. A high specific capacitance of 91 F g −1 in an aqueous electrolyte and 156 F g −1 using an ionic liquid is achieved. Furthermore a very steady specific capacitance over the course of 10,000 charge-discharge cycles is demonstrated. In addition, electrochemical impedance spectroscopy studies revealed that these carbons can feature a stable performance over several orders of magnitude of frequency, which render them interesting candidates for future electrochemical energy storage systems.

The reaction of a metastable SiCl2 solution with the sterically less-demanding carbene N,N-diisopropylimidazo-2-ylidene (IPr) yields the salt [(IPr3 Si3 Cl5 )(+) ]Cl(-) (1-Cl), containing a silyl cation with a Si3 backbone. Salt 1 is highly reactive, but it can be used as a reagent in deuterated dichloromethane, whereby dehalogenation with Me3 SiOTf (OTf=O3 SCF3 ) gives the dicationic silyl halide [(IPr3 Si3 Cl4 )](2+) 2. Quantum chemical calculations show that the HOMO is localized at the negatively charged central silicon atom of 1 and 2, and thus although both compounds are cations they are better described as silanides, which was also corroborated by NMR investigations.

The bacterium Pseudomonas aeruginosa is especially pathogenic, often being associated with intractable pneumonia and high mortality. How P. aeruginosa avoids immune clearance and persists in the inflamed human airway remains poorly understood. In this study, we show that P. aeruginosa can exploit the host immune response to maintain infection. Notably, unlike other opportunistic bacteria, we found that P. aeruginosa alters its metabolic and immunostimulatory properties in response to itaconate, an abundant host-derived immunometabolite in the infected lung. Itaconate induces bacterial membrane stress, resulting in downregulation of lipopolysaccharides (LPS) and upregulation of extracellular polysaccharides (EPS). These itaconate-adapted P. aeruginosa accumulate lptD mutations, which favor itaconate assimilation and biofilm formation. EPS, in turn, induces itaconate production by myeloid cells, both in the airway and systemically, skewing the host immune response to one permissive of chronic infection. Thus, the metabolic versatility of P. aeruginosa needs to be taken into account when designing therapies.

We exploit electrolyte confinement effects in porous membranes to electrosynthesize a two-engine micromachine from a single electrolyte solution. Taking advantage of the often undesired overplating observed in template-assisted deposition, we can produce micromachines consisting of hollow microstructures with a compositionally graded mushroom-like shape that consist of a manganese oxide-based stipe and an iron oxide-based cap. While the stipe acts as the catalytic motor of the machine, the cap serves as a magnetic steering wheel.

We have previously reported the inhibition of bacterial topoisomerase I activity by a fluoroquinophenoxazine compound (FP-11g) with a 6-bipiperidinyl lipophilic side chain that exhibited promising antituberculosis activity (MIC = 2.5 μM againstMycobacterium tuberculosis, SI = 9.8). Here, we found that the compound is bactericidal towardsMycobacterium smegmatis, resulting in greater than 5 Log10reduction in colony-forming units [cfu]/mL following a 10 h incubation at 1.25 μM (4X MIC) concentration. Growth inhibition (MIC = 50 μM) and reduction in cfu could also be observed against a clinical isolate ofMycobacterium abscessus.Stepwise isolation of resistant mutants ofM. smegmatiswas conducted to explore the mechanism of resistance. Mutations in the resistant isolates were identified by direct comparison of whole-genome sequencing data from mutant and wild-type isolates. These include mutations in genes likely to affect the entry and retention of the compound. FP-11g inhibitsMtbtopoisomerase I andMtbgyrase with IC50of 0.24 and 31.5 μM, respectively. Biophysical analysis showed that FP-11g binds DNA as an intercalator but the IC50for inhibition ofMtbtopoisomerase I activity is >10 fold lower than the compound concentrations required for producing negatively supercoiled DNA during ligation of nicked circular DNA. Thus, the DNA-binding property of FP-11g may contribute to its antimycobacterial mechanism, but that alone cannot account for the observed inhibition of Mtb topoisomerase I.

Ceftazidime-avibactam (CAZ-AVI) is a promising novel treatment for infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Despite improved treatment outcomes compared to those achieved with aminoglycoside- and colistin-based regimens, the rapid evolution of CAZ-AVI resistance during treatment has previously been reported in Klebsiella pneumoniae sequence type 258 (ST258) bla KPC-3 -harboring isolates. Here, we report the stepwise evolution and isolation of two phenotypically distinct CAZ-AVI-resistant Klebsiella pneumoniae isolates from a patient with pancreatitis. All susceptible ( n = 3) and resistant ( n = 5) isolates were of the ST307 clonal background, a rapidly emerging clone. Taking advantage of short-read Illumina and long-read Oxford Nanopore sequencing and full-length assembly of the core chromosome and plasmids, we demonstrate that CAZ-AVI resistance first occurred through a 532G → T bla KPC-2 point mutation in bla KPC-2 (D179Y protein substitution) following only 12 days of CAZ-AVI exposure. While subsequent isolates exhibited substantially decreased meropenem (MEM) MICs (≤2 μg/ml), later cultures demonstrated a second CAZ-AVI resistance phenotype with a lower CAZ-AVI MIC (12 μg/ml) but also MEM resistance (MIC > 128 μg/ml). These CAZ-AVI- and MEM-resistant isolates showed evidence of multiple genomic adaptations, mainly through insertions and deletions. This included amplification and transposition of wild-type bla KPC-2 into a novel plasmid, an IS 1 insertion upstream of ompK36 , and disruption of the rfb gene locus in these isolates. Our findings illustrate the potential of CAZ-AVI resistance to emerge in non- K. pneumoniae ST258 clonal backgrounds and alternative bla KPC variants. These results raise concerns about the strong selective pressures incurred by novel carbapenemase inhibitors, such as avibactam, on isolates previously considered invulnerable to CAZ-AVI resistance. There is an urgent need to further characterize non-KPC-mediated modes of carbapenem resistance and the intrinsic bacterial factors that facilitate the rapid emergence of resistance during treatment.

Evidence for a critical pathophysiological role of aberrant cytoskeletal dynamics is being uncovered in a growing number of neuropsychiatric syndromes. A sedentary lifestyle as well as overt psychopathology is prevalent in patients with the metabolic syndrome. Using mice deficient in gelsolin (Gsn-/-), a crucial actin-severing protein, we here investigated reduced actin turnover as a potential common driver of metabolic disturbances, sedentary behavior, and an anxious/depressive phenotype. Gelsolin deficiency resulted in reduced lifespan. As compared to wildtype controls, Gsn-/- mice (~ 9 weeks) fed a high-fat diet (HFD) over a span of 12 weeks showed increased body weight gain, fat mass, hepatic steatosis, and adipocyte hypertrophy as well as a significantly reduced respiratory quotient. Moreover, increased rigidity of the actin cytoskeleton in mice on HFD induced mRNA expression of Acc1, Acc2, Fasn, and Lipe, key genes involved in fatty acid metabolism in the liver. Glucose tolerance and insulin sensitivity were worsened in Gsn-/- HFD relative to Gsn+/+ HFD mice. Hypertension in Gsn-/- mice was associated with reduced endothelial NO synthase (eNOS) mRNA expression and reduced eNOS protein trafficking to the plasma membrane. Furthermore, acetylcholine-induced cGMP production and relaxation of aortic rings were impaired by actin filament stabilization. Gsn-/- mice on HFD displayed reduced corticosterone concentrations and reduced energy expenditure as compared to Gsn+/+ HFD mice. Moreover, Gsn-/- HFD mice displayed an overall pattern of hypoactive and anxious/depressive-like behavior. In aggregate, our results demonstrate that impaired actin filament dynamics promote the development of key behavioral and physiological aspects of the metabolic syndrome.

We have studied the conformational preferences of the sulfonamide drug sulfanilamide, its dimer, and its monohydrated complex through laser desorption single-conformation UV and IR spectroscopy in a molecular beam. Based on potential energy curves for the inversion of the anilinic and the sulfonamide NH2 groups calculated at DFT level, we suggest that the zero-point level wave function of the sulfanilamide monomer is appreciably delocalized over all four conformer wells. The sulfanilamide dimer, and the monohydrated complex each exhibit a single isomer in the molecular beam. The isomeric structures of the sulfanilamide dimer and the monohydrated sulfanilamide complex were assigned based on their conformer-specific IR spectra in the NH and OH stretch region. Quantum Theory of Atoms in Molecules (QTAIM) analysis of the calculated electron density in the water complex suggests that the water molecule is bound side-on in a hydrogen bonding pocket, donating one O–H⋯OS hydrogen bond and accepting two hydrogen bonds, a NH⋯O and a CH⋯O hydrogen bond. QTAIM analysis of the dimer electron density suggests that the Ci symmetry dimer structure exhibits two dominating N–H⋯OS hydrogen bonds, and three weaker types of interactions: two CH⋯O bonds, two CH⋯N bonds, and a chalcogen O⋯O interaction. Most interestingly, the molecular beam dimer structure closely resembles the R22 dimer unit – the dimer unit with the greatest interaction energy – of the α, γ, and δ crystal polymorphs. Interacting Quantum Atoms analysis provides evidence that the total intermolecular interaction in the dimer is dominated by the short-range exchange–correlation contribution.

Background Patients with bloodstream infections (BSIs) due to carbapenem-resistant Enterobacteriaceae (CRE) have long delays until receipt of appropriate antimicrobial therapy and high mortality rates. Rapid molecular diagnostics and novel therapies, such as ceftazidime–avibactam (CAZ-AVI), offer promise to improve outcomes, but their clinical impact is unclear. Methods We conducted an observational study of patients with CRE BSI from January 2016 to June 2018 at 8 New York and New Jersey medical centers. Patient demographics, comorbidities, clinical presentations, diagnostic methods, and treatments were compared between patients who died within 30 days of BSI onset and survivors. Independent risk factors for mortality were identified using logistic regression. We then compared time to receipt of active antimicrobial therapy between patients whose positive blood culture bottles underwent testing for the Klebsiella pneumoniae carbapenemase gene (blaKPC PCR) and patients where this test was not used. Results We identified 178 patients with CRE BSI (K. pneumoniae: n = 104, 58%; Enterobacter cloacae: n = 26, 15%; Escherichia coli: n = 26, 15%). The 30-day mortality rate was 38%. An increasing Acute Physiology and Chronic Health Evaluation II score (adjusted odds ratio [aOR] 1.06, P = 0.005) was independently associated with increased 30-day mortality; whereas, use of blaKPC PCR (aOR 0.31, P = 0.005), urinary tract source (aOR 0.12, P = 0.001), and source control (aOR 0.25, P = 0.001) were independently associated with survival. Initial targeted therapy with CAZ-AVI was associated with a 28% 30-day mortality rate, compared with a 49% 30-day mortality rate among patients who received a polymyxin or aminoglycoside (P = 0.036). Patients whose blood culture underwent blaKPC PCR were more likely to receive active antimicrobial therapy within 24 hours of BSI onset (42% vs. 28%; P = 0.07) and had a decreased median time until receipt of active therapy (25 hours vs. 46 hours; P = 0.07), although these differences did not achieve statistical significance. Conclusion The use of PCR to rapidly identify blood cultures with blaKPC and definitive therapy with CAZ-AVI instead of polymyxins or aminoglycosides were associated with decreased mortality after CRE bacteremia. Disclosures All Authors: No reported Disclosures.

In the brain, retinoic acid (RA) concentrations are under tight spatio-temporal control. Here, we show that challenge of primary mouse microglia with lipopolysaccharide (LPS) results in increased release of nitric oxide (NO) and tumor necrosis factor-α (TNF-α). Co-administration of RA attenuated microglial activation. Similarly, pretreatment with RA-metabolism inhibitor liarozole potently reduced NO and TNF-α release. Conversely, activated microglia showed increased protein expression of RA-degrading cytochromes CYP26A1, CYP26B1, CYP3A4 and CYP2C. Correspondingly, RA catabolism by activated microglia was significantly increased. Our results indicate that RA reduces microglial activation, but also, conversely, that the activation state of microglia influences RA metabolism.

Conventional alkaline solutions used for capacitive performance of electrodeposited cobalt hydroxides have a number of disadvantages as they are corrosive, environmentally unfriendly and provide a small working potential range. In this study, the capacitive properties of electrodeposited cobalt hydroxide/oxide were investigated in 1 M Na 2 SO 4 solution with pH 5.5 by means of cyclic voltammetry, galvanostatic charging/discharging experiments and electrochemical impedance spectroscopy. The capacitance of the cobalt hydroxide/oxide was demonstrated to have high values of 141 F g −1 at scan rate 8 mV s −1 in this 1 M Na 2 SO 4 solution. The anodic potential range is extended by 0.8–1.3 V vs. Ag/AgCl. A good cyclic stability and reversibility were observed.

The influence of a magnetic field yielding high magnetic flux densities and high flux density gradients on the free corrosion behavior of iron in a low concentrated acidic solution with and without chloride ions is studied by long time exposure experiments and electrochemical impedance spectroscopy (EIS). A decrease of the corrosion rate in electrode surface regions of high magnetic flux density is detected. This decrease of the dissolution rate is significantly stronger in the presence of chloride ions. The observed effects are discussed on the basis of the magnetically induced forces acting on the ions present in the solution, the surface coverage fraction of adsorbed species, and the stability of these adsorbed species.

Antimalarial drug resistance poses a major threat to the control of malaria. In Plasmodium falciparum infection, resistance has evolved to all classes of antimalarial drugs with the exception of the artemisinin derivatives. Resistance mechanisms underlying this mainly involve mutations in the genes encoding target enzymes or transporters [1, 2]. Despite tight control of its use, significant resistance to mefloquine (MFQ) emerged within 6 years after it was first deployed in Thailand in 1984 [3]. MFQ resistance is largely mediated by a P-glycoprotein pump (Pgh), which is encoded by the pfmdr1 gene [4, 5] on chromosome 5. Pgh affects the intraparasitic concentrations of several important antimalarial drugs. Point mutations in pfmdr1 are associated with resistance to chloroquine and are negatively associated with resistance to MFQ [6, 7]. Amplification of wild-type pfmdr1 is associated with reduced susceptibility in vitro to structurally unrelated antimalarial drugs, such as MFQ, artesunate (ART), lumefantrine, and quinine (QU) [5, 8]. In vivo, increased pfmdr1 copy number accounts for more than half of the treatment failures after MFQ, MFQ plus artesunate (MAS), and artemether-lumefantrine (AL) [5, 8]. Over the past 20 years, prospective studies of antimalarial drug efficacy have been conducted on the northwestern border of Thailand. We have utilized samples taken during these studies from patients who experienced treatment failure to investigate how administration of different antimalarial drugs selects for point mutations and amplification in pfmdr1.

Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes., This work was funded in part by the National Institutes of Health (R01 AI50234, AI124678 and AI109023) and a Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Diseases award to D.A.F. This research also received funding from the Portuguese Fundacao para a Ciencia e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2-O Novo Norte); from the Quadro de Referencia Estrategico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). M.I.V. is the recipient of a postdoctoral fellowship from FCT/Ministerio da Ciencia e Ensino Superior, Portugal-MCES (SFRH/BPD/76614/2011). A.M.L. was supported by an Australian National Health and Medical Research Council (NHMRC) Overseas Biomedical Fellowship (585519). R.E.M. was supported by an NHMRC RD Wright Biomedical Fellowship (1053082). A.C.U. was supported by an Irving scholarship from Columbia University. We thank Dr Andrea Ecker for her help with plasmid design and Pedro Ferreira for his expert help with Fig. 6., info:eu-repo/semantics/publishedVersion

NMR structure determination of large membrane proteins is hampered by broad spectral lines, overlap, and ambiguity of signal assignment. Chemical shift and NOE assignment can be facilitated by amino acid selective isotope labeling in cell-free protein synthesis system. However, many biological detergents are incompatible with the cell-free synthesis, and membrane proteins often have to be synthesized in an insoluble form. We report cell-free synthesis of subunits a and c of the proton channel of Escherichia coli ATP synthase in a soluble form in a mixture of phosphatidylcholine derivatives. In comparison, subunit a was purified from the cell-free system and from the bacterial cell membranes. NMR spectra of both preparations were similar, indicating that our procedure for cell-free synthesis produces protein structurally similar to that prepared from the cell membranes.

Wilson disease (WD) is a disorder of copper metabolism caused by mutations in the Cu-transporting ATPase ATP7B. WD is characterized by significant phenotypic variability, the molecular basis of which is poorly understood. The E1064A mutation in the N-domain of ATP7B was previously shown to disrupt ATP binding. We have now determined, by NMR, the structure of the N-domain containing this mutation and compared properties of E1064A and H1069Q, another mutant with impaired ATP binding. The E1064A mutation does not change the overall fold of the N-domain. However, the position of the α1,α2-helical hairpin (α-HH) that houses Glu(1064) and His(1069) is altered. The α-HH movement produces a more open structure compared with the wild-type ATP-bound form and misaligns ATP coordinating residues, thus explaining complete loss of ATP binding. In the cell, neither the stability nor targeting of ATP7B-E1064A to the trans-Golgi network differs significantly from the wild type. This is in a contrast to the H1069Q mutation within the same α-HH, which greatly destabilizes protein both in vitro and in cells. The difference between two mutants can be linked to a lower stability of the α-HH in the H1069Q variant at the physiological temperature. We conclude that the structural stability of the N-domain rather than the loss of ATP binding plays a defining role in the ability of ATP7B to reach the trans-Golgi network, thus contributing to phenotypic variability in WD.

A series of multifunctional (mercaptomethyl)silanes of the general formula type R(n)Si(CH(2)SH)(4-n) (n = 0-2; R = organyl) was synthesized, starting from the corresponding (chloromethyl)silanes. They were used as multidentate ligands for the conversion of dodecacarbonyltriiron, Fe(3)(CO)(12), into iron carbonyl complexes in which the deprotonated (mercaptomethyl)silanes act as μ-bridging ligands. These complexes can be regarded as models for the [FeFe] hydrogenase. They were characterized by elemental analyses (C, H, S), NMR spectroscopic studies ((1)H, (13)C, (29)Si), and single-crystal X-ray diffraction. Their electrochemical properties were investigated by cyclic voltammetry to disclose a new mechanism for the formation of dihydrogen catalyzed by these compounds, whereby one sulfur atom was protonated in the catalytic cycle. The reaction of the tridentate ligand MeSi(CH(2)SH)(3) with Fe(3)(CO)(12) yielded a tetranuclear cluster compound. A detailed investigation by X-ray diffraction, electrochemical, Raman, Mössbauer, and susceptibility techniques indicates that for this compound initially [Fe(2){μ-MeSi(CH(2)S)(2)CH(2)SH}(CO)(6)] is formed. This dinuclear complex, however, is slowly transformed into the tetranuclear species [Fe(4){μ-MeSi(CH(2)S)(3)}(2)(CO)(8)].

Emotional stress is associated with e.g. increased hormone release, high blood-sugar level and blood pressure. Stress clearly affects metabolism. Whether chronic stress exposure leads to altered urinary compositions with increased risk of CaOx; urolithiasis was examined by investigating the relation between stress burden and urine composition. 29 controls (CG), 29 CaOx stone formers (SF), and 28 patients with chronic inflammatory bowel diseases (CIBD) were advised to avoid unfavorable aliment. Any urolithiasis-related medications were stopped. At day 5, a 24-h urine was collected and comprehensive urinalysis performed. AP (CaOx) index was calculated. Subjects completed a questionnaire designed to measure perceived stress ("Trier-Inventory-of-Chronic-Stress"). Mean AP (CaOx) in CG, SF and CIBD amount to 0.8 (+/-0.3), 1.2 (+/-0.7), and 1.9 (+/-1.2), respectively. Increased AP (CaOx) in SF is mainly attributed to an increased effect of calcium and oxalate, whereas in CIBD this is additionally caused by a reduced effect of citrate, magnesium and volume. Stress dimensions are correlated to any investigated urinary parameter with an absolute value of ror = 0.600; some correlations are statistically significant: whereas in SF only one combination, "lack of social recognition" versus calcium, shows significance, in CIBD various combinations are significantly related. In particular, sodium excretion increases with stress. In CG, some stress dimensions are directly related to citrate; with increasing stress, protection against CaOx crystallization tends to increase. It could be shown that stress load and urinary composition are related by statistical means. The observed metabolic stress response patterns in urinary compositions are different for the distinct groups, thereby, reflecting a conclusive picture. This is in particular in CIBD, for which a link between stress and inflammatory activity and between inflammatory activity and altered urinary composition is well established.

The anodic polarisation behaviour of neodymium was investigated in various solutions (pH 1–12). While in sulphuric acid solution high dissolution rates were observed, spontaneous passivity occurred in phosphoric acid solutions, oxalic acid solutions and sodium hydroxide solutions. However, the stability of these protecting layers strongly depends on the kind and concentration of anions present, especially in acidic environments. A mechanism of the passive layer breakdown is proposed. During pitting corrosion erosive degradation of the electrode was observed. In all solutions, abnormal hydrogen evolution was observed when neodymium was in the active state during anodic polarisation.

This paper describes recent results from the authors' labs dealing with the electrodeposition of thin cobalt layers from 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)amide ([Py1,4] ¬TFSA) ionic liquid with tailor-made metal salts. We applied the electrochemical quartz crystal microbalance (EQCM) with damping monitoring for the in-situ determination of the mass-charge balance and of the current efficiency of the deposition process. Higher temperatures improved the quality of the deposited layers. Thus uniform deposits with a grain size of some tens of nm were obtained at 120 degrees Celsius whereas no Co layers could be electrodeposited at room temperature from the [Py1,4] ¬TFSA either by potentiostatic or galvanostatic control.

The aim of this study was to assess the ability of currently deployed antimalarials to inhibit mammalian sarcoendoplasmic reticulum calcium adenosine triphosphatase (SERCA). Artemisinins exert their antiplasmodial action by inhibiting parasite PfATP6, a SERCA enzyme, and possess neurotoxic potential; mefloquine is neurotoxic and inhibits mammalian SERCA, an orthologue of PfATP6. SERCA in rabbit muscle was tested in vitro for inhibition by artemisinin and amino alcohol antimalarials. Significant inhibition of mammalian SERCA, as mean difference from uninhibited, control values was seen with both enantiomers of mefloquine: (+)-mefloquine (10 microM: -35.83, 95% CI -59.63 to -12.03; 50 microM: -54.06, 95% CI -77.86 to -30.26); (-)-mefloquine (10 microM: -24.35, 95% CI -41.56 to -7.15; 50 microM: -58.42, 95% CI -75.62 to -41.22); lumefantrine (1 microM: -25.46, 95% CI -45.82 to -5.10; 5 microM -34.83, 95% CI -60.08 to -9.58; 10 microM: -25.80, 95% CI -51.05 to -0.55); desbutyl-lumefantrine (5 microM: -50.16, 95% CI -84.24 to -16.08); dihydroartemisinin (1 microM: -39.25, 95% CI -63.74 to -14.76; 5 microM: -39.30, 95% CI -64.88 to -13.72). Dihydroartemisinin in higher concentrations (10 microM) stimulated SERCA activity: (+40.90, 95% CI 11.37 to 70.44). No statistically significant inhibition was seen with artemether at 1, 5 and 10 microM. Equimolar combinations of artemether and lumefantrine or of dihydroartemisinin and lumefantrine, when studied at concentrations that inhibit SERCA individually, failed to show any inhibition. Dihydroartemisinin, mefloquine, lumefantrine and desbutyl lumefantrine inhibit mammalian SERCA at periphysiological concentrations, although the neurotoxicity of mefloquine is not wholly attributable to this property. Candidate antimalarials should be screened pre-clinically for SERCA inhibition.

The effect of an uniform magnetic field applied parallel to the electrode surface, with flux density up to 1 T on the pH value close to the electrode surface during the electrodeposition of Co, Fe, CoFe alloys as well as for the pure hydrogen evolution reaction (HER) has been investigated. Voltammetric and chronoamperometric experiments have been carried out with the in situ pH measurements at the electrode surface. Results show that the limiting current for all the investigated systems is increased due to the magnetohydrodynamic (MHD) effect. The hydroxides formation in the metal containing electrolytes buffers the cathodic layer and the interfacial pH value increases to a lesser extent compared to the case of HER electrolyte. The increase of the pH value at the electrode surface is lower in the applied magnetic field compared to the case without a magnetic field. It was found that the interfacial pH value is a power function of the magnetic flux density. This effect is attributed to enhanced convection induced by the Lorentz force. The depletion of H + concentration at the electrode surface is compensated by the MHD effect and the hydroxide formation is suppressed, moreover the hydroxyl products are removed faster from the electrode surface in the magnetic field resulting in better quality of the deposited layers. The pH value close to the electrode surface during CoFe alloys deposition is high enough for the precipitation of the iron hydroxide, what satisfies the model proposed by Dahms and Croll.

The results of Fe(2+)-induced decomposition of the clinically used artemisinins, artemisone, other aminoartemisinins, 10-deoxoartemisinin, and the 4-fluorophenyl derivative have been compared with their antimalarial activities and their ability to inhibit the parasite SERCA PfATP6. The clinical artemisinins and artemisone decompose under aqueous conditions to give mixtures of C radical marker products, carbonyl compounds, and reduction products. The 4-fluorophenyl derivative and aminoartemisinins tend to be inert to aqueous iron(II) sulfate and anhydrous iron(II) acetate. Anhydrous iron(II) bromide enhances formation of the carbonyl compounds and provides a deoxyglycal from DHA and enamines from the aminoartemisinins. Ascorbic acid (AA) accelerates the aqueous Fe(2+)-mediated decompositions, but does not alter product distribution. 4-Oxo-TEMPO intercepts C radicals from a mixture of an antimalaria-active trioxolane, 10-deoxoartemisinin, and anhydrous iron(II) acetate to give trapped products in 73 % yield from the trioxolane, and 3 % from the artemisinin. Artemisone provides a trapped product in 10 % yield. Thus, in line with its structural rigidity, only the trioxolane provides a C radical eminently suited for intermolecular trapping. In contrast, the structural flexibility of the C radicals from the artemisinins allows facile extrusion of Fe(2+) and collapse to benign isomerization products. The propensity towards the formation of radical marker products and intermolecular radical trapping have no relationship with the in vitro antimalarial activities of the artemisinins and trioxolane. Desferrioxamine (DFO) attenuates inhibition of PfATP6 by, and antagonizes antimalarial activity of, the aqueous Fe(2+)-susceptible artemisinins, but has no overt effect on the aqueous Fe(2+)-inert artemisinins. It is concluded that the C radicals cannot be responsible for antimalarial activity and that the Fe(2+)-susceptible artemisinins may be competitively decomposed in aqueous extra- and intracellular compartments by labile Fe(2+), resulting in some attenuation of their antimalarial activities. Interpretations of the roles of DFO and AA in modulating antimalarial activities of the artemisinins, and a comparison with antimalarial properties of simple hydroperoxides and their behavior towards thapsigargin-sensitive SERCA ATPases are presented. The general basis for the exceptional antimalarial activities of artemisinins in relation to the intrinsic activity of the peroxide within the uniquely stressed environment of the malaria parasite is thereby adumbrated.

We study a continuous separation process for 2-furyl oxirane from its reaction medium which is a quaternary mixture. Continuous process flowsheeting has been used in order to compare two different separation processes which are based upon solvent extraction and heteroazeotropic distillation. The improved production process totals five unit operations: synthesis of 2-furyl oxirane; filtration of the reaction medium; heteroazeotropic distillation; synthesis of trimethylsulphonium bromide; and filtration of trimethylsulphonium bromide