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The COVID-19 pandemic has affected more than 20 million people worldwide, with mortality exceeding 800,000 patients. Risk factors associated with severe disease and mortality include advanced age, hypertension, diabetes, and obesity. Each of these risk factors pathologically disrupts the lipidome, including immunomodulatory eicosanoid and docosanoid lipid mediators (LMs). We hypothesized that dysregulation of LMs may be a defining feature of the severity of COVID-19. By examining LMs and polyunsaturated fatty acid precursor lipids in serum from hospitalized COVID-19 patients, we demonstrate that moderate and severe disease are separated by specific differences in abundance of immune-regulatory and proinflammatory LMs. This difference in LM balance corresponded with decreased LM products of ALOX12 and COX2 and an increase LMs products of ALOX5 and cytochrome p450. Given the important immune-regulatory role of LMs, these data provide mechanistic insight into an immuno-lipidomic imbalance in severe COVID-19.

Compared to females, male COVID-19 patients have more kynurenic acid, which may underlie their poorer immune response., Sex-specific metabolism and COVID-19 Males and females have different immune responses to SARS-CoV-2 infection, with male sex being a risk factor for mortality, particularly among older individuals. Cai et al. performed metabolomics analysis of serum from COVID-19 patients and uninfected health care workers and identified 17 metabolites that were associated with the disease. However, in male COVID-19 patients only, the amount of the tryptophan metabolite kynurenic acid (KA) correlated with age, inflammation, and disease outcome. KA inhibits glutamate release, and glutamate abundance was reduced in patients who deteriorated. Together, these findings indicate that KA is associated with sex-specific differences in immune responses to COVID-19, suggesting that it might be targeted in male patients., Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA–to–kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.

Individuals with acute malaria infection generated high levels of antibodies that cross-react with the SARS-CoV-2 Spike protein. Cross-reactive antibodies specifically recognized the sialic acid moiety on N-linked glycans of the Spike protein and do not neutralize in vitro SARS-CoV-2. Sero-surveillance is critical for monitoring and projecting disease burden and risk during the pandemic; however, routine use of Spike protein-based assays may overestimate SARS-CoV-2 exposure and population-level immunity in malaria-endemic countries.

SARS-CoV-2 infection has so far affected over 42 million people worldwide, causing over 1.1 million deaths. With the large majority of SARS-CoV-2 infected individuals being asymptomatic, major concerns have been raised about possible long-term consequences of the infection. We developed an antigen capture assay to detect SARS-CoV-2 spike protein in urine samples from COVID-19 patients whose diagnosis was confirmed by PCR from nasopharyngeal swabs (NP-PCR+). The study used a collection of 233 urine samples from 132 participants from Yale New Haven Hospital and the Children’s Hospital of Philadelphia obtained during the pandemic (106 NP-PCR+ and 26 NP-PCR-) as well as a collection of 20 urine samples from 20 individuals collected before the pandemic. Our analysis identified 23 out of 91 (25%) NP-PCR+ adult participants with SARS-CoV-2 spike S1 protein in urine (Ur-S+). Interestingly, although all NP-PCR+ children were Ur-S-, 1 NP-PCR-child was found to be positive for spike protein in urine. Of the 23 Ur-S+ adults, only 1 individual showed detectable viral RNA in urine. Our analysis further showed that 24% and 21% of NP-PCR+ adults have high levels of albumin and cystatin C in urine, respectively. Among individuals with albuminuria (>0.3 mg/mg of creatinine) statistical correlation could be found between albumin and spike protein in urine. Together, our data showe that 1 of 4 of SARS-CoV-2 infected individuals develop renal abnormalities such as albuminuria. Awareness about the long-term impact of these findings is warranted.

Dithiocarbamate (DTC) derivatives of N-vinylpyrrolidone-N-vinylamine (VP&ndash, VA) copolymers were synthesized via reaction between the copolymers and carbon disulfide in alkaline medium, molecular masses of the products were 12 and 29 kDa, the VP:VDTC ratios were 94:6 and 83:17 mol.%. Complexation between the obtained DTC derivatives and metal ions (indium and gallium) was investigated. It was demonstrated that metal&ndash, DTC ligand complexes with 1:3 ratio between components were formed. Gallium metal&ndash, polymer complexes (MPC) were unstable in solution. Individual indium MPC were isolated and characterized by spectral and chromatographic methods. Unlike similar gallium MPC, they appeared to be stable in histidine challenge reaction.

Coronavirus disease-2019 (COVID-19) has poorer clinical outcomes in males compared to females, and immune responses underlie these sex-related differences in disease trajectory. As immune responses are in part regulated by metabolites, we examined whether the serum metabolome has sex-specificity for immune responses in COVID-19. In males with COVID-19, kynurenic acid (KA) and a high KA to kynurenine (K) ratio was positively correlated with age, inflammatory cytokines, and chemokines and was negatively correlated with T cell responses, revealing that KA production is linked to immune responses in males. Males that clinically deteriorated had a higher KA:K ratio than those that stabilized. In females with COVID-19, this ratio positively correlated with T cell responses and did not correlate with age or clinical severity. KA is known to inhibit glutamate release, and we observed that serum glutamate is lower in patients that deteriorate from COVID-19 compared to those that stabilize, and correlates with immune responses. Analysis of Genotype-Tissue Expression (GTEx) data revealed that expression of kynurenine aminotransferase, which regulates KA production, correlates most strongly with cytokine levels and aryl hydrocarbon receptor activation in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes, in COVID-19 infection.

Fogarty International Center (R25 TW009338, R01 TW009504) and National Institute of Allergy and Infectious Diseases (F31 AI114245, R01 AI121207) from the National Institutes of Health; the UK Medical Research Council (MR/P0240841), the Wellcome Trust (102330/Z/13/Z), and the Fulbright Foundation.

Spirochete bacteria, including important pathogens, exhibit a distinctive means of swimming via undulations of the entire cell. Motility is powered by the rotation of supercoiled ‘endoflagella’ that wrap around the cell body, confined within the periplasmic space. To investigate the structural basis of flagellar supercoiling, which is critical for motility, we determined the structure of native flagellar filaments from the spirocheteLeptospiraby integrating high-resolution cryo-electron tomography and X-ray crystallography. We show that these filaments are coated by a highly asymmetric, multi-component sheath layer, contrasting with flagellin-only homopolymers previously observed in exoflagellated bacteria. Distinct sheath proteins localize to the filament inner and outer curvatures to define the supercoiling geometry, explaining a key functional attribute of the spirochete flagellum.One Sentence summaryThe corkscrew-like motility of Spirochete bacteria is enabled by a unique, asymmetrically constructed flagellum that wraps around the cell body within the periplasm.

It has been demonstrated that the adhesive wafer bonding technique benefits the fabrication of capacitive micromachined ultrasonic transducers (CMUTs) in the aspects of structural flexibility, CMOS process compatibility, and fabrication yield. Recently, the feasibility of fabricating CMUTs using benzocyclobutene (BCB) based polymer as both the adhesive and structural material was reported. However, the issues of voids at the wafer bonding interface, material deformation and electrode distance control need to be addressed. In this paper, we present an improved fabrication process that allows a void-free device with reduced polymer deformation. The chemical reactions during the BCB curing process were revealed using Fourier transform infrared spectroscopy. Microscopy and cross-sectional SEM images were employed to illustrate the structure improvement in terms of voids and polymer deformation. In addition, an inverse structure that allows an accurate control of the effective electrode distance was presented. The cross-sectional SEM images and the impedance measurement showing the dynamic response of the CMUT demonstrated the feasibility of this inverse structure. The differences between the inverse structure and the conventional structure were also discussed and compared.

Developing a real-time, portable, and inexpensive sensor for pathogenic bacteria is crucial since the conventional detection approaches such as enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) assays are high cost, time-consuming, and require an expert operator. Here we present a portable, inexpensive, and convenient impedance-based biosensor using Interdigitated Electrode (IDE) arrays to detect Escherichia coli (E. coli) as a model to demonstrate the feasibility of an impedance-based biosensor. We manipulated the affinity of the IDE array towards E. coli (E. coli BL21 series) by functionalizing the IDEs’ surface with an E. coli outer membrane protein (OMP) Ag1 Aptamer. To determine the dominant factors affecting the sensitivity and the performance of the biosensor in detecting E. coli, we investigated the roles of the substrate material used in the fabrication of the IDE, the concentration of the aptamer, and the composition of the carboxy aliphatic thiol mixture used in the pre-treatment of the IDE surface. In the sensing experiments we used an E. coli concentration range of 25–1000 cfu mL−1 and confirmed the binding of the OMP Ag1 Aptamer to the outer membrane protein of the E. coli by Field Emission Scanning Electron Microscopy (FESEM), Optical Microscopy, and Atomic Force Microscopy (AFM). By tuning the surface chemistry, the IDEs’ substrate material, and the concentration of the OMP Ag1 Aptamer, our sensor could detect E. coli with the analytical sensitivity of approximately 1.8 Ohm/cfu and limit of detection of 9 cfu mL−1. We found that the molecular composition of the self-assembled monolayer (SAM) formed on the top of the IDEs before the attachment of the OMP Ag1 Aptamer significantly impacted the sensitivity of the sensor. Notably, with straightforward changes to the molecular recognition elements, this platform device can be used to detect a wide range of other microorganisms and chemicals relevant for environmental monitoring and public health.

COVID-19 is a global crisis of unimagined dimensions. Currently, Remedesivir is only fully licensed FDA therapeutic. A major target of the vaccine effort is the SARS-CoV-2 spike-hACE2 interaction, and assessment of efficacy relies on time consuming neutralization assay. Here, we developed a cell fusion assay based upon spike-hACE2 interaction. The system was tested by transient co-transfection of 293T cells, which demonstrated good correlation with standard spike pseudotyping for inhibition by sera and biologics. Then established stable cell lines were very well behaved and gave even better correlation with pseudotyping results, after a short, overnight co-incubation. Results with the stable cell fusion assay also correlated well with those of a live virus assay. In summary we have established a rapid, reliable, and reproducible cell fusion assay that will serve to complement the other neutralization assays currently in use, is easy to implement in most laboratories, and may serve as the basis for high throughput screens to identify inhibitors of SARS-CoV-2 virus-cell binding and entry., Author summary COVID-19 continues to be a global public health concern. Currently, the in vitro assessment of efficacy of any vaccine or therapeutic is based on time-consuming neutralization assays using live or pseudotyped virus at BSL2/BSL3 biocontainment. There are many factors which will affect the neutralization assay, including quality of plasmid, transfection efficiency, virus titer, etc. Here, we developed a novel cell fusion assay based upon spike-hACE2 interaction, which demonstrated excellent correlation with standard spike pseudotyping for inhibition by convalescent sera, cloned antibodies, and biologics, after 16–24 hours co-incubation. It also correlated well with a live virus assay. Other than two stable cell lines, our cell fusion assay requires no specialized research reagents or laboratory equipment and should be easy to adapt for use in most investigative and clinical settings. It will allow for the testing of sera after vaccination or infection, to assess for level of immune protection, and it could be used for high throughput screening for monoclonal antibodies, compounds, and biologics that interfere with virus-cell binding and entry.

The activity of glucose catabolism pathways of staphylococci strains able to form biofilm and isolated from vagina of women with dysbiosis of reproductive tract and strains isolated from women without disorders of microflora was studied. It was established that the investigated film-forming strains utilized the carbohydrates by pentose phosphate pathway mainly, as indicated by 23-33% higher enzyme activity compare to strains isolated from healthy women. Instead strains, isolated from women without reproductive tract dysbiosis, have higher activity of glycolytic enzymes on 13-28%. The prevalence of glycolytic transformation of glucose by strains isolated from healthy women also indicates by the depression of glucose oxidation during action of monoiodinacetate – classical inhibitor of glycolysis. It inhibit glycolysis of strains isolated from healthy women more significant. It was established that oxidase activity of film-forming strains isolated from women with dysbiosis, increased over 40% during the use of basic substrates of citric acid cycle. These data indicate a general increase of catabolic activity of oxidative type of staphylococci isolated during vaginal dysbiosis and able to form biofilm.

Capacitive micromachined ultrasonic transducers (CMUTs) exhibit wide-bandwidth and can be made into tiny 2-D arrays that are integrable with electronics. A simple implementation of such 2-D array is the row–column addressed CMUT array. However, one critical limitation of a row–column array is its narrow field of view, which can be improved by curving the array. This paper reports a novel fabrication method that realizes a flexible 32 + 32 elements row–column addressed CMUT array using a two stage fabrication process. First, a functional row–column CMUT array is fabricated with a double silicon-on-insulator wafer bonding process. The second stage involves encapsulating the device with a polymer coating, yet leaving the bottom silicon substrate exposed for wet etching. The bottom buried oxide layer will also act as an etch stop layer. Pitch-catch experiments are presented to verify the functionality. Our final device, excluding the encapsulation layer, is less than $5~\mu \text{m}$ thick with a 12.8-mm $\times \,\, 12.8$ -mm aperture. The final flexible device exhibits a 4.5-MHz center frequency with a −3-dB fractional bandwidth of 82%. [2015-0317]

Metal-intermetallic laminate composites are considered as promising materials for application in the aerospace industry. In this study, Ti-Al3Ti composites enclosed in titanium cases were produced by reactive spark plasma sintering. Sintering was carried out at 1103 K and 1323 K (830 °C and 1050 °C) for 10 minutes. In both cases, high-quality Ti-Al3Ti composites containing thin transition layers at the interfaces were obtained. Al2Ti, AlTi, and AlTi3 intermetallic phases and a solid solution of aluminum in titanium were observed in the transition layers by scanning and transmission electron microscopy. The material sintered at 1323 K (1050 °C) had higher strength in comparison with the composite obtained at 1103 K (830 °C). However, the hardness of the intermetallic component in the sample sintered at higher temperature decreased due to the grain growth. The impact toughness values of both materials were approximately identical.

The protein FcpA is a unique component of the flagellar filament of spirochete bacteria belonging to the genusLeptospira. Although it plays an essential role in translational motility and pathogenicity, no structures of FcpA homologues are currently available in the PDB. Its three-dimensional structure will unveil the novel motility mechanisms that render pathogenicLeptospiraparticularly efficient at invading and disseminating within their hosts, causing leptospirosis in humans and animals. FcpA fromL. interroganswas purified and crystallized, but despite laborious attempts no useful X ray diffraction data could be obtained. This challenge was solved by expressing a close orthologue from the related saprophytic speciesL. biflexa. Three different crystal forms were obtained: a primitive and a centred monoclinic form, as well as a hexagonal variant. All forms diffracted X-rays to suitable resolutions for crystallographic analyses, with the hexagonal type typically reaching the highest limits of 2.0 Å and better. A variation of the quick-soaking procedure resulted in an iodide derivative that was instrumental for single-wavelength anomalous diffraction methods.

Leptospirosis is a zoonotic disease that causes severe manifestations such as Weil's disease and pulmonary hemorrhage syndrome. The aim of this study was to evaluate whether reactive oxygen species (ROS) production and antioxidant reduced glutathione (GSH) levels are related to complications in patients hospitalized with leptospirosis. The ROS production and GSH levels were measured in blood samples of 12 patients and nine healthy controls using chemiluminescence and absorbance assays. We found that ROS production was higher and GSH levels were lower in leptospirosis patients compared with healthy individuals. Among patients, GSH depletion was correlated with thrombocytopenia and elevated serum creatinine, whereas a strong positive correlation was observed between ROS production and elevated serum potassium. Additional investigation of the biological significance of ROS production and GSH levels is warranted as they may guide the development of novel adjuvant therapies for leptospirosis targeting oxidative stress.

Computer models of the head can be used to simulate the events associated with traumatic brain injury (TBI) and quantify biomechanical response within the brain. Marmarou’s impact acceleration rodent model is a widely used experimental model of TBI mirroring axonal pathology in humans. The mechanical properties of the low density polyurethane (PU) foam, an essential piece of energy management used in Marmarou’s impact device, has not been fully characterized. The foam used in Marmarou’s device was tested at seven strain rates ranging from quasi-static to dynamic (0.014 ~ 42.86 s−1) to quantify the stress-strain relationships in compression. Recovery rate of the foam after cyclic compression was also determined through the periods of recovery up to three weeks. The experimentally determined stress-strain curves were incorporated into a material model in an explicit Finite Element (FE) solver to validate the strain rate dependency of the FE foam model. Compression test results have shown that the foam used in the rodent impact acceleration model is strain rate dependent. The foam has been found to be reusable for multiple impacts. However the stress resistance of used foam is reduced to 70% of the new foam. The FU_CHANG_FOAM material model in an FE solver has been found to be adequate to simulate this rate sensitive foam.

To study mechanisms that regulate the construction of inhibitory circuits, we examined the role of brain-derived neurotrophic factor (BDNF) in the assembly of GABAergic inhibitory synapses in the mouse cerebellar cortex. We show that within the cerebellum, BDNF-expressing cells are restricted to the internal granular layer (IGL), but that the BDNF protein is present within mossy fibers which originate from cells located outside of the cerebellum. In contrast to deletion of TrkB, the cognate receptor for BDNF, deletion of Bdnf from cerebellar cell bodies alone did not perturb the localization of pre- or postsynaptic constituents at the GABAergic synapses formed by Golgi cell axons on granule cell dendrites within the IGL. Instead, we found that BDNF derived from excitatory mossy fiber endings controls their differentiation. Our findings thus indicate that cerebellar BDNF is derived primarily from excitatory neurons—precerebellar nuclei/spinal cord neurons that give rise to mossy fibers—and promotes GABAergic synapse formation as a result of release from axons. Thus, within the cerebellum the preferential localization of BDNF to axons enhances the specificity through which BDNF promotes GABAergic synaptic differentiation.

Hot-melt pressure-sensitive adhesives (PSAs) advantageously reduce or eliminate the use of organic solvents. To provide for easy processing and good coating quality, hot-melt PSAs typically are relatively low in molecular weight, but this can compromise cohesive strength. Physical cross-linking and ionic cross-linking provide thermoreversible methods to increase cohesive strength. This study focuses on the use of acid/base interaction between two polymers as a possible route toward hot melt coatable acrylate PSAs. Adhesive performance and rheological data suggest that a good balance of properties can be obtained while maintaining melt processibility. The rheological data also clearly demonstrate that the strength of the acid/base interaction and the structure of the base have a significant effect on the final properties of the adhesive.

PubMed: 26091292 Pathogenic Leptospira species cause a prevalent yet neglected zoonotic disease with mild to life-threatening complications in a variety of susceptible animals and humans. Diagnosis of leptospirosis, which primarily relies on antiquated serotyping methods, is particularly challenging due to presentation of non-specific symptoms shared by other febrile illnesses, often leading to misdiagnosis. Initiation of antimicrobial therapy during early infection to prevent more serious complications of disseminated infection is often not performed because of a lack of efficient diagnostic tests. Here we report that specific regions of leptospiral 16S ribosomal RNA molecules constitute a novel and efficient diagnostic target for PCR-based detection of pathogenic Leptospira serovars. Our diagnostic test using spiked human blood was at least 100-fold more sensitive than corresponding leptospiral DNA-based quantitative PCR assays, targeting the same 16S nucleotide sequence in the RNA and DNA molecules. The sensitivity and specificity of our RNA assay against laboratory-confirmed human leptospirosis clinical samples were 64% and 100%, respectively, which was superior then an established parallel DNA detection assay. Remarkably, we discovered that 16S transcripts remain appreciably stable ex vivo, including untreated and stored human blood samples, further highlighting their use for clinical detection of L. interrogans. Together, these studies underscore a novel utility of RNA targets, specifically 16S rRNA, for development of PCRbased modalities for diagnosis of human leptospirosis, and also may serve as paradigm for detection of additional bacterial pathogens for which early diagnosis is warranted. Copyright: © 2015 Backstedt et al. National Institute of Allergy and Infectious Diseases: 1R43AI114064-01 National Institute of Allergy and Infectious Diseases: AI052473 National Institute of Allergy and Infectious Diseases: AI088752 National Institute of Allergy and Infectious Diseases: AI114064-01 National Institute of Allergy and Infectious Diseases: TW009504 Yale University

Addition of sulfonyl carbanions with or without an electrophilic tether has been shown, under certain conditions, to add to α,β-unsaturated oxazolines in good yields and high de's. When 4-bromobutylsulfonyl carbanions are added to unsaturated oxazolines, three contiguous stereocenters are formed and good yields of 1,2,3-substituted cyclohexanes are obtained as a 5:1 mixture of only two diastereomers. The sulfonyl substituent may be reductively cleaved to form selectively 1,2-disubstituted cyclohexanes.

Background Leptospirosis, a re-emerging disease of global importance caused by pathogenic Leptospira spp., is considered the world's most widespread zoonotic disease. Rats serve as asymptomatic carriers of pathogenic Leptospira and are critical for disease spread. In such reservoir hosts, leptospires colonize the kidney, are shed in the urine, persist in fresh water and gain access to a new mammalian host through breaches in the skin. Methodology/Principal Findings Previous studies have provided evidence for post-translational modification (PTM) of leptospiral proteins. In the current study, we used proteomic analyses to determine the presence of PTMs on the highly abundant leptospiral protein, LipL32, from rat urine-isolated L. interrogans serovar Copenhageni compared to in vitro-grown organisms. We observed either acetylation or tri-methylation of lysine residues within multiple LipL32 peptides, including peptides corresponding to regions of LipL32 previously identified as epitopes. Intriguingly, the PTMs were unique to the LipL32 peptides originating from in vivo relative to in vitro grown leptospires. The identity of each modified lysine residue was confirmed by fragmentation pattern analysis of the peptide mass spectra. A synthetic peptide containing an identified tri-methylated lysine, which corresponds to a previously identified LipL32 epitope, demonstrated significantly reduced immunoreactivity with serum collected from leptospirosis patients compared to the peptide version lacking the tri-methylation. Further, a subset of the identified PTMs are in close proximity to the established calcium-binding and putative collagen-binding sites that have been identified within LipL32. Conclusions/Significance The exclusive detection of PTMs on lysine residues within LipL32 from in vivo-isolated L. interrogans implies that infection-generated modification of leptospiral proteins may have a biologically relevant function during the course of infection. Although definitive determination of the role of these PTMs must await further investigations, the reduced immune recognition of a modified LipL32 epitope suggests the intriguing possibility that LipL32 modification represents a novel mechanism of immune evasion within Leptospira., Author Summary Leptospirosis, caused by pathogenic Leptospira spp., constitutes an increasing global public health threat. Humans are accidental hosts, and acquire the disease primarily from contact with water sources that have been contaminated with urine from infected animals. Rats are asymptomatic carriers of infection and are critical for disease transmission to humans, particularly in urban slum environments. In this study, investigation of Leptospira directly isolated from the urine of infected rats showed acetylation or tri-methylation of the highly abundant leptospiral lipoprotein, LipL32. In comparison, Leptospira grown in culture did not result in any LipL32 lysine modifications. A synthetic peptide derived from LipL32 that incorporated a tri-methylated lysine modification exhibited less reactivity with serum from leptospirosis patients compared to an unmodified version of the peptide, suggesting LipL32 modifications may alter protein recognition by the immune response. This study reports, for the first time, modification of a Leptospira protein during infection, and suggests these modifications may have a functional consequence that contributes to bacterial persistence during infection.

The potential use of waste tyre rubber granules (WTRG) for the batch adsorption of naphthalene from aqueous solutions was investigated. The effect of various operational variables such as contact time, initial naphthalene concentration, adsorbent dose, size of adsorbent particles, and temperature of solution on the adsorption capacity of WTRG was evaluated. The adsorption of naphthalene by WTRG was a fast kinetic process with an equilibrium contact time of 60 min. A low temperature (5°C), small adsorbent particle size (0.212 mm) and higher adsorbent dosage favored the adsorption process. Results of isotherm studies revealed that adsorption of naphthalene was best described by the Langmuir isotherm equation (R2=0.997) while the kinetics of the process was best described by the Lagergren pseudofirst order kinetic equation (R2=0.998). This study has demonstrated the suitability of WTRG for the removal of naphthalene from aqueous solution.

Synthesis of protected tetradehydro-(6,6'-S)-(14,14'-S)-(16,16'-R)-disorazole (3), a potential precursor to the natural product disorazole C1 (1), is described. Key features of this work include (a) an unprecedented sequential 1,5 O --O silyl rearrangement/Horner-Wadsworth-Emmons reaction used to construct 18, (b) a highly convergent Sonogashira reaction between the dienyl iodide 7 and the alkyne 8 to assemble the dienyne monomeric fragment 5, and (c) the selective cyclization of 5 to give either the cyclic monomer 23 or the dimer 3.

Three enantiomerically and geometrically pure building blocks representing fragments of the antifungal antibiotic viridenomycin have been prepared.

A second generation approach toward the synthesis of viridenomycin is described. Three key fragments of the molecule have been synthesized in stereochemically pure form. Initial studies toward the coupling of these fragments with the aim of assembling the macrocycle are detailed. Final efforts to reach the title compound are documented.

Objective: To describe the use of multiple nonsteroidal antiinflammatory drugs (NSAIDs) and the cost implications in a Medicare managed care population. Design: Retrospective analysis of prescription drug database records. Setting: Three Medicare managed care plans in the West and South. Patients: The population consisted of 22,544 patients who filled prescriptions for one or more different nonaspirin NSAIDs during a six-month period beginning March 1, 1998. Main Outcome Measure: Prescriptions for nonaspirin NSAIDs, misoprostol, proton-pump inhibitors, sucralfate, and analgesic drugs. Results: A total of 12.6% of individuals filled prescriptions for two different NSAIDs, and 2.3% filled prescriptions for between three and five different NSAIDs. As the number of NSAIDs increased from one to five, there was a decrease in the generic:brand-name ratio from 4.3:1 to 0.93:1, an increase in the total days' supply from 39 to 310 days (for the 180-d period), an eightfold increase in the coprescription of misoprostol, a twofold increase in coprescription of analgesics, and an increase in payments per person for all NSAIDs and listed coprescribed drugs from $51.67 to $403.00. Conclusions: A small subset of individuals in Medicare health plans fill prescriptions for multiple NSAIDs, concomitant with increased use of brand-name drugs, increased coprescription of misoprostol and analgesics, and increased drug costs. Healthcare providers should scrutinize this population and consider whether alternative therapeutic approaches might be appropriate.

Cyclobutannulation of the bicyclic lactam with allyldimethyltritylsilane is accomplished in high yield with good diastereoselectivity. The resulting tricyclic system is converted to a enantiomerically pure cyclobutane-fused pyrrolidine.

The enantioselective synthesis of branched polyhydroxylated pyrrolidines from a novel α-methylene bicyclic lactam (4b) is described.

Chiral 3-alkyl-3-arylpyrrolidines were prepared from the substituted bicyclic lactams. Stereoselectivity in the alkylation of bicyclic lactams was improved by using an alkyl triflate or tosylate as the electrophile.

The enantioselective synthesis of (+)-euphococcinine (1), a homotropane alkaloid, has been achieved in five steps from bicyclic lactam 5.

The asymmetric synthesis of the hydroindolone core ( 5 ) of the Amaryllidaceae alkaloids employing chiral bicyclic lactams is described. The vicinal quaternary and tertiary stereocenters were assembled via an addition of lactam 14 enolate to acrolein.

A remote steric effect in the bicyclic lactam oxazolidine ring has been shown to affect the stereochemical outcome in the thio-Claisen rearrangement taking place in the piperidone ring.

Pd, Ni, and Lewis acid catalyzed rearrangements occur under milder conditions than the thermal version of the titled rearrangements.

Reactions of aliphatic isocyanates with a phenolic ester alcohol (PHEA) were investigated using 13C-NMR spectroscopy. PHEA has two reactive sites: a phenolic OH group and a secondary aliphatic OH group. Both OH groups react with the isocyanate groups. With an organotin catalyst, dibutyltin dilaurate (DBTDL), the aliphatic OH group reacts first. With a tertiary amine catalyst, 1,4-diazabicyclo[2.2.2]octane (DABCO), or triphenylphosphine (Ph3P) or even in the absence of a catalyst at room temperature (RT) the phenolic OH group reacts first. With the organotin catalyst, the reactions are generally complete in a day at RT. With DABCO or triphenylphosphine or DNNDSA catalysts, the reactions are almost complete only in 3–4 days at RT in ethyl acetate or acetonitrile. Uncatalyzed reactions are slower. With an acid catalyst such as dinonylnaphthalenedisulfonic acid (DNNDSA), both OH groups react with the isocyanate. When equimolar quantities of PHEA and hexamethylenediisocyanate (HDI) polymerize at RT or reflux in the presence of a catalyst, both OH groups react, with the phenol reacting slowly. Upon refluxing, the phenolic OH-based urethane slowly rearranges (transcarbamoylation) to the aliphatic OH-based urethane. DABCO and Ph3P catalysts effect this rearrangement at a much slower rate than does the acid catalyst. In the presence of a catalytic amount of DBDTL in a refluxing solvent, this rearrangement is complete in 2 h. By refluxing the phenolic–OH-based urethane in isopropanol, the mechanism of transcarbamoylation was found to be intermolecular. The mechanism is likely to involve deblocking of the phenolic urethane and subsequent reaction of the isocyanate generated, with the aliphatic OH group. This conclusion was confirmed by differential scanning calorimetry (DSC) experiments. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 2212–2228, 2000

Enantiomerically pure cis -2,4-disubstituted piperidines were synthesized from chiral thiolactam 2 in six steps via a highly diastereoselective homoenolate alkylation which set the stereochemistry at the C4 carbon. In addition, two cleavage methods were used to cleave the lactam to the desired piperidines with a high level of diastereoselection at the newly created C2 stereocenter.

A remote steric effect in the Sakurai addition to unsaturated esters containing small to large alkyl groups has been detected which leads to either cyclobutane or allyl adducts.

Axially chiral binaphthyls 3a and 3b were synthesized taking, advantage of Ullman coupling of 4a and 4b, respectively. The binaphthyls were shown to be stable to atropisomerization. Binaphthol 3b was resolved with (−)-(1S)-menthyl chloroformate (11). R-axis diastereomer of bisoxazoline 3b was used for enantioselective cyclopropanation of styrene with ethyl diazoacetate.

By employing the appropriate chiral bicyclic lactams, the asymmetric total synthesis of four enantiopure azasugars mentioned in the title were successfully achieved. A series of diastereoselective oxidations ( OsO 4 NMO ) followed by diastereoselective reductions (BH3, 9-BBN) gave good yields of the trisubstituted (16) and tetrasubstituted (2,3,4) pyrrolidine and piperidines respectively.

A novel asymmetric oxazoline ketenimine rearrangement has been observed to construct α-quaternary substituted ketones. Levels of asymmetric induction in the ketones, of up to 87% ee, were observed for this unusual rearrangement.

Using chiral bicyclic lactams, containing an α,β-unsaturation, the key precursor of (−)-indolizomycin was obtained in optically pure form. The sequence involved a > 20:1 diastereoselective cyclopropanation of the unsaturated lactam 5 employing sulfoxonium methylide. TiCl 4 mediated addition of allyltrimethylsilane afforded pyrrolidone 7 in a diastereomeric ratio of > 20:1. The appropriately substituted pyrrolidone 2 was prepared by debenzylation and subsequent alkylation with 3-bromoproponic ester. The six step sequence from commercially available starting materials was performed in 26% overall yield.

Sequential allylation of chiral, nonracemic thiolactam 8 affords clean thio-Claisen [3,3] products 11. The stereoselectivity of the rearrangement was found to be on the order of 10-11:1, with the exo-endo products responsible for the mixture. Addition of hydride or methyllithium-cerium chloride gave clean addition to the thiolactam in the form of its iminium salts 12. Hydrolysis gave 4,4-dialkylcyclohexenones 15, which were cyclized to the cyclopentene derivatives 16 using Grubbs' catalyst.

Two synthetic approaches to the title compounds using the chiral non-racemic lactam 3 via additions to the lactam carbonyl lead to the requisite chiral cyclohexen-2-ones.