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Methanogens are restricted to a few genera of Archaea, however they have great importance in the carbon cycle, impacting climactic considerations, and also find a role in renewable energy in the form of biogas. Here, we examine the microbial contribution to the production of methane in a sargassum fed anaerobic saltwater bioreactor, which are poorly characterized compared to fresh water bioreactors, using a comprehensive functional metagenomics approach. Despite abundant production of methane, we detected a low proportion of Archaea in the system using 16S rRNA community profile analyses. We address the low representation using an additional 16S rRNA analysis of shotgun data and a consideration of CO2:CH4production. Using a novel network alignment and tree building approach, we measured similarity between the meta-metabolic capabilities of different anaerobic microbial communities. The saltwater bioreactor samples clustered together, validating the approach and providing a method of determining meta-metabolic similarity between microbial communities, with a range of potential applications. We also introduce a number of additional approaches for examining and interpreting meta-metabolic network topology. The low abundance of methanogens appears as a common property of such anaerobic systems and likely reflects the relatively poor energetics of methanogens, while examination of key enzymes confirms that hydrogen producing bacteria are the major fermentative guild. Our results indicate that the use of readily available seawater and marine macroalgae is a promising approach to the production of biogas as a source of renewable energy.

We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship established with an oral phosphatidylinositol 3-kinase (PI3K)δ inhibitor (Idelalisib) in a nasal allergen challenge study to determine whether a comparable PK/PD/efficacy relationship with PI3Kδ inhibitors was observed in preclinical respiratory models of type 2 T helper cell (TH2) and type 1 T helper cell (TH1) inflammation. Results from an in vitro rat blood basophil (CD63) activation assay were used as a PD biomarker. IC50 values for PI3Kδ inhibitors, MSD-496486311, MSD-126796721, Idelalisib, and Duvelisib, were 1.2, 4.8, 0.8, and 0.5 μM. In the ovalbumin Brown Norway TH2 pulmonary inflammation model, all PI3Kδ inhibitors produced a dose-dependent inhibition of bronchoalveolar lavage eosinophils (maximum effect between 80% and 99%). In a follow-up experiment designed to investigate PK attributes [maximum (or peak) plasma concentration (Cmax), area under the curve (AUC), time on target (ToT)] that govern PI3Kδ efficacy, MSD-496486311 [3 mg/kg every day (QD) and 100 mg/kg QD] produced 16% and 93% inhibition of eosinophils, whereas doses (20 mg/kg QD, 10 mg/kg twice per day, and 3 mg/kg three times per day) produced 54% to 66% inhibition. Our profiling suggests that impact of PI3Kδ inhibitors on eosinophils is supported by a PK target with a ToT over the course of treatment close to the PD IC50 rather than strictly driven by AUC, Cmax, or Cmin (minimum blood plasma concentration) coverage. Additional studies in an Altenaria alternata rat model, a sheep Ascaris-sensitive sheep model, and a TH1-driven rat ozone exposure model did not challenge our hypothesis, suggesting that an IC50 level of TE (target engagement) sustained for 24 hours is required to produce efficacy in these traditional models. We conclude that the PK/PD observations in our animal models appear to align with clinical results associated with a TH2 airway disease.

[Image: see text] A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.

As the Oil and Gas Industry continues to evolve, operators are pushing the limit to lengthen their reach in the reservoir to contact more payzone. Correspondingly, challenges for traditional downhole operations are steadily increasing. One of the more significant challenges is coiled tubing's ability to reach target depth. This has flooded the industry with a number of vibratory tools which would enable the traditional practices of coiled tubing to continue. A study of vibratory tools was conducted on five wells in the Eagle Ford field. The purpose of the vibratory tool study was to gain a better understanding of top competing tools and how they compared. A total of five different wells were drilled out. Four of the five wells were drilled out using different vibratory tools while one of the wells was drilled out without any vibratory tool. While the wellbore geometries varied slightly, general characteristics remained consistent. The four tools chosen for the trial were identified as top competing tools in the industry for the Eagle Ford area. Three of the tools used exerted an axial force on the coiled tubing while the fourth tool exerted a radial / lateral force. The trial well with no tool used friction reducer in place of the vibratory tool. Coiled tubing was only successful at reaching bottom on three out of the five trial wells. While results are inconclusive as to what "the best" tool is; they certainly can provide contrast between each tool. Certain variables such as the wellbore geometry, inconsistencies in chemical usage and fluid condition differed from well to well and may have played a role in a tool's performance. Despite these differences, the tool that performed considerably well has a fluidic design and operates with no moving parts.

A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified.

In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed.

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor that has been reported to modulate inflammatory responses in various rodent models of asthma, allergic rhinitis and atopic dermatitis. In this study, we describe the biological and pharmacological properties of {(7R)-7-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetic acid (MK-7246), a novel synthetic CRTH2 antagonist. We show that MK-7246 1) has high affinity for the human, monkey, dog, rat, and mouse CRTH2, 2) interacts with CRTH2 in a reversible manner, 3) exhibits high selectivity over all prostanoid receptors as well as 157 other receptors and enzymes, 4) acts as a full antagonist on recombinant and endogenously expressed CRTH2, 5) demonstrates good oral bioavailability and metabolic stability in various animal species, 6) yields ex vivo blockade of CRTH2 on eosinophils in monkeys and sheep, and 7) significantly blocks antigen-induced late-phase bronchoconstriction and airway hyper-responsiveness in sheep. MK-7246 represents a potent and selective tool to further investigate the in vivo function of CRTH2.

We describe herein a novel series of 3-amino-4-hydrazine-cyclobut-3-ene-1,2-diones as potent and selective inhibitors against the CXCR2 chemokine receptor and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Furthermore, these alkyl-hydrazine series inhibitors such as 5b demonstrated acceptable metabolic stability when incubated in human and rat microsomes.

Chronic obstructive pulmonary disease (COPD) is characterized by the degradation of elastin, the major insoluble protein of lung tissues. The degradation of elastin gives rise to desmosine (DES) and isodesmosine (IDES), two major urinary products typified by a hydrophilic pyridinium-based cross-linker structure. A high sensitivity method based on nanoflow liquid chromatography tandem mass spectrometry with multiple reaction monitoring was developed for the analysis of urinary DES and IDES. The analytes were derivatized with propionic anhydride and deuterated DES (D(4)-DES) was used as an internal standard. This method enables the quantification of DES and IDES in as little as 50 microL of urine and provides a detection limit of 0.10 ng/mL (0.95 fmol on-column). We report the analysis of DES and IDES in a cohort of 40 urine specimens from four groups of individuals: (a) COPD rapid decliners (11.8 +/- 3.7 ng/mg creatine (crea)), (b) COPD slow decliners (16.0 +/- 3.1 ng/mg crea), (c) healthy smokers (13.2 +/- 1.9 ng/mg crea), and (d) healthy nonsmokers (14.9 +/- 2.9 ng/mg crea). Our analysis reveals a statistically significant decrease in the level of urinary DES and IDES in COPD rapid decliner patients compared to healthy nonsmoker controls and COPD slow decliner patients. This methodology may be useful for monitoring DES and IDES levels in well controlled animal models for COPD or for longitudinal studies in COPD patients.

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor whose function in vivo has been incompletely characterized. One of the reasons is that its current known ligands, prostaglandin D(2) and some of its metabolites, have either poor selectivity for CRTH2 or are metabolically unstable in vivo. In this study, we describe the biological and pharmacological properties of L-888,607, the first synthetic potent and selective CRTH2 agonist. We show that L-888,607 exhibits 1) subnanomolar affinity for the human CRTH2 receptor, 2) high selectivity over all other prostanoid receptors and other receptors tested, 3) agonistic activity on recombinant and endogenously expressed CRTH2 receptor, and 4) relative stability in vivo. L-888,607 thus represents a suitable tool to investigate the in vivo function of CRTH2.

Rationale Prostaglandin D 2 (PGD 2 ) is released from mast cells during the allergic response. Since PGD 2 has been shown to induce nasal congestion in humans, we investigated the distribution of hematopoietic Prostaglandin D synthase (PGDS) and the two PGD 2 receptors, DP and CRTH2 in human nasal mucosa from healthy subjects and subjects suffering from polyposis, a severe form of chronic rhinosinusitis. Methods DP mRNA expression was detected by in situ hybridization while PGDS, CRTH2 and various leukocyte markers expression was revealed by immunohistochemistry. Results In the normal mucosa, PGDS was only detected in few resident mast cells while CRTH2 was undetectable. In contrast, DP receptor mRNA was detected in epithelial goblet cells, serous glands and in the vasculature. In the nasal mucosa of subjects suffering from polyposis: 1) PGDS was detected in mast cells and other large infiltrating inflammatory cells, 2) both DP mRNA and CRTH2 were detected in eosinophils and 3) CRTH2 was detected on a subset of infiltrating T-cells. Although DP mRNA could not be detected in the T-cells invading the nasal mucosa, it was found to be expressed in the T-cells present in the lymph node and the thymus from normal individuals. Conclusions This study indicates that cells capable of producing PGD 2 are present in the nasal mucosa and that both PGD 2 receptors, DP and CRTH2, might play a role in inflammatory disease of the upper airways.

1. The recombinant human prostaglandin D(2) (PGD(2)) receptor, hCRTH2, has been expressed in HEK293(EBNA) and characterized with respect to radioligand binding and signal transduction properties. High and low affinity binding sites for PGD(2) were identified in the CRTH2 receptor population by saturation analysis with respective equilibrium dissociation constants (K(D)) of 2.5 and 109 nM. This revealed that the affinity of PGD(2) for CRTH2 is eight times less than its affinity for the DP receptor. 2. Equilibrium competition binding assays revealed that of the compounds tested, only PGD(2) and several related metabolites bound with high affinity to CRTH2 (K(i) values ranging from 2.4 to 34.0 nM) with the following rank order of potency: PGD(2)>13,14-dihydro-15-keto PGD(2)>15-deoxy-Delta(12,14)-PGJ(2)>PGJ(2)>Delta(12)-PGJ(2)>15(S)-15 methyl-PGD(2). This is in sharp contrast with the rank order of potency obtained at DP : PGD(2)>PGJ(2)>Delta(12)-PGJ(2)>15-deoxy-Delta(12,14)-PGJ(2) >>>13,14-dihydro-15-keto-PGD(2). 3. Functional studies demonstrated that PGD(2) activation of recombinant CRTH2 results in decrease of intracellular cAMP in a pertussis toxin-sensitive manner. Therefore, we showed that CRTH2 can functionally couple to the G-protein G(alphai/o). PGD(2) and related metabolites were tested and their rank order of potency followed the results of the membrane binding assay. 4. By Northern blot analysis, we showed that, besides haemopoietic cells, CRTH2 is expressed in many other tissues such as brain, heart, thymus, spleen and various tissues of the digestive system. In addition, in situ hybridization studies revealed that CRTH2 mRNA is expressed in human eosinophils. Finally, radioligand binding studies demonstrated that two eosinophilic cell lines, butyric acid-differentiated HL-60 and AML 14.3D10, also endogenously express CRTH2.

Background: PGD 2 is the major prostanoid released by mast cells during an allergic response. Its role in the allergic response, however, remains unclear. Objective: Because the accumulation of eosinophils is a feature of allergic reactions, we investigated the role of PGD 2 in the modulation of eosinophil function. Methods: Circulating human eosinophils were isolated and challenged with PGD 2 . The effects of PGD 2 on various eosinophil functions were then analyzed. Results: PGD 2 binds with high affinity preferentially to 2 receptors, DP and chemoattractant receptor-homologous molecule expressed on T H 2 cells (CRTH2). We show that both DP and CRTH2 are detectable on circulating eosinophils. We demonstrate that PGD 2 (1-10 nmol/L) induces a rapid change in human eosinophil morphology and an increase in chemokinesis and promotes eosinophil degranulation. These effects are induced by the CRTH2-selective agonist 13-14-dihydro-15-keto-PGD 2 (DK-PGD 2 ) but not by the DP-selective agonist BW245C. These results suggest a role for CRTH2 in the modulation of eosinophil movement and in triggering the release of cytotoxic proteins. Finally, we demonstrate that BW245C, but not DK-PGD 2 , can delay the onset of apoptosis in cultured eosinophils, presumably through interaction with DP. Conclusion: These data support the hypothesis that PGD 2 controls eosinophil functions through 2 pharmacologically distinct receptors with independent functions. Blockade of PGD 2 -mediated effects on human eosinophils may reduce the damage caused by these cells during an allergic response, but inhibition of both receptors may be required. (J Allergy Clin Immunol 2001;108:982-8.)

We commend Baum and colleagues (2009) for undertaking a much-needed exploratory examination of public opinion concerning social distancing during a pandemic. We concur with Baum and colleagues and ...

The ground-state band of the Z=102 isotope {sup 254}No has been identified up to spin 14, indicating that the nucleus is deformed. The deduced quadrupole deformation, {beta}=0.27 , is in agreement with theoretical predictions. These observations confirm that the shell-correction energy responsible for the stability of transfermium nuclei is partly derived from deformation. The survival of {sup 254}No up to spin 14 means that its fission barrier persists at least up to that spin. {copyright} {ital 1999} {ital The American Physical Society }

Malm and colleagues (2008) provide a valuable and compelling analysis of the effectiveness and feasibility of different strategies for establishing a duty to work during a severe pandemic. To encou...

Results are presented of a systematic survey of {Delta}I=4 bifurcation in 19 superdeformed bands in A{approximately}150 Eu and Gd nuclei. The majority of bands show no sign of this regular oscillation in energy levels. The statistical significance of the few examples that exhibit the effect is examined. {copyright} {ital 1998} {ital The American Physical Society}

Focal adhesion kinase (Fak) is a non-receptor protein-tyrosine kinase that stimulates cell spreading and motility by promoting the formation of contact sites between the cell and the extracellular matrix (focal adhesions). It suppresses apoptosis by transducing survival signals that emanate from focal adhesions via the clustering of transmembrane integrins by components of the extracellular matrix. We demonstrate that Fak is cleaved by caspases at two distinct sites during apoptosis. The sites were mapped to DQTD772, which was preferentially cleaved by caspase-3, and VSWD704, which was preferentially cleaved by caspase-6 and cytotoxic T lymphocyte-derived granzyme B. The cleavage of Fak during apoptosis separates the tyrosine kinase domain from the focal adhesion targeting (FAT) domain. The carboxyl-terminal fragments that are generated suppress phosphorylation of endogenous Fak and thus resemble a natural variant of Fak, FRNK, that inhibits Fak activity by preventing the localization of Fak to focal adhesions. The cleavage of Fak by caspases may thus play an important role in the execution of the suicide program by disabling the anti-apoptotic function of Fak. Interestingly, rodent Fak lacks an optimal caspase-3 consensus cleavage site although it is cleaved in murine cells undergoing apoptosis at an upstream site. This appears to be the first example of a caspase substrate where the cleavage sites are not conserved between species.

Eight superdeformed bands have been observed in the nuclei {sup 147,148}Eu. Some of these are identical to bands in the Z+1 nuclei {sup 148,149}Gd, and are interpreted as having the same single-particle configurations with the exception of a hole in one of the [301]1/2 proton orbitals. Some of the bands in {sup 147}Eu exhibit either upbends or downbends in their moments of inertia which are related to the crossing of {pi}6{sup 1} and {pi}6{sup 3} proton intruder configurations. These results constitute the first evidence of this crossing. {copyright} {ital 1998} {ital The American Physical Society}

{Delta}I=4 bifurcation has been observed in two superdeformed bands, the newly discovered yrast superdeformed band of {sup 148}Eu, and a previously known excited band in {sup 148}Gd. Both of these bands have moments of inertia that are identical to the yrast band of {sup 149}Gd, the first superdeformed band in which this bifurcation was observed. This first observation of {Delta}I=4 bifurcation in identical superdeformed bands provides a crucial test of recent models. {copyright} {ital 1997} {ital The American Physical Society}

To further understand the functional interactions between CD45 and p56(lck) in T-cells, we stably reconstituted their expression in a nonlymphoid system. The results of our analyses demonstrated that CD45 could dephosphorylate tyrosine 505 of p56(lck) in NIH 3T3 fibroblasts. As is the case for T-cells, removal of the unique domain of p56(lck) interfered with dephosphorylation of tyrosine 505 in fibroblasts, further stressing the importance of this region in the interactions between CD45 and p56(lck). The ability of CD45 to dephosphorylate tyrosine 505 in NIH 3T3 cells was also greatly influenced by the catalytic activity of p56(lck). Indeed, whereas CD45 provoked dephosphorylation of kinase-defective Lck molecules in this system, it failed to stably dephosphorylate kinase-active p56(lck) polypeptides. Finally, our studies showed that CD45 was also able to inhibit the oncogenic potential of a constitutively activated version of p56(lck) in NIH 3T3 cells. This effect did not require the Lck unique domain and apparently resulted from selective dephosphorylation of substrates of activated p56(lck) in fibroblasts. In addition to providing insights into the nature and regulation of the interactions between CD45 and p56(lck) in T-cells, these results indicated that CD45 clearly has the capacity to both positively and negatively regulate p56(lck)-mediated functions in vivo.

International audience; This article presents a methodology developed in order to identify the potential by-products of emerging chemical pollutants generated during oxidation treatments like chlorination and ozonation. As an example, the study of ozonated real river water samples spiked with estrone sulfate (E1-S) was used to evaluate the impact of ozonation on E1-S concentration and to identify the generated treatment by-products (TBPs). After a large-scale solid phase extraction, samples were analyzed by liquid chromatography coupled with high resolution mass spectrometry (HRMS) and data were processed according to a differential metabolomic-like approach to uncover the produced compounds. Four main TBPs were found. ER alpha-CALUX bioassays were performed to measure the estrogenic potency of samples before and after treatment. Results show that the estrogenic potency decreases drastically in drinking water with ozonation.

A review of human fetal tissue policies over the past 40 years reveals an increasing awareness that the use of this tissue raises unique ethical and policy issues. Initially it was believed that the use of fetal tissue was no different from using any other abandoned surgical waste specimen. Then state laws were passed requiring fetal tissue to be treated with the same respect and protection as tissue obtained from cadaver donors generally. Most recently, a few state and federal policies suggest that the use of fetal tissue requires a unique set of provisions, that it is unlike either the use of tissue from a routine cadaver donor or the use of tissue from abandoned waste specimens. In this paper we identify four central features of fetal tissue donation that make it a unique type of tissue donation requiring its own framework of respect and protection for the parties involved. We then critically review the most important current state and federal fetal tissue policies, including the NIH Revitalization Act of 1993.

The catalytic function of Src-related tyrosine protein kinases is repressed by phosphorylation of a conserved carboxy-terminal tyrosine residue. Recent studies suggest that this inhibitory event is not the result of autophosphorylation but that it is mediated by another cytoplasmic tyrosine protein kinase, termed p50csk. In this report, we have evaluated the processes regulating the extent of phosphorylation of the inhibitory carboxy-terminal tyrosine residue of p56lck, a lymphocyte-specific member of the Src family. By analyzing kinase-defective variants of p56lck expressed in mouse NIH 3T3 cells, we have found that the noncatalytic Src homology 2 (SH2) domain, but not the SH3 sequence or the sites of Lck myristylation and autophosphorylation, is necessary for stable phosphorylation at the carboxy-terminal tyrosine 505. Further studies in which Lck and Csk were coexpressed in S. cerevisiae indicated that the absence of the SH2 domain did not affect the ability of Csk to phosphorylate p56lck at tyrosine 505. However, we observed that incubation of cells with the tyrosine phosphatase inhibitor pervanadate restored the tyrosine 505 phosphorylation of Lck polypeptides devoid of the SH2 motif. Additionally, the presence of the SH2 sequence protected tyrosine 505 from in vitro dephosphorylation by the hemopoietic tyrosine protein phosphatase CD45. Taken together, these findings raised the possibility that the SH2 motif contributes to the physiological suppression of the catalytic function of p56lck at least in part through its ability to stabilize phosphorylation at the inhibitory site.

A new class of 7-azaindole analogs of MK-7246 as potent and selective CRTH2 antagonists is reported. The SAR leading to the identification of the optimal azaindole regioisomer as well as the pharmacokinetics and off-target activities of the most potent antagonists are disclosed.

Chronic obstructive pulmonary disease (COPD) is a prevalent pulmonary disease characterized by a progressive decline in lung function. The identification of biomarkers capable of predicting the rate of lung function decline or capable of giving an early read on drug efficacy in clinical trials would be very useful. The aim of this study was to identify plasma biomarkers capable of accurately distinguishing patients with COPD from healthy controls. Eighty-nine plasma markers in 40 COPD patients and 20 healthy smoker controls were analyzed. The COPD patients were divided into two subgroups, rapid and slow decliners based on their rate of lung function decline measured over 15 years. Univariate analysis revealed that 25 plasma markers were statistically different between rapid decliners and controls, 4 markers were different between slow decliners and controls, and 10 markers were different between rapid and slow decliners (p < 0.05). Multivariate analysis led to the identification of groups of plasma markers capable of distinguishing rapid decliners from controls (signature 1), slow decliners from controls (signature 2) and rapid from slow decliners (signature 3) with over 90% classification accuracy. Importantly, signature 1 was shown to be longitudinally stable using plasma samples taken a year later from a subset of patients. This study describes a novel set of plasma markers differentiating slow from rapid decline of lung function in COPD. If validated in distinct and larger cohorts, the signatures identified will have important implications in both disease diagnosis, as well as the clinical evaluation of new therapies.

A new gene, designated rcsF, was located adjacent to drpA at the 5.2-min position of the genetic map of Escherichia coli. The deduced amino acid sequence encoded by the rcsF gene indicates a small protein of 133 amino acid residues with a calculated pI of 10.8 that is rich in proline, serine, alanine, and cysteine residues. When overexpressed as a result of its presence on a multicopy plasmid, rcsF confers a mucoid phenotype and restores colony formation to ftsZ84 mutant cells on L agar medium containing no added NaCl. These two phenotypes are not observed in rcsB mutant cells. Ion mutant cells harboring an rcsF mutation accumulate considerably lower levels of exopolysaccharides, whereas the presence of a multicopy rcsF plasmid not only increases capsule synthesis but also confers a mucoid phenotype at 37 degrees C, a temperature at which ion mutant cells are known not to form mucoid colonies. RcsF does not stimulate the expression of rcsB, indicating that it exerts its action through the RcsB protein, possibly by phosphorylation. It is also shown that RcsF stimulation of capsule synthesis is RcsA-dependent, whereas colony formation of ftsZ84 mutant cells can be restored by RcsF in the absence of RcsA.

Although the timing and severity of the next influenza pandemic is impossible to predict, there is broad agreement that one will occur. Preparation is vital to mitigating its effects. A severe influenza pandemic like that which began in 1918 would be unlike other disasters in nature, scale, and duration. It could cripple normal business operations and disrupt global distribution of essential goods and services. It could force ethical decisions that many in a country accustomed to relative abundance are poorly prepared to make. Although sound evidence and clinical and public health expertise are needed to make informed decisions, so is an understanding of our common and diverse values. This article outlines some of the challenges the state would face during a pandemic, especially concerning the rationing of resources and care. It also describes a process currently underway to develop guidelines for how the state should approach the ethical questions that would arise.

Using a tilted-field geometry, the effect of an in-plane magnetic field on the even denominator nu=5/2 fractional quantum Hall state is studied. The energy gap of the nu=5/2 state is found to collapse linearly with the in-plane magnetic field above approximately 0.5 T. In contrast, a strong enhancement of the gap is observed for the nu=7/3 state. The radically distinct tilted-field behavior between the two states is discussed in terms of Zeeman and magneto-orbital coupling within the context of the proposed Moore-Read Pfaffian wave function for the 5/2 fractional quantum Hall effect.

A multiresidue analysis method has been developed for the determination of pesticides in water by ultra-performance liquid chromatography (UPLC) combined with tandem mass spectrometry (MS/MS). The selected pesticides represent a broad range of polarity and volatility [benzoylcyclohexanedione (mesotrione and sulcotrione); chloroacetamide (acetochlor, alachlor, dimethenamide, and metolachlor); phenoxyacetic acid (2,4-D and MCPA); phenoxypropionic (dichloprop and mecoprop); phenylurea (chlortoluron, diuron, isoproturon, linuron, and metoxuron); sulfonylurea (foramsulfuron, iodosulfuron, and nicolsulfuron); triazine (atrazine, cyanazine, desethylatrazine (DEA), desisopropylatrazine (DIA), simazine, and terbutylazine)]. The analytes were extracted using solid-phase extraction (SPE). The separation was carried out on an acquity UPLC BEH C18 column (1.7 μm, 50 mm × 1 mm ID) using a gradient elution profile and mobile phase consisting of 0.1% formic acid in water and acetonitrile. The pesticides were detected with a tandem mass spectrometer after being ionised positively or negatively (depending on the molecule) using an electrospray ionisation (ESI) source. To achieve the suitable extraction conditions for sample preparation, several parameters affecting the efficiency of SPE such as the nature of the sorbent and the eluent, extractant volume and pH were studied. The best recovery was obtained by the extraction with an Oasis HLB cartridge and 3 mL of a solution of acetonitrile/dichloromethane (1:1, v/v) at pH 2. The average recoveries of the pesticides in different samples ranged from 82 to 109%. The weight least squares (WLS) linear regression was used to calculate the limits of detection and quantification (LOD and LOQ) because the dispersion was heteroskedastic. All the pesticides could be correctly quantified at a concentration level of 50 ng L −1 and most of them could be detected at a concentration inferior or equal to 8 ng L −1 . Efficiency and robustness of this method were evaluated by the analysis of several samples of real natural water.

We consider theoretically the possibility of observing unusual quantum fluid behavior in liquid $^{3}$He and solutions of $^{3}$He in $^{4}$He systems confined to nano-channels. In the case of pure ballistic flow at very low temperature conductance will be quantized in units of $2m^{2}/h$. We show that these steps should be sensitive to increases in temperature. We also use of a random scattering matrix simulation to study flow with diffusive wall scattering. Universal conductance fluctuations analogous to those seen in electron systems should then be observable. Finally we consider the possibility of the cross-over to a one-dimensional system at sufficiently low temperature where the system could form a Luttinger liquid.

A public–private, multidisciplinary work group developed recommendations for rationing vaccines in Minnesota during a worst-case influenza pandemic. The recommendations encompass an ethical framework of principles, goals, and strategies. The primary goal is to maximize Minnesotans’ chances of surviving both the pandemic and the years immediately thereafter and to limit two major causes of death: (a) influenza and complications of influenza, and (b) disruption of basic health care, public health, and public safety infrastructures. The work group also developed a sample rationing plan, but stressed that any final plan must reflect the best available evidence during an actual pandemic.

Two superdeformed bands have been observed in the nucleus {sup 145}Sm in an experiment performed with the Gammasphere multidetector array. One of these bands demonstrates a sudden rise in its dynamic moment of inertia at low frequency which may be related to the interaction between N=6 Nilsson orbitals at the Fermi surface. The other band has a moment of inertia identical to the yrast band of {sup 149}Gd, making it the fourth case in the A{approx_equal}150 mass region of identical bands in nuclei differing by an {alpha} particle. {copyright} {ital 1998} {ital The American Physical Society}

North American researchers' perspectives on designing neurosurgical implant studies for Parkinson disease (PD) challenged the custom of holding surgical trials to less stringent evidentiary standards than other clinical studies. Researchers supported placebo surgery-controlled trials. The framework they used to design and evaluate studies both of deep brain stimulation and cellular implants for PD may be applicable to a broad range of surgical implants for other disorders.

The formin homology (FH) proteins play a crucial role in cytoskeleton remodelling during many essential processes. In this study, we demonstrate for the first time that the formin-homology-domain-containing protein FHOD1 is cleaved by caspase-3 at the SVPD(616) site during apoptosis. Using confocal microscopy, we further demonstrate that while full length FHOD1 is mostly cytoplasmic, the FHOD1 N-terminal cleavage product is diffusely localized throughout the cytoplasm and the nucleoplasm, whereas the C-terminal cleavage product is almost exclusively nuclear with some nucleolar localization. Finally, using a run-on transcription assay we show that the C-terminal FHOD1 cleavage product has the ability to inhibit RNA polymerase I transcription when overexpressed in HeLa cells as shown by blockage of BrUTP incorporation.

The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a β-lactamase assay in CHO-NFAT-bla-Gα16 cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.

Superfluid 3He in high porosity aerogel is the system in which the effects of static impurities on a p-wave superfluid can be investigated in a systematic manner. We performed shear acoustic impedance measurements on this system (98% porosity aerogel) in the presence of magnetic fields up to 15 T at the sample pressures of 28.4 and 33.5 bars. We observed the splitting of the superfluid transition into two transitions in high fields in both bulk and liquid in aerogel. The field dependence of the splitting in aerogel resembles that of the bulk superfluid 3He caused by the presence and growth of the A1 phase. Our results provide the first evidence of the A1 phase in superfluid (3)He/aerogel.

The specific heat of superfluid 3He, disordered by a silica aerogel, is found to have a sharp discontinuity marking the thermodynamic transition to superfluidity at a temperature reduced from that of bulk 3He. The magnitude of the discontinuity is also suppressed. This disorder effect can be understood from the Ginzburg-Landau theory which takes into account elastic quasiparticle scattering suppressing both the transition temperature and the amplitude of the order parameter. We infer that the limiting temperature dependence of the specific heat is linear at low temperatures in the disordered superfluid state, consistent with predictions of gapless excitations everywhere on the Fermi surface.

Is it ethical to use the tissues of electively aborted fetuses for transplantation purposes, and if so, under what conditions? The answer depends on the respect and protection owed those involved in the donation of fetal tissue, and whether it is possible to implement policies to assure such respect and protection.