ABSTRACT
Understanding magnetic phases in quantum mechanical systems is one of the essential goals in condensed matter physics, and the advent of prototype quantum simulation hardware has provided new tools for experimentally probing such systems. We report on the experimental realization of a quantum simulation of interacting Ising spins on three-dimensional cubic lattices up to dimensions 8 × 8 × 8 on a D-Wave processor (D-Wave Systems, Burnaby, Canada). The ability to control and read out the state of individual spins provides direct access to several order parameters, which we used to determine the lattice's magnetic phases as well as critical disorder and one of its universal exponents. By tuning the degree of disorder and effective transverse magnetic field, we observed phase transitions between a paramagnetic, an antiferromagnetic, and a spin-glass phase.
ABSTRACT
OBJECTIVE: Community-based, family-centered obesity prevention/treatment initiatives have been shown to be effective in reducing body mass index (BMI) and improving healthy habits in children if implemented with high intensity and sufficient duration. Let's Go! 5-2-1-0 Program (5-2-1-0) was incorporated into family-centered, monthly physical activity classes and cooking classes over six months delivered by Young Men's Christian Association (YMCA) staff. We hypothesized that implementation of this intervention would improve 5-2-1-0 knowledge attainment, increase healthy behavior (based on 5- 2-1-0 curriculum), and improve BMI and waist circumference measurements in children. METHODS: Children attending YMCA summer camps in Rochester, MN, during 2016 were recruited via study packets mailed to their families. Height, weight, and waist circumference measurements as well as the results of the Modified Healthy Habits Survey and the 5-2-1-0 Knowledge Acquisition Survey were recorded for each participating child at baseline and 6-month follow-up. The intervention group received monthly healthy habit reminder emails, and was invited to monthly evening cooking and physical activity classes for 7 sessions over a 6-month period. RESULTS: Fifteen families in the intervention group attended classes. Of those, 13 families regularly participated in (attended at least 5 out of 7) both the monthly physical activity and cooking classes. The children in the intervention group had a significant improvement in the number of Knowledge Acquisition Survey questions answered correctly (p<0.001), while there was no improvement in the control group. As compared to children in the control group, there was no significant change in BMI or waist circumference or healthy habits in the intervention group. CONCLUSION: Our study findings indicate that our intervention resulted in improved knowledge about healthy habits, but did not significantly impact healthy habits or BMI. Potential reasons for this were the small sample size and the attenuated length and/or intensity of the intervention.
ABSTRACT
A new polyoxovanadium cluster compound, [VO6{(OCH2CH2)2N(CH2CH2OH)}6]·0.5CH3CN, was synthesized and characterized by single-crystal X-ray diffraction analysis, FTIR and UV-vis spectroscopy, and TGA. The cluster is composed of a fully reduced cyclic {V6N6O18} framework, which adopts an Anderson-like structure and is comprised of a ring of six edge-sharing {VO5N} octahedra incorporating six {(OCH2CH2)2N(CH2CH2OH)} ligands. Two (OCH2CH2-) arms of each of the six triethanolamine ligands are directly incorporated into the oxometalate core and the third {-CH2CH2OH} arm remains pendant. In the condensed phase, the clusters form discrete hcp layers through inter-cluster hydrogen bonding. These layers stack through soft chemical interactions to form a 3D network structure. The neutral cluster, [VO6{(OCH2CH2)2N(CH2CH2OH)}6], is the isopolyoxovanadium analogue to the cationic clusters contained in a series of heteropolyoxovanadium compounds previously introduced by our laboratory, e.g., [LiVO6{(OCH2CH2)2N(CH2CH2OH)}6]+; its existence shows that a heteroatom is not required to form or stabilize the common organofunctionalized vanadium oxide framework: [VO6{(OCH2CH2)2N(CH2CH2OH)}6]. To the best of our knowledge, the isopolyoxovanadium and heteropolyoxovanadium clusters represent the first reported isopoly-heteropoly analogues in the polyoxometalate field. We compare the TGA profile, FTIR and UV-vis spectra of the new compound with two of its cationic heteropoly analogues.
ABSTRACT
Suboptimal untimed plasma drug levels (UDL) have been associated with lower rates of virologic suppression and the emergence of drug resistance. Our aim was to evaluate whether UDL among patients with low-level viremia (LLV) while receiving highly active antiretroviral therapy (HAART) can predict subsequent virologic failure (plasma viral load ≥1000 copies/mL) and emergence of resistance. The first documented LLV episode of 328 consenting patients was analysed in terms of drug levels, viral load and resistance, which were monitored while patients were on a consistent HAART regimen. UDL of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), were categorized as 'therapeutic' or 'subtherapeutic' based on predefined target trough concentrations. Drug resistance genotype was assessed using the Stanford algorithm. Time to virologic failure was evaluated by Kaplan-Meier analysis and Cox proportional hazards regression. We found 78 of 328 patients (24%) with subtherapeutic drug levels at time of first detectable LLV, while 19% harboured drug-resistant virus. Both subtherapeutic UDL and drug resistance independently increased the risk of subsequent virologic failure (p <0.001 and p 0.04, respectively). In a multivariable model, variables associated with LLV and virologic failure included subtherapeutic UDL, elevated plasma viral load, and drug resistance. Patients with subtherapeutic UDL accumulated further drug resistance faster during follow-up (p 0.03). Together, resistance and UDL variables can explain a higher proportion of virologic failure than either measure alone. Our results support further prospective evaluation of UDL in the management of low-level viremia.
Subject(s)
Anti-HIV Agents/blood , HIV Infections/drug therapy , HIV-1/isolation & purification , Viremia/blood , Adult , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Drug Resistance, Viral/genetics , Female , Follow-Up Studies , Genotyping Techniques , HIV Infections/blood , HIV-1/genetics , Humans , Kaplan-Meier Estimate , Male , Medication Adherence , Middle Aged , Proportional Hazards Models , Protease Inhibitors/pharmacology , Retrospective Studies , Viral LoadABSTRACT
People who engage in non-suicidal self-injury (NSSI) often conceal their practices, which limits examination and understanding of their engagement. The goal of this research is to utilize data from public online social networks (namely, LiveJournal, a major blogging social networking site) to observe the NSSI population in a naturally occurring setting. Specifically, the focus of this paper is the interests publicly declared by LiveJournal users. In the course of study, we collected the self-declared interests of 25,000 users who are members of or participate in 139 NSSI-related communities. We constructed a family of semantic networks of interests based on their similarity. The semantic networks are structured and contain several dense clusters-semantic domains-that include NSSI-specific interests (such as self-injury and razor), references to music performers (such as evanescence), and general daily life and creativity related interests (such as poetry and friendship). Assuming users are genuine in their declarations, the clusters reveal distinct patterns of interest and may signal keys to NSSI.
ABSTRACT
We characterized maraviroc susceptibility of dual/mixed tropic viruses from subjects enrolled onto phase IIb study A4001029. Maraviroc baseline plasma samples from 13 multidrug-experienced subjects were sequenced and the HIV-1-env gene cloned into pNL4.3Δenv to obtain recombinant viruses. The V3 region was sequenced by the Sanger method and ultradeep sequencing. By analysing subjects having a weighted optimized background therapy susceptibility (wOBT) score of <1, 3/7 subjects were characterized by good in vivo and in vitro response to maraviroc therapy. Molecular docking simulations allowed us to rationalize the maraviroc susceptibility of dual/mixed tropic viruses. A subset of subjects with dual/mixed tropic viruses responded to maraviroc. Further investigations are warranted of CCR5 antagonists in subjects carrying dual/mixed tropic virus that explore the feasible use of maraviroc in subjects that is potentially larger than those infected with a pure R5 virus.
Subject(s)
CCR5 Receptor Antagonists/pharmacology , Cyclohexanes/pharmacology , HIV Infections/virology , HIV-1/drug effects , Triazoles/pharmacology , HIV Infections/epidemiology , HIV-1/genetics , Humans , Maraviroc , Mutation/genetics , Viral TropismABSTRACT
INTRODUCTION: The prevalence of pediatric obesity has increased over the past 3 decades and is a pressing public health program. New technology advancements that can encourage more physical in children are needed. The Zamzee program is an activity meter linked to a motivational website designed for children 8-14 years of age. The objective of the study was to use a collaborative approach between a medical center, the private sector and local school staff to assess the feasibility of using the Zamzee Program in the school-based setting to improve physical activity levels in children. METHODS: This was a pilot 8-week observational study offered to all children in one fifth grade classroom. Body mass index (BMI), the amount of physical activity by 3-day recall survey, and satisfaction with usability of the Zamzee Program were measured pre- and post-study. RESULTS: Out of 11 children who enrolled in the study, 7 completed all study activities. In those who completed the study, the median (interquartile range) total activity time by survey increased by 17 (1042) minutes and the BMI percentile change was 0 (8). Both children and their caregivers found the Zamzee Activity Meter (6/7) and website (6/7) "very easy" or "easy" to use. CONCLUSION: The Zamzee Program was found to be usable but did not significantly improve physical activity levels or BMI. Collaborative obesity intervention projects involving medical centers, the private sector and local schools are feasible but the effectiveness needs to be evaluated in larger-scale studies.
ABSTRACT
A new heteropolyoxovanadium compound, [NaV6O6{(OCH2CH2)2NH}6]·(OH)0.5Cl0.5·3(H2O), was synthesized and characterized by single-crystal X-ray diffraction analysis, cyclic voltammetry, FTIR and UV-vis spectroscopy, and TGA. [NaV6O6{(OCH2CH2)2NH}6]·(OH)0.5Cl0.5·3(H2O) contains the diethanolamine functionalized oxovanadium cationic cluster, [NaV(IV)6O6{(OCH2CH2)2NH}6](+). The cluster cation is composed of a fully reduced cyclic {NaV6N6O18} framework which adopts an Anderson-like structure and is comprised of a ring of six edge-sharing {VO5N} octahedra linked to a central {NaO6} unit. Two (OCH2CH2-) arms of each of the six diethanolamine ligands are incorporated into the oxometalate core. FTIR spectra are consistent with the presence of expected V=Ot stretching modes and functionalization with diethanolamine. Electrochemical and UV-vis absorption properties are consistent with two distinct MLCT processes: the characteristic V=Ot dπ-pπ interaction, and a second process occurring through the hydrogen-terminated nitrogen atoms (V-N-H) of the octahedra forming the cyclic {NaV6N6O18} core.
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BACKGROUND: Low-level viremia (LLV; human immunodeficiency virus [HIV-1] RNA 50-999 copies/mL) occurs frequently in patients receiving antiretroviral therapy (ART), but there are few or no data available demonstrating that HIV-1 drug resistance testing at a plasma viral load (pVL) <1000 copies/mL provides potentially clinically useful information. Here, we assess the ability to perform resistance testing by genotyping at LLV and whether it is predictive of future virologic outcomes in patients beginning ART. METHODS: Resistance testing by genotyping at LLV was attempted on 4915 plasma samples from 2492 patients. A subset of previously ART-naive patients was analyzed who achieved undetectable pVL and subsequently rebounded with LLV (n = 212). A genotypic sensitivity score (GSS) was calculated based on therapy and resistance testing results by genotyping, and stratified according to number of active drugs. RESULTS: Eighty-eight percent of LLV resistance assays produced useable sequences, with higher success at higher pVL. Overall, 16 of 212 (8%) patients had pretherapy resistance. Thirty-eight of 196 (19%) patients without pretherapy resistance evolved resistance to 1 or more drug classes, primarily the nucleoside reverse transcriptase (14%) and/or nonnucleoside reverse transcriptase (9%) inhibitors. Patients with resistance at LLV (GSS <3) had a 2.1-fold higher risk of virologic failure (95% confidence interval, 1.2- to 3.7-fold) than those without resistance (P = .007). Progressively lower GSS scores at LLV were associated with a higher increase in pVL over time (P < .001). Acquisition of additional resistance mutations to a new class of antiretroviral drugs during LLV was not found in a subset of patients. CONCLUSIONS: Routine HIV-1 genotyping of LLV samples can be performed with a reasonably high success rate, and the results appear predictive of future virologic outcomes.
Subject(s)
Drug Resistance, Viral , Genotyping Techniques/methods , HIV Infections/diagnosis , HIV Infections/virology , HIV-1/drug effects , Viral Load , Adult , Evolution, Molecular , Female , Genotype , HIV-1/genetics , HIV-1/isolation & purification , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Prognosis , Reproducibility of Results , Treatment OutcomeABSTRACT
BACKGROUND: DSM-IV specifies a hierarchal diagnostic structure such that an oppositional defiant disorder (ODD) diagnosis is applied only if criteria are not met for conduct disorder (CD). Genetic studies of ODD and CD support a combination of shared genetic and environmental influences but largely ignore the imposed diagnostic structure. METHOD: We examined whether ODD and CD share an underlying etiology while accounting for DSM-IV diagnostic specifications. Data from 1446 female twin pairs, aged 11-19 years, were fitted to two-stage models adhering to the DSM-IV diagnostic hierarchy. RESULTS: The models suggested that DSM-IV ODD-CD covariation is attributed largely to shared genetic influences. CONCLUSIONS: This is the first study, to our knowledge, to examine genetic and environmental overlap among these disorders while maintaining a DSM-IV hierarchical structure. The findings reflect primarily shared genetic influences and specific (i.e. uncorrelated) shared/familial environmental effects on these DSM-IV-defined behaviors. These results have implications for how best to define CD and ODD for future genetically informed analyses.
Subject(s)
Attention Deficit and Disruptive Behavior Disorders/genetics , Conduct Disorder/genetics , Diseases in Twins/genetics , Adolescent , Adult , Attention Deficit and Disruptive Behavior Disorders/etiology , Child , Conduct Disorder/etiology , Diagnostic and Statistical Manual of Mental Disorders , Diseases in Twins/etiology , Female , Humans , Young AdultABSTRACT
We describe a new mK-range nanoscale thermometer, based on a unique three-junction radio frequency single-electron transistor. The three-junction geometry allows separation of the thermal and electronic pathways, providing a potentially significant reduction of measurement-induced Joule heating. A radio frequency embedding tank circuit allows very fast readout. We demonstrate electronic and thermal operation, supported by numerical simulations. Applications to minimal back-action calorimetry and bolometry are discussed.
Subject(s)
Calorimetry/instrumentation , Nanotechnology/instrumentation , Thermography/instrumentation , Transistors, Electronic , Calorimetry/methods , Diffusion , Electrons , Equipment Design , Equipment Failure Analysis , Nanotechnology/methods , Radio Waves , Sensitivity and Specificity , Thermography/methodsABSTRACT
We present two critical innovations that enable a unique, purely electronic approach to microfluidic whole-cell analysis, focusing on the problem of cell identification and sorting. We used fully-scalable lithographic techniques to microfabricate digital barcodes, providing a means for low-cost, large volume production. We have demonstrated molecular functionalization of the barcodes, using biotin-streptavidin, as well as human CD4 antibody, and we have successfully linked the barcodes to polystyrene beads using the biotin-streptavidin complex. This functionalization allows unique barcodes to be attached to specific cell types, based on phenotype. We have also implemented an electronic barcode readout scheme, using a radio frequency microsensor integrated in an elastomeric microfluidic channel, that can read individual barcodes at rates in excess of 1000 labels s(-1). The barcodes are biologically compatible, and coupled with the electronic sensing technology, provide a route to compact, inexpensive, disposable cell identification, sorting and purification.
Subject(s)
CD4 Antigens/chemistry , Microfluidics/instrumentation , Biotechnology/methods , Biotin/chemistry , Computers , Electronic Data Processing , Electronics , Humans , Molecular Diagnostic Techniques/instrumentation , Polystyrenes/chemistry , Radio Waves , Software , Streptavidin/chemistry , Time FactorsABSTRACT
By using information derived from questionnaires sent to registered owners of drever dams and sires in Sweden with offspring born in 1992 and/or 1994, two groups of offspring were identified: one with one parent said to have had breathing difficulties after hunting, and another with both parents unaffected. Questionnaires were sent to the owners of these offspring, and multiple logistic regression was used to analyse the offspring data, with the status of their sire and dam with respect to breathing difficulties after hunting included as covariates. For the outcome 'breathing difficulties after hunting' in the 266 offspring, the odds ratio (OR) was 4.4 (95 per cent confidence interval [CI] 1.8 to 10.8) if the dam was affected and 3-9 (95 per cent CI 1.2 to 11.1) if the sire was affected. The OR for male offspring was 2.4 (95 per cent CI 1.1 to 5.7). The heritability of the condition was estimated to be 0.34 from the dogs born in 1992, and 0.28 from the dogs born in 1994.
Subject(s)
Dog Diseases/epidemiology , Dog Diseases/genetics , Genetic Predisposition to Disease , Pulmonary Edema/veterinary , Animal Husbandry , Animals , Cohort Studies , Dog Diseases/etiology , Dogs , Female , Male , Pedigree , Pulmonary Edema/epidemiology , Pulmonary Edema/genetics , Surveys and Questionnaires , Sweden/epidemiologyABSTRACT
Fear is a common behavioral problem in dogs. In this paper, we studied the association between behavioral and physiological responses in two potentially fear-eliciting situations. The aim was to establish whether it is possible to separate dogs of the collie breed that are fearful of floors and gunshots from those that are not by studying changes in heart rate and hematocrit, plasma cortisol, progesterone, testosterone, vasopressin, and beta-endorphin concentrations. Thirteen privately owned male dogs of the collie breed were studied during a floor test, using different types of floors, and a subsequent gunshot test. Seven of the dogs were identified as being fearful of floors and six were declared as fearless. Out of the 13 dogs, seven were fearful of gunshots and six were fearless of gunshots. Since fear of floors did not always occur concomitantly with fear of gunshots, there were consequently four different groups of dogs. The heart rate increased during the floor test in all groups, but dogs that were fearful of floors had higher heart rates than dogs that were fearless of floors. Dogs that were fearful of gunshots had higher heart rates, higher hematocrit levels and higher plasma concentrations of cortisol, progesterone, vasopressin, and beta-endorphins during the gunshot test than did dogs that were found to be fearless of gunshots. Plasma cortisol and progesterone increased drastically during the gunshot test in dogs identified as being fearful of gunshots. In fearful dogs, the testosterone concentration increased after completion of the floor test and before the gunshot test started, but there were no significant differences in testosterone between the groups. Since dogs fearful of gunshots had increased levels of several physiological parameters, the results demonstrated that this fear is a serious stress for the individual, a fear which it is possible to register with physiological variables.
Subject(s)
Adaptation, Physiological , Adjustment Disorders/psychology , Dog Diseases/psychology , Fear , Adjustment Disorders/blood , Animals , Dog Diseases/blood , Dogs , Environment , Heart Rate , Hematocrit , Hydrocortisone/blood , Noise , Progesterone/blood , Psychological Tests , Vasopressins/blood , beta-Endorphin/bloodABSTRACT
Sorcin is a 22 kD calcium-binding protein that is found in a wide variety of cell types, such as heart, muscle, brain and adrenal medulla. It belongs to the penta-EF-hand (PEF) protein family, which contains five EF-hand motifs that associate with membranes in a calcium-dependent manner. Prototypic members of this family are the calcium-binding domains of calpain, such as calpain dVI. Full-length human sorcin has been crystallized in the absence of calcium and the structure determined at 2.2 A resolution. Apart from an extended N-terminal portion, the sorcin molecule has a globular shape. The C-terminal domain is predominantly alpha-helical, containing eight alpha-helices and connecting loops incorporating five EF hands. Sorcin forms dimers through the association of the unpaired EF5, confirming this as the mode of association in the dimerization of PEF proteins. Comparison with calpain dVI reveals that the general folds of the individual EF-hand motifs are conserved, especially that of EF1, the novel EF-hand motif characteristic of the family. Detailed structural comparisons of sorcin with other members of PEF indicate that the EF-hand pair EF1-EF2 is likely to correspond to the two physiologically relevant calcium-binding sites and that the calcium-induced conformational change may be modest and localized within this pair of EF-hands. Overall, the results derived from the structural observations support the view that, in sorcin, calcium signaling takes place through the first pair of EF-hands.
Subject(s)
Calcium-Binding Proteins/chemistry , Amino Acid Motifs , Amino Acid Sequence , Annexins/chemistry , Calpain/chemistry , Crystallography, X-Ray , Dimerization , EF Hand Motifs , Humans , Models, Molecular , Molecular Sequence Data , Protein Conformation , Protein Folding , Protein Structure, Secondary , Protein Structure, Tertiary , Sequence Homology, Amino AcidABSTRACT
GSK3beta was identified as the kinase that phosphorylates glycogen synthase but is now known to be involved in multiple signaling pathways. GSK3beta prefers prior phosphorylation of its substrates. We present the structure of unphosphorylated GSK3beta at 2.7 A. The orientation of the two domains and positioning of the activation loop of GSK3beta are similar to those observed in activated kinases. A phosphate ion held by Arg 96, Arg 180 and Lys 205 occupies the same position as the phosphate group of the phosphothreonine in activated p38gamma, CDK2 or ERK2. A loop from a neighboring molecule in the crystal occupies a portion of the substrate binding groove. The structure explains the unique primed phosphorylation mechanism of GSK3beta and how GSK3beta relies on a phosphoserine in the substrate for the alignment of the beta- and alpha-helical domains.
Subject(s)
CDC2-CDC28 Kinases , Calcium-Calmodulin-Dependent Protein Kinases/chemistry , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Amino Acid Motifs , Apoenzymes/chemistry , Apoenzymes/metabolism , Binding Sites , Crystallography, X-Ray , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinases/chemistry , Enzyme Activation , Glycogen Synthase Kinase 3 , Mitogen-Activated Protein Kinase 1/chemistry , Mitogen-Activated Protein Kinase 12 , Mitogen-Activated Protein Kinases/chemistry , Models, Molecular , Peptides/metabolism , Phosphates/metabolism , Phosphorylation , Phosphoserine/metabolism , Protein Serine-Threonine Kinases/chemistry , Protein Structure, Secondary , Protein Structure, Tertiary , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Industrial hygienists (IHs) are called upon to investigate exposures to mold in indoor environments, both residential and commercial. Because exposure standards for molds or mycotoxins do not exist, it is important for the industrial hygienist to have a broad knowledge of the potential for exposure and health effects associated with mold in the indoor environment. This review focuses on the toxic effects of molds associated with the production of mycotoxins, and the putative association between health effects due to mycotoxin exposure in the indoor environment. This article contains background information on molds and mycotoxins, and a brief summary and review of animal exposure studies, case reports, and epidemiological studies from the primary literature concerning inhalation of mycotoxins or potentially toxin-producing molds. The relevance of the findings in the reviewed articles to exposures to mold in indoor, non-agricultural environments is discussed. Although evidence was found of a relationship between high levels of inhalation exposure or direct contact to mycotoxin-containing molds or mycotoxins, and demonstrable effects in animals and health effects in humans, the current literature does not provide compelling evidence that exposure at levels expected in most mold-contaminated indoor environments is likely to result in measurable health effects. Even though there is general agreement that active mold growth in indoor environments is unsanitary and must be corrected, the point at which mold contamination becomes a threat to health is unknown. Research and systematic field investigation are needed to provide an understanding of the health implications of mycotoxin exposures in indoor environments.
Subject(s)
Air Microbiology , Air Pollution, Indoor/adverse effects , Environmental Exposure/adverse effects , Fungi , Mycotoxins/adverse effects , Environmental Exposure/prevention & control , Environmental Exposure/statistics & numerical data , Fungi/classification , Humans , Hypersensitivity/etiology , Mycoses/etiology , Mycotoxins/poisoningABSTRACT
BACKGROUND: Peptide inhibitors of caspases have helped define the role of these cysteine proteases in biology. Structural and biochemical characterization of the caspase enzymes may contribute to the development of new drugs for the treatment of caspase-mediated inflammation and apoptosis. RESULTS: The crystal structure of the previously unpublished caspase-7 (Csp7; 2.35 A) bound to the reversible tetrapeptide aldehyde inhibitor acetyl-Asp-Glu-Val-Asp-CHO is compared with crystal structures of caspases-1 (2.3 A), -3 (2.2 A), and -8 (2.65 A) bound to the same inhibitor. Csp7 is a close homolog of caspase-3 (Csp3), and these two caspases possess some quarternary structural characteristics that support their unique role among the caspase family. However, although Csp3 and Csp7 are quite similar overall, they were found to have a significantly different substitution pattern of amino acids in and around the S4-binding site. CONCLUSIONS: These structures span all three caspase subgroups, and provide a basis for inferring substrate and inhibitor binding, as well as selectivity for the entire caspase family. This information will influence the design of selective caspase inhibitors to further elucidate the role of caspases in biology and hopefully lead to the design of therapeutic agents to treat caspase-mediated diseases, such as rheumatoid arthritis, certain neurogenerative diseases and stroke.
Subject(s)
Caspases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Amino Acid Sequence , Caspase Inhibitors , Caspases/chemistry , Models, Molecular , Molecular Sequence Data , Protein Conformation , Protein Structure, Secondary , Sequence Homology, Amino AcidABSTRACT
We conducted an evaluation of shredded paper insulation to identify potentially toxic components. The study was to provide a preliminary characterization of a few samples of insulation currently in use. The following samples were analyzed: previously produced insulation (PPI) containing fire retardants, shredded recycled paper (PPI feedstock), freshly produced insulation (FPI), and insulation which had been installed in a residence (II). Volatile constituents were analyzed by GC-MS from headspace air of samples held at room temperature or heated to 90 degrees C. Extractable constituents were sampled by extracting with methylene chloride, and analyzing by GC-MS. Formaldehyde analysis was done according to EPA Method TO11. Headspace air at room temperature contained no detectable quantities of volatile constituents for any sample measured. In headspace air at 90 degrees C, only PPI contained traces of aliphatic and aromatic hydrocarbons and higher aldehydes, and FPI traces of toluene. Extracts of PPI contained traces of octadecadienoic acid methyl ester and aliphatic and aromatic hydrocarbons and higher aldehydes. Extracts of PPI feedstock contained traces of a substituted cyclohexenecarboxylic acid. FPI contained extractable diethyl phthalate (30-50 micrograms/g). Extracts of II contained traces of methyl palmitate, an octadecenoic acid methyl ester, and a phthalate plasticizer. No formaldehyde was detected. PPI was composed of approximately 98 percent paper fiber and 2 percent pre-gelatinized starch. PPI samples agglomerated together with less than 0.01 percent separating from clumps as fine dust. Boron and sodium were expected and confirmed because they were added to PPI and FPI as fire retardants. Chromium, copper, iron, potassium, magnesium, manganese, phosphorus, and silicon were present at detectable concentrations. Study calculations indicate that an occupant would have to completely consume all the fine particles produced from 3.3 kg of insulation per day to have an intake of boron equivalent to the EPA RfD. No other constituent appeared to be present even close to toxicologically relevant amounts.