240 research outputs found
A Fluorinated Sialic Acid Vaccine Lead Against Meningitis B and C
Inspired by the specificity of α-(2,9)-sialyl epitopes in bacterial capsular polysaccharides (CPS), a doubly fluorinated disaccharide has been validated as a vaccine lead against Neisseria meningitidis serogroups C and/or B. Emulating the importance of fluorine in drug discovery, this molecular editing approach serves a multitude of purposes, which range from controlling α-selective chemical sialylation to mitigating competing elimination. Conjugation of the disialoside with two carrier proteins (CRM197 and PorA) enabled a semisynthetic vaccine to be generated; this was then investigated in six groups of six mice. The individual levels of antibodies formed were compared and classified as highly glycan-specific and protective. All glycoconjugates induced a stable and long-term IgG response and binding to the native CPS epitope was achieved. The generated antibodies were protective against MenC and/or MenB; this was validated in vitro by SBA and OPKA assays. By merging the fluorinated glycan epitope of MenC with an outer cell membrane protein of MenB, a bivalent vaccine against both serogroups was created. It is envisaged that validation of this synthetic, fluorinated disialoside bioisostere as a potent antigen will open new therapeutic avenues
Flexible, High-Speed, Small Satellite Production
Planetâs first mission is to image the entire land mass of the Earth every day in an effort to make global change visible, accessible, and actionable. To do this, Planet designs and builds highly capable Earth-imaging satellites and today operates the largest Earth-imaging fleet in history. To support this mission, Planet had to develop an adaptable concurrent product development cycle associated with a unique assembly and manufacturing line to support the quick production and delivery of satellites. This paper introduces how Planet achieved that objective by building multiple spacecraft design iterations concurrently and how Planet orchestrates a production line for speed, flexibility, and high throughput of satellite delivery in just over a few weeks
Inverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple HâF Bioisosterism
Fluorinated motifs have a venerable history in drug
discovery, but as C(sp3
)@F-rich 3D scaffolds appear with
increasing frequency, the effect of multiple bioisosteric changes
on molecular recognition requires elucidation. Herein we
demonstrate that installation of a 1,3,5-stereotriad, in the
substrate for a commonly used lipase from Pseudomonas
fluorescens does not inhibit recognition, but inverts stereoselectivity. This provides facile access to optically active,
stereochemically well-defined organofluorine compounds (up
to 98% ee). Whilst orthogonal recognition is observed with
fluorine, the trend does not hold for the corresponding
chlorinated substrates or mixed halogens. This phenomenon
can be placed on a structural basis by considering the
stereoelectronic gauche effect inherent to F@C@C@X systems
(s!s*). Docking reveals that this change in selectivity (H
versus F) with a common lipase results from inversion in the
orientation of the bound substrate being processed as a consequence of conformation. This contrasts with the stereochemical interpretation of the biogenetic isoprene rule, whereby
product divergence from a common starting material is also
a consequence of conformation, albeit enforced by two discrete
enzymes
Sample characterization of automobile and forklift diesel exhaust particles and comparative pulmonary toxicity in mice.
Two samples of diesel exhaust particles (DEPs) predominate in health effects research: an automobile-derived DEP (A-DEP) sample and the National Institute of Standards Technology standard reference material (SRM 2975) generated from a forklift engine. A-DEPs have been tested extensively for their effects on pulmonary inflammation and exacerbation of allergic asthmalike responses. In contrast, SRM 2975 has been tested thoroughly for its genotoxicity. In the present study, we combined physical and chemical analyses of both DEP samples with pulmonary toxicity testing in CD-1 mice to compare the two materials and to make associations between their physicochemical properties and their biologic effects. A-DEPs had more than 10 times the amount of extractable organic material and less than one-sixth the amount of elemental carbon compared with SRM 2975. Aspiration of 100 micro g of either DEP sample in saline produced mild acute lung injury; however, A-DEPs induced macrophage influx and activation, whereas SRM 2975 enhanced polymorphonuclear cell inflammation. A-DEPs stimulated an increase in interleukin-6 (IL-6), tumor necrosis factor alpha, macrophage inhibitory protein-2, and the TH2 cytokine IL-5, whereas SRM 2975 only induced significant levels of IL-6. Fractionated organic extracts of the same quantity of DEPs (100 micro g) did not have a discernable effect on lung responses and will require further study. The disparate results obtained highlight the need for chemical, physical, and source characterization of particle samples under investigation. Multidisciplinary toxicity testing of diesel emissions derived from a variety of generation and collection conditions is required to meaningfully assess the health hazards associated with exposures to DEPs. Key words: automobile, diesel exhaust particles, forklift, mice, pulmonary toxicity, SRM 2975
Symbolic Formulae for Linear Mixed Models
A statistical model is a mathematical representation of an often simplified
or idealised data-generating process. In this paper, we focus on a particular
type of statistical model, called linear mixed models (LMMs), that is widely
used in many disciplines e.g.~agriculture, ecology, econometrics, psychology.
Mixed models, also commonly known as multi-level, nested, hierarchical or panel
data models, incorporate a combination of fixed and random effects, with LMMs
being a special case. The inclusion of random effects in particular gives LMMs
considerable flexibility in accounting for many types of complex correlated
structures often found in data. This flexibility, however, has given rise to a
number of ways by which an end-user can specify the precise form of the LMM
that they wish to fit in statistical software. In this paper, we review the
software design for specification of the LMM (and its special case, the linear
model), focusing in particular on the use of high-level symbolic model formulae
and two popular but contrasting R-packages in lme4 and asreml
Contra-thermodynamic E â Z isomerization of cinnamamides via selective energy transfer catalysis
A bio-inspired, photocatalytic E â Z isomerization of cinnamides is reported using inexpensive (â)-riboflavin (vitamin B2) under irradiation at λâŻ=âŻ402âŻnm. This operationally simple transformation is compatible with a range of amide derivatives including âNR2, âNHSO2R and N(Boc)2 (up to 99:1 Z:E). Selective energy transfer from the excited state photocatalyst to the starting E-isomer ensures that directionality is achieved: The analogous process with the Z-isomer is inefficient due to developing allylic strain causing chromophore deconjugation. This is supported by X-ray analysis and Stern-Volmer photo-quenching studies. Preliminary validation of the method in manipulating the conformation of a simple model Leu-enkephalin penta-peptide is disclosed via the incorporation of a cinnamamide-based amino acid
Thymus transplantation for complete DiGeorge syndrome: European experience
Background: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). Methods: Twelve patients with cDGS were transplanted with allogeneic cultured thymus. Objective: To confirm and extend the results previously obtained in a single centre. Results: Two patients died of pre-existing viral infections without developing thymopoeisis and one late death occurred from autoimmune thrombocytopaenia. One infant suffered septic shock shortly after transplant resulting in graft loss and the need for a second transplant. Evidence of thymopoeisis developed from 5-6 months after transplantation in ten patients. The median (range) of circulating naïve CD4 counts (x10663 /L) were 44(11-440) and 200(5-310) at twelve and twenty-four months post-transplant and T-cell receptor excision circles were 2238 (320-8807) and 4184 (1582 -24596) per106 65 T-cells. Counts did not usually reach normal levels for age but patients were able to clear pre-existing and later acquired infections. At a median of 49 months (22-80), eight have ceased prophylactic antimicrobials and five immunoglobulin replacement. Histological confirmation of thymopoeisis was seen in seven of eleven patients undergoing biopsy of transplanted tissue including five showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator (AIRE) expression was also demonstrated. Autoimmune complications were seen in 7/12 patients. In two, early transient autoimmune haemolysis settled after treatment and did not recur. The other five suffered ongoing autoimmune problems including: thyroiditis (3); haemolysis (1), thrombocytopaenia (4) and neutropenia (1). Conclusions: This study confirms the previous reports that thymus transplantation can reconstitute T cells in cDGS but with frequent autoimmune complications in survivors
Enhancing glycan stability via site-selective fluorination: modulating substrate orientation by molecular design
Single site OH â F substitution at the termini of maltotetraose leads to significantly improved hydrolytic stability towards α-amylase and α-glucosidase relative to the natural compound. To explore the effect of molecular editing, selectively modified oligosaccharides were prepared via a convergent α-selective strategy. Incubation experiments in purified α-amylase and α-glucosidase, and in human and murine blood serum, provide insight into the influence of fluorine on the hydrolytic stability of these clinically important scaffolds. Enhancements of ca. 1 order of magnitude result from these subtle single point mutations. Modification at the monosaccharide furthest from the probable enzymatic cleavage termini leads to the greatest improvement in stability. In the case of α-amylase, docking studies revealed that retentive C2-fluorination at the reducing end inverts the orientation in which the substrate is bound. A co-crystal structure of human α-amylase revealed maltose units bound at the active-site. In view of the evolving popularity of C(sp3)âF bioisosteres in medicinal chemistry, and the importance of maltodextrins in bacterial imaging, this discovery begins to reconcile the information-rich nature of carbohydrates with their intrinsic hydrolytic vulnerabilities
Design of Experiments for Screening
The aim of this paper is to review methods of designing screening
experiments, ranging from designs originally developed for physical experiments
to those especially tailored to experiments on numerical models. The strengths
and weaknesses of the various designs for screening variables in numerical
models are discussed. First, classes of factorial designs for experiments to
estimate main effects and interactions through a linear statistical model are
described, specifically regular and nonregular fractional factorial designs,
supersaturated designs and systematic fractional replicate designs. Generic
issues of aliasing, bias and cancellation of factorial effects are discussed.
Second, group screening experiments are considered including factorial group
screening and sequential bifurcation. Third, random sampling plans are
discussed including Latin hypercube sampling and sampling plans to estimate
elementary effects. Fourth, a variety of modelling methods commonly employed
with screening designs are briefly described. Finally, a novel study
demonstrates six screening methods on two frequently-used exemplars, and their
performances are compared
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