Deliberately Losing Control of C−H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism

Combined photochemical arylation, “nuisance effect” (S_NAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with S_NAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.     

Real-time organic aerosol chemical speciation in the indoor environment using extractive electrospray ionization mass spectrometry

Understanding the sources and composition of organic aerosol (OA) in indoor environments requires rapid measurements, since many emissions and processes have short timescales. However, real-time molecular-level OA measurements have not been reported indoors. Here, we present quantitative measurements, at a time resolution of five seconds, of molecular ions corresponding to diverse aerosol-phase species, by applying extractive electrospray ionization mass spectrometry (EESI-MS) to indoor air analysis for the first time, as part of the highly instrumented HOMEChem field study. We demonstrate how the complex spectra of EESI-MS are screened in order to extract chemical information and investigate the possibility of interference from gas-phase semivolatile species. During experiments that simulated the Thanksgiving US holiday meal preparation, EESI-MS quantified multiple species, including fatty acids, carbohydrates, siloxanes, and phthalates. Intercomparisons with Aerosol Mass Spectrometer (AMS) and Scanning Mobility Particle Sizer suggest that EESI-MS quantified a large fraction of OA. Comparisons with FIGAERO-CIMS shows similar signal levels and good correlation, with a range of 100 for the relative sensitivities. Comparisons with SV-TAG for phthalates and with SV-TAG and AMS for total siloxanes also show strong correlation. EESI-MS observations can be used with gas-phase measurements to identify co-emitted gas- and aerosol-phase species, and this is demonstrated using complementary gas-phase PTR-MS observations.     

The CD40-CD154 system in anti-infective host defense

Research in the past few years has documented significant advances in our understanding of the CD40-CD40 ligand (CD154) system in diverse immune functions. This system influences many T cell mediated inflammatory immune responses and effector functions, unmasking a previously unexpected role for CD40-CD154 in cell mediated immunity. Manipulation of CD154 in animal models of infection by the use of CD154-deficient mice or anti-CD154 antibodies has shown the importance of this system in the initiation of the inflammatory response, in the activation of antigen-presenting cells and in resistance to infections.     

Review of thymic pathology in 30 cats and 36 dogs

Data are presented from 30 cats and 36 dogs in which thymic disease was recognised clinically or on postmortem examination. The diagnoses included thymic lymphoma (19 cats, 12 dogs), thymoma (five cats, 18 dogs), thymic branchial cyst formation or cystic change (one cat, four dogs), thymic hyperplasia (two cats), congenital hypoplasia (one cat, one dog), thymic haemorrhage (one cat, one dog) and thymic amyloidosis (one cat). Thymic lymphoma occurred in younger dogs and cats, and was recorded equally among domestic shorthaired and purebred (especially Siamese) cats. Eight cats with thymic lymphoma were tested for feline leukaemia virus and four were positive. Thymoma occurred more frequently in older cats and dogs, and in Labradors and German shepherd dogs. Thymic tumours were associated with paraneoplastic hypercalcaemia (six dogs), megaoesophagus (two dogs) or interface dermatitis with basement membrane immune complex deposition (one cat). Non-neoplastic thymic diseases were associated with myasthenia gravis (one cat), pemphigus foliaceus (one cat) and superficial necrolytic dermatitis (one cat).     

The function of the reproductive system in x-ray-irradiated male rats after the transplantation of a culture of testicular cells from newborn piglets

The effect exerted by transplantation of the 5 day culture of testicles from newly born piglets on the hypogonadal state of mature X-ray irradiated (3 Gy) rats was studied. It has been found that a month after transplantation (two months after irradiation) the hypogonadal state disappeared for a while, which is confirmed by normalization of the weight of seminal vesicles, content of testosterone and biologically active lutropine, restoration of the reproductive function of rats. No significant changes in steroidogenesis activity have been found, which proves a substituent character of transplantation. The effect disappears three months later but certain restoration of the content of nucleic acids in the testicles is observed.     

Stochastic model for a wavelike exothermal reaction in condensed heterogeneous systems

The labile protons of two 32-base-pair, four-arm models of immobile Holliday junctions have been studied by two-dimensional 1H nuclear magnetic resonance (NMR) spectroscopy. Overlap of resonances in the imino-imino region of two-dimensional nuclear Overhauser enhancement (NOE) spectra necessitates the use of a multi-pathway approach for obtaining sequence-specific assignments wherein all possible NOE connectivities to the labile protons are utilized, including those from the 2H of adenine, 5CH3 of thymine, and 5H of cytosine. Resonance assignments are obtained for all slowly exchanging imino and cytosine amino protons. Base-pairing up to and including the junction point is found in all four arms of both Holliday junctions. Several cross-arm NOE connectivities are identified and can be used to infer the geometry of the helical stacking domains. The two Holliday junctions studied, which differ only by the exchange of two base pairs at the branch point, appear to have opposite arm stacking geometries. These assignments form an important part of the critical background for detailed NMR analysis of Holliday junction structure and dynamics.     

The cross product of interconnection networks

We study the cross product as a method for generating and analyzing interconnection network topologies for multiprocessor systems. Consider two interconnection graphs G₁ and G₂ each with some established properties such as symmetry, low degree and diameter, scalability, simple optimal routing, recursive structure (partitionability), fault tolerance, existence of node-disjoint paths, low cost embedding, and efficient broadcasting. We investigate and evaluate the corresponding properties for the cross product of G₁ and G₂ based on the properties of G₁ and those of G₂. We also give a mathematical characterization of product families of graphs which are closed under the cross product operation. This investigation is useful in two ways. On one hand, it gives a new tool for further studying some of the known interconnection topologies, such as the hypercube and the mesh, which can be defined using the cross product operation. On the other hand, it can be used in defining and evaluating new interconnection graphs using the cross product operation on known topologies     

An epidemiologic, clinical, and therapeutic study of childhood Guillain-Barré syndrome in Kuwait: is it related to the oral polio vaccine?

We studied Guillain-Barré syndrome, affecting children 12 years old or less, throughout Kuwait, in the period between January 1, 1992, and March 31, 1997. Nineteen children had the diagnostic criteria of Guillain-Barré syndrome, with an overall annual incidence rate of 0.95/100,000 population at risk. Female patients outnumbered male patients with a sex ratio of 1.4:1. There was a clustering of cases in winter and spring and in the year 1996. The disease symptoms were relatively severe in our patients because only 16% (3 of 19) of them were able to walk at the height of their illness, whereas the rest were bed or chair bound or needed assisted ventilation. Two patients had the electrodiagnostic features of axonal neuropathy and both had residual deficits on follow-up, whereas the rest recovered fully. All the patients received intravenous immunoglobulin. The mean time to walk unaided was 23.5 days (range, 2-84 days) after intravenous immunoglobulin and excluding the two patients with axonal neuropathy, and full recovery was achieved in a mean time of 103 days (range, 30-300 days). Contrary to previous studies, we found no correlation between oral polio vaccine administration and Guillain-Barré syndrome in 2 successive years (1995 and 1996) during a nationwide campaign targeting children less than 5 years old.     

Desensitization of mutant acetylcholine receptors in transgenic mice reduces the amplitude of neuromuscular synaptic currents

While the slow onset of desensitization of nicotinic acetylcholine receptors (AChRs), relative to the rate of acetylcholine removal, excludes this kinetic state from shaping synaptic responses in normal neuromuscular transmission, its role in neuromuscular disorders has not been examined. The slow-channel congenital myasthenic syndrome (SCCMS) is a disorder caused by point mutations in the AChR subunit-encoding genes leading to kinetically abnormal (slow) channels, reduced miniature endplate current amplitudes (MEPCs), and degeneration of the postsynaptic membrane. Because of this complicated picture of kinetic and structural change in the neuromuscular junction, it is difficult to assess the importance of the multiple factors that may be responsible for the reduced endplate current amplitudes, and ultimately the clinical syndrome. In order to address this we have used a transgenic mouse model for the SCCMS that has slow AChR ion channels and reduced endplate responsiveness in the absence of any of the degenerative changes. We found that the reduction in MEPC amplitudes in these mice could not be explained by either reduced AChR number or by reduced AChR channel conductance. Rather, we found that the mutant AChRs in situ manifested an activity-dependent reduction in sensitivity that caused diminished MEPC and endplate current amplitude with nerve stimulation. This observation demonstrates that the basis for the reduction in MEPC amplitudes in the SCCMS may be multifactorial. Moreover, these findings demonstrate that, under conditions that alter their rate of desensitization, the kinetic properties of nicotinic AChRs can control the strength of synaptic responses.     

Sulfation of parabens and tyrosylpeptides by bacterial arylsulfate sulfotransferases

Arylsulfate sulfotransferase purified from Eubacterium A-44 has higher specific activity than the enzymes from Klebsiella K-36 and Haemophilus K-12. Propylparaben and butylparaben were good substrates among several parabens. The antibacterial activity of parabens was reduced by the sulfation of the phenolic hydroxy group. Tyrosine-containing peptides, kyotorphin, enkephalin and cholecystokinin non-sulfate, were effective as acceptor substrates by A-44, K-36 and K-12 sulfotransferases.