Spontaneous S–Si bonding of alkanethiols to Si(111)–H: towards Si–molecule–Si circuits

We report the synthesis of covalently linked self-assembled monolayers (SAMs) on silicon surfaces, using mild conditions, in a way that is compatible with silicon-electronics fabrication technologies. In molecular electronics, SAMs of functional molecules tethered to gold via sulfur linkages dominate, but these devices are not robust in design and not amenable to scalable manufacture. Whereas covalent bonding to silicon has long been recognized as an attractive alternative, only formation processes involving high temperature and/or pressure, strong chemicals, or irradiation are known. To make molecular devices on silicon under mild conditions with properties reminiscent of Au–S ones, we exploit the susceptibility of thiols to oxidation by dissolved O2, initiating free-radical polymerization mechanisms without causing oxidative damage to the surface. Without thiols present, dissolved O2 would normally oxidize the silicon and hence reaction conditions such as these have been strenuously avoided in the past. The surface coverage on Si(111)–H is measured to be very high, 75% of a full monolayer, with density-functional theory calculations used to profile spontaneous reaction mechanisms. The impact of the Si–S chemistry in single-molecule electronics is demonstrated using STM-junction approaches by forming Si–hexanedithiol–Si junctions. Si–S contacts result in single-molecule wires that are mechanically stable, with an average lifetime at room temperature of 2.7 s, which is five folds higher than that reported for conventional molecular junctions formed between gold electrodes. The enhanced “ON” lifetime of this single-molecule circuit enables previously inaccessible electrical measurements on single molecules

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

ABSTRACT Despite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuated Mycobacterium tuberculosis strains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oral M. tuberculosis vaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4 + T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can develop vaccine-induced SIV-specific IgA and IgG antibodies and cellular immune responses within weeks of life. Our data further suggest that affinity maturation of vaccine-induced plasma antibodies and induction of mucosal IgA responses at potential SIV entry sites are associated with better control of viral replication, thereby likely reducing SIV morbidity. IMPORTANCE Despite significant progress in reducing peripartum MTCT of HIV with ART, continued access to ART throughout the breastfeeding period is still a limiting factor. Breast milk exposure to HIV accounts for up to 44% of MTCT. Alternative measures, in addition to ART, are needed to achieve the goal of an AIDS-free generation. Pediatric HIV vaccines constitute a core component of such efforts. The results of our pediatric vaccine study highlight the potential importance of vaccine-elicited mucosal Env-specific IgA responses in combination with high-avidity systemic Env-specific IgG in protection against oral SIV transmission and control of viral replication in infant macaques. The induction of potent mucosal IgA antibodies by our vaccine is remarkable considering the age-dependent development of mucosal IgA responses postbirth. A deeper understanding of postnatal immune development may inform the design of improved vaccine strategies to enhance systemic and mucosal SIV/HIV antibody responses

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality

Approaching magnetic field effects in biology using the radical pair mechanism

The goal of my graduate work has been to try to understand or explain some of the reported magnetic field effects in biology (see Chapter 1 for examples) using the radical pair mechanism, a quantum mechanical mechanism known for over 20 years that lets the yields of certain radical pair reactions depend on the applied magnetic field [1, 2, 3]. This goal seems reasonable considering the known roles of many biological free radicals in cancer, disease, aging, development, and cellular signaling, the constant reminders in the media to take anti-oxidant vitamins to protect against dangerous free radicals, and the success of the radical pair mechanism in explaining magnetic field effects in photosynthetic reaction centers. The radical pair mechanism (as detailed in Chapter 2) occurs when a pair of radicals forms a cage radical pair, a system composed of two unpaired electron spins whose spin motion is affected by nearby nuclear spins via the hyperfine interaction, by applied magnetic fields via the Zeeman effect, and by each other via the exchange and dipole interactions. The spin motion varies in singlet/triplet character, and if the chemical reaction is more (or less) favorable in a singlet/triplet state, the reaction rate can depend on applied magnetic fields, even ones very weak and near earth-strength. To approach the above goal, during my graduate work I have developed and published several new perturbation treatments for combinations of steady and oscillating magnetic fields in the radical pair mechanism: one based on the Schri::idinger Equation (see [4, 5] or Chapter 3), another based on the Liouville Equation (see [6] or Chapter 4), and two more mixed perturbation methods that bridge the gap between the Schri::idinger and Liouville formalisms (see Chapter 5). All of these iterative approaches can be used to calculate singlet-to-triplet yields when the strength of the oscillating magnetic field is weak compared to the other terms in the spin Hamiltonian. This range occurs both in the natural magnetic environment (where oscillating fields tend to be smaller than 0.03 G and steady fields tend to be near 0.5 G) and in many man-made environments. Thus, these perturbation treatments should be applicable both in studies of magnetic sensory mechanisms in animals and in studies of health effects of electromagnetic fields. These perturbation methods also allow much faster calculation of singlet-to-triplet yields than do numerical integration methods and are more generally applicable than the rotating frame treatment, allowing treatment of anisotropic spin Hamiltonians and treatment of multiple oscillating fields at any orientation with respect to the steady field. Finally, the different perturbation methods complement each other; that is, the Liouville Equation method yields a more efficient and reliable computer algorithm while the Schrodinger Equation method yields more insight into how effects of steady and oscillating magnetic fields occur and can more easily be used to generate analytical expressions for field and frequency dependences of singlet-to-triplet yields. Also, while the Liouville formalism allows one to calculate effects on steady and oscillating field sensitivity of different escape rates (ks and kr) for singlet and triplet pairs and can be generalized to include relaxation, the Schrodinger formalism lets one treat both exponential and Noyes time-dependences. Together these new methods can be quite useful for studying biological effects of oscillating magnetic fields, and their sample results show a number of behaviors in the singletto- triplet yields (such as saturation effects, oscillating field strength and frequency resonances, and steady field strength- and orientation- dependent frequency shifts) that, while typical in quantum mechanics or magnetic resonance, seem surprising in biology and may account for conflicts in the magnetic field bioeffects literature. Also during my graduate work I have used EPR (Electron Paramagnetic Resonance) data for the cage radical pairs formed by the homolytic cleavage of Co-C bonds in several coenzyme B12 dependent enzymes to calculate effects of earth-strength steady and oscillating magnetic fields on their singlet-to-triplet yields via the radical pair mechanism (see [7] or Chapter 6). Energy level repulsions and the state-mixing they induce are found to be very important for determining overall sizes of effects and lower bounds on oscillating-field frequencies that can cause effects in such systems. B12 and similar systems with nearly axial zero-field spin Hamiltonians, dominated by terms over 100 times larger than Zeeman terms due to earth-strength steady fields, if under relatively immobile conditions of long lifetime, slow molecular tumbling, and slow spin relaxation, may be useful as biological sensors of both steady and oscillating fields that occur in nature, since the yields calculated show sensitivity to steady field strength (even after powder averaging) and orientation, and undergo steadyfield- dependent shifts in the oscillating-field frequencies of maximal effect. Thus, since B12 is used by a number of enzymes (including ribonucleotide reductase, which converts RNA to DNA nucleotides; methyl malonyl CoA mutase, which controls the metabolism of certain fatty acids in mammals; and methionine synthase, which in mammals is used to regenerate active methyl groups on S-adenosyl methionine, which is involved in DNA methylation, melatonin and epinephrine synthesis, myelination, and methylation of chemotaxis proteins) and since some of these B12-dependent processes have been reported to be influenced by magnetic fields, coenzyme B12 may be an interesting candidate target for magnetic field effects in biology.U of I Onlydissertation/thesi

Effects of respiratory muscle training (RMT) in children with infantile-onset Pompe disease and respiratory muscle weakness

PURPOSE: Respiratory muscle weakness is a primary therapeutic challenge for patients with infantile Pompe disease. We previously described the clinical implementation of a respiratory muscle training (RMT) regimen in two adults with late-onset Pompe disease; both demonstrated marked increases in inspiratory and expiratory muscle strength in response to RMT. However, the use of RMT in pediatric survivors of infantile Pompe disease has not been previously reported. METHOD: We report the effects of an intensive RMT program on maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) using A-B-A (baseline-treatment-posttest) single subject experimental design in two pediatric survivors of infantile Pompe disease. Both subjects had persistent respiratory muscle weakness despite long-term treatment with alglucosidase alfa. RESULTS: Subject 1 demonstrated negligible to modest increases in MIP/MEP (6% increase in MIP, d=0.25; 19% increase in MEP, d=0.87), while Subject 2 demonstrated very large increases in MIP/MEP (45% increase in MIP, d=2.38; 81% increase in MEP, d=4.31). Following three-month RMT withdrawal, both subjects maintained these strength increases and demonstrated maximal MIP and MEP values at follow-up. CONCLUSION: Intensive RMT may be a beneficial treatment for respiratory muscle weakness in pediatric survivors of infantile Pompe disease