Highly Scalable,Closed‐Loop Synthesis of Drug‐Loaded,Layer‐by‐Layer Nanoparticles

Layer‐by‐layer (LbL) self‐assembly is a versatile technique from which multi­component and stimuli‐responsive nanoscale drug‐carriers can be constructed. Despite the benefits of LbL assembly, the conventional synthetic approach for fabricating LbL nanoparticles requires numerous purification steps that limit scale, yield, efficiency, and potential for clinical translation. In this report, a generalizable method for increasing throughput with LbL assembly is described by using highly scalable, closed‐loop diafiltration to manage intermediate purification steps. This method facilitates highly controlled fabrication of diverse nanoscale LbL formulations smaller than 150 nm composed from solid‐polymer, mesoporous silica, and liposomal vesicles. The technique allows for the deposition of a broad range of polyelectrolytes that included native polysaccharides, linear polypeptides, and synthetic polymers. The cytotoxicity, shelf life, and long‐term storage of LbL nanoparticles produced using this approach are explored. It is found that LbL coated systems can be reliably and rapidly produced: specifically, LbL‐modified liposomes could be lyophilized, stored at room temperature, and reconstituted without compromising drug encapsulation or particle stability, thereby facilitating large scale applications. Overall, this report describes an accessible approach that significantly improves the throughput of nanoscale LbL drug‐carriers that show low toxicity and are amenable to clinically relevant storage conditions.     

Inside Cover: Cognitive‐Performance Recovery of Alzheimer's Disease Model Mice by Modulation of Early Soluble Amyloidal Assemblies (Angew. Chem. Int. Ed. 11/2009)

The accumulation of amyloid‐β (Aβ) as amyloid fibril deposits may play a central role in the pathogenesis of Alzheimer's disease, which is among the most common diseases of the 21st century. E. Gazit and co‐workers describe in their Communication on page 1981 ff. a novel Aβ fibrilization inhibitor, whose mechanism of action is based on targeting aromatic recognition modules together with a unique C^α‐methylation β‐breakage strategy. We thank Tal Mazor for the graphical assistance with the cover.

     

The photo-dissociation of the pyrrole-ammonia complex--the role of hydrogen bonding in Rydberg states photochemistry

The photochemistry of the pyrrole-ammonia cluster is analyzed theoretically. Whereas in neat pyrrole the dominant photochemical reaction is H-atom cleavage, recent experiments show that in pyrrole-ammonia clusters the major reaction is H-transfer to form the NH(4) radical (solvated by ammonia molecules in the case of large clusters) and the pyrrolyl radical. A mechanism involving the hydrogen-bonded Rydberg state is offered to account for these results and verified computationally. Two minima are located on the lowest excited singlet PES. Both of them are Rydberg states, one leads to the formation of NH(4) and pyrrolyl radicals, the other is connected to the πσ* state through a relatively high barrier, leading to a 3-body dissociation reaction to form a pyrrolyl radical, ammonia and an H-atom. The former is the energetically and statistically preferred one.     

Determination of the lithium binding site in inositol monophosphatase, the putative target for lithium therapy, by magic-angle-spinning solid-state NMR

Inositol monophosphatase (IMPase) catalyzes the hydrolysis of inositol monophosphate to inorganic phosphate and inositol. For this catalytic process to occur, Mg(2+) cations must exist in the active site. According to the inositol depletion hypothesis, IMPase activity is assumed to be higher than normal in patients suffering from bipolar disorder. Treatment with Li(+), an inhibitor of IMPase, reduces its activity, but the mechanism by which lithium exerts its therapeutic effects is still at a stage of conjecture. The Escherichia coli SuhB gene product possesses IMPase activity, which is also strongly inhibited by Li(+). It has significant sequence similarity to human IMPase and has most of its key active-site residues. Here we show that by using (7)Li magic-angle-spinning solid-state NMR spectroscopy, including {(13)C}(7)Li dipolar recoupling experiments, the bound form of lithium in the active site of wild-type E. coli SuhB can be unambiguously detected, and on the basis of our data and other biochemical data, lithium binds to site II, coupled to aspartate residues 84, 87, and 212.     

The perceptual nature of vocal register change

This study focuses on the perceptual nature of chest and falsetto registers as a function of various production tokens and methods of perceptual evaluation. Fifteen target tones, ranging from G#3 to A#4, were sung by a male and a female subject in the context of ascending and descending sequences on the vowels /a/ and /i/. Register transitions were elicited by setting strict constraints on production. Segments of 1-s duration were extracted from the target notes, digitized, and acoustically analyzed. These excerpts were presented to ten trained listeners in four different perceptual tasks. Identification and discrimination tasks yielded nearly identical results, suggesting that the primary registers are perceived as distinct entities. The marked change from chest to falsetto as well as the locus of the transition between these registers did not vary systematically as a function of production token or perceptual task. Mean register shift-point frequencies of the male and female subjects were perceived at 320 Hz and 353 Hz, respectively. Multidimensional scaling and hierarchical clustering analyses were utilized to capture the dimensionality and the internal structure of perceptual data sets derived from the pair-wise similarity ratings. Optimal spatial representation of these data required no more than two orthogonal dimensions, with the quality attribute represented by the dominant dimension. The representation of pitch differences was reflected only in the internal ordering of the stimuli within registers, but did not affect the perceptual discontinuity between registers.     

The presence of antimony in various dental filling materials

Antimony has been determined in a number of nonmetallic dental materials currently used for tooth restoration. The method applied was instrumental neutron activation analysis. The concentration of antimony in some of the brands tested was found to be as high as 900 fold that in the normal hard dental tissues.     

A Push–Pull Network with Infinite Supply of Work

We consider a two-node multiclass queueing network with two types of jobs moving through two servers in opposite directions, and there is infinite supply of work of both types. We assume exponential processing times and preemptive resume service. We identify a family of policies which keep both servers busy at all times and keep the queues between the servers positive recurrent. We analyze two specific policies in detail, obtaining steady state distributions. We perform extensive calculations of expected queue lengths under these policies. We compare this network with the Kumar–Seidman–Rybko–Stolyar network, in which there are two random streams of arriving jobs rather than infinite supply of work.     

Enhanced Antibacterial Activity of Nanocrystalline ZnO Due to Increased ROS‐Mediated Cell Injury

An innovative study aimed at understanding the influence of the particle size of ZnO (from the microscale down to the nanoscale) on its antibacterial effect is reported herein. The antibacterial activity of ZnO has been found to be due to a reaction of the ZnO surface with water. Electron‐spin resonance measurements reveal that aqueous suspensions of small nanoparticles of ZnO produce increased levels of reactive oxygen species, namely hydroxyl radicals. Interestingly, a remarkable enhancement of the oxidative stress, beyond the level yielded by the ZnO itself, is detected following the antibacterial treatment. Likewise, an exposure of bacteria to the small ZnO nanoparticles results in an increased cellular internalization of the nanoparticles and bacterial cell damage. An examination of the antibacterial effect is performed on two bacterial species: Escherichia coli (Gram negative) and Staphylococcus aureus (Gram positive). The nanocrystalline particles of ZnO are synthesized using ultrasonic irradiation, and the particle sizes are controlled using different solvents during the sonication process. Taken as a whole, it is apparent that the unique properties (i.e., small size and corresponding large specific surface area) of small nanometer‐scale ZnO particles impose several effects that govern its antibacterial action. These effects are size dependent and do not exist in the range of microscale particles.