High-throughput discovery of organic cages and catenanes using computational screening fused with robotic synthesis.

Supramolecular synthesis is a powerful strategy for assembling complex molecules, but to do this by targeted design is challenging. This is because multicomponent assembly reactions have the potential to form a wide variety of products. High-throughput screening can explore a broad synthetic space, but this is inefficient and inelegant when applied blindly. Here we fuse computation with robotic synthesis to create a hybrid discovery workflow for discovering new organic cage molecules, and by extension, other supramolecular systems. A total of 78 precursor combinations were investigated by computation and experiment, leading to 33 cages that were formed cleanly in one-pot syntheses. Comparison of calculations with experimental outcomes across this broad library shows that computation has the power to focus experiments, for example by identifying linkers that are less likely to be reliable for cage formation. Screening also led to the unplanned discovery of a new cage topology-doubly bridged, triply interlocked cage catenanes.

Chirality as a tool for function in porous organic cages.

The control of solid state assembly for porous organic cages is more challenging than for extended frameworks, such as metal-organic frameworks. Chiral recognition is one approach to achieving this control. Here we investigate chiral analogues of cages that were previously studied as racemates. We show that chiral cages can be produced directly from chiral precursors or by separating racemic cages by co-crystallisation with a second chiral cage, opening up a route to producing chiral cages from achiral precursors. These chiral cages can be cocrystallized in a modular, 'isoreticular' fashion, thus modifying porosity, although some chiral pairings require a specific solvent to direct the crystal into the desired packing mode. Certain cages are shown to interconvert chirality in solution, and the steric factors governing this behavior are explored both by experiment and by computational modelling.

Reticular synthesis of porous molecular 1D nanotubes and 3D networks.

Synthetic control over pore size and pore connectivity is the crowning achievement for porous metal-organic frameworks (MOFs). The same level of control has not been achieved for molecular crystals, which are not defined by strong, directional intermolecular coordination bonds. Hence, molecular crystallization is inherently less controllable than framework crystallization, and there are fewer examples of 'reticular synthesis', in which multiple building blocks can be assembled according to a common assembly motif. Here we apply a chiral recognition strategy to a new family of tubular covalent cages to create both 1D porous nanotubes and 3D diamondoid pillared porous networks. The diamondoid networks are analogous to MOFs prepared from tetrahedral metal nodes and linear ditopic organic linkers. The crystal structures can be rationalized by computational lattice-energy searches, which provide an in silico screening method to evaluate candidate molecular building blocks. These results are a blueprint for applying the 'node and strut' principles of reticular synthesis to molecular crystals.

Functional porous composites by blending with solution-processable molecular pores.

We present a simple method for rendering non-porous materials porous by solution co-processing with organic cage molecules. This method can be used both for small functional molecules and for polymers, thus creating porous composites by molecular blending, rather than the more traditional approach of supporting functional molecules on pre-frabricated porous supports.

Side-chain control of porosity closure in single- and multiple-peptide-based porous materials by cooperative folding.

Porous materials are attractive for separation and catalysis-these applications rely on selective interactions between host materials and guests. In metal-organic frameworks (MOFs), these interactions can be controlled through a flexible structural response to the presence of guests. Here we report a MOF that consists of glycyl-serine dipeptides coordinated to metal centres, and has a structure that evolves from a solvated porous state to a desolvated non-porous state as a result of ordered cooperative, displacive and conformational changes of the peptide. This behaviour is driven by hydrogen bonding that involves the side-chain hydroxyl groups of the serine. A similar cooperative closure (reminiscent of the folding of proteins) is also displayed with multipeptide solid solutions. For these, the combination of different sequences of amino acids controls the framework's response to the presence of guests in a nonlinear way. This functional control can be compared to the effect of single-point mutations in proteins, in which exchange of single amino acids can radically alter structure and function.

Shape selectivity by guest-driven restructuring of a porous material.

A flexible metal-organic framework selectively sorbs para- (pX) over meta-xylene (mX) by synergic restructuring around pX coupled with generation of unused void space upon mX loading. The nature of the structural change suggests more generally that flexible structures which are initially mismatched in terms of fit and capacity to the preferred guest are strong candidates for effective molecular separations.

Prevalence and risk factors for hepatitis C virus infection at an urban Veterans Administration medical center.

This study was designed to determine the seroprevalence and risk factors for hepatitis C virus (HCV) infection in veterans. Anti-HCV testing was performed in 1,032 patients and a questionnaire regarding sociodemographic characteristics and potential risk factors was administered. Adjusted prevalence of unique HCV-positive patients using outpatient services was 17.7% (95% confidence interval [CI] 17.2%, 18.2%). The following risk factors were associated with HCV infection: a history of injection drug use (IDU), receipt of blood transfusion prior to 1992, history of tattoo (odds ratio [OR], 2.93; 95% CI, 1.70-5.08), combat job as a medical worker (OR, 2.68; 95% CI, 1.25-5.60), history of incarceration over 48 hours (OR, 2.56; 95% CI, 1.52-4.32), greater than 15 lifetime sexual partners (OR, 1.61; 95% CI, 0.94-2.76) and sexual relations with a prostitute (OR, 0.46; 95% CI, 0.25-0.82). We concluded that HCV is common in veterans. Risk factors independently associated with infection are IDU, prior transfusion, prior tattoo, combat medical work, incarceration, and multiple opposite sex partners. Infection with HCV among veterans is strongly associated with traditional risk factors for infection and less strongly associated with combat-related risk.

Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy is an important cause of intracerebral hemorrhage in the elderly. The epsilon 4 allele of the apolipoprotein E gene, recently established as a genetic risk for Alzheimer's disease, has also been suggested as a possible risk factor for cerebral amyloid angiopathy. We sought to determine whether this allele is specifically associated with hemorrhages related to amyloid angiopathy and whether it correlates with the age at which first amyloid angiopathy-related hemorrhage occurs. METHODS: Forty-five consecutive patients presenting with lobar hemorrhage were prospectively classified according to clinical, radiological, and when available, pathological features and evaluated for apolipoprotein E genotype. They were compared with 1899 elderly patients from a population-based sample and with 18 consecutive patients with hemorrhages in deep regions typical of a hypertensive mechanism. RESULTS: Patients with multiple hemorrhages confined to the lobar territory demonstrated a greater than twofold overrepresentation (P < .001) in frequency of the apolipoprotein E epsilon 4 allele compared with the population-based sample. Apolipoprotein E genotypes of patients with hemorrhages in deep territories resembled the population sample. Among patients with strictly lobar hemorrhages, carriers of the epsilon 4 allele had their first hemorrhage more than 5 years earlier than noncarriers (mean age at first hemorrhage, 73.4 +/- 8.0 versus 78.9 +/- 7.4 years; P = .033). These effects were independent of the accompanying presence of Alzheimer's disease. CONCLUSIONS: The data support a specific role for apolipoprotein E epsilon 4 in accelerating the process that leads to amyloid angiopathy-related hemorrhage.

Statistical fitting accuracy in photon correlation spectroscopy.

Continuing our experimental investigation of the fitting accuracy associated with photon correlation spectroscopy, we collect 150 correlograms of light scattered at 90° from a thermostated sample of 91-nm-diameter, polystyrene latex spheres in water. The correlograms are taken with two correlators: one with linearly spaced channels and one with geometrically spaced channels. Decay rates are extracted from the single-exponential correlograms with both nonlinear, least-squares fits and second-order cumulant fits. We make several statistical comparisons between the two fitting techniques and verify an earlier result that there is no sample-time dependence in the decay rate errors. We find, however, that the two fitting techniques give decay rates that differ by 1%.