Dynamic Transformation of High-Architectural Nanocrystal Superlattices upon Solvent Molecule Exposure.

The cluster-based body-centered-cubic superlattice (cBCC SL) represents one of the most complicated structures among reported nanocrystal assemblies, comprised of 72 truncated tetrahedral quantum dots per unit cell. Our previous report revealed that truncated tetrahedral quantum dots within cBCC SLs possessed highly controlled translational and orientational order owing to an unusual energetic landscape based on the balancing of entropic and enthalpic contributions during the assembly process. However, the cBCC SL's structural transformability and mechanical properties, uniquely originating from such complicated nanostructures, have yet to be investigated. Herein, we report that cBCC SLs can undergo dynamic transformation to face-centered-cubic SLs in response to post-assembly molecular exposure. We monitored the dynamic transformation process using in situ synchrotron-based small-angle X-ray scattering, revealing a dynamic transformation involving multiple steps underpinned by interactions between incoming molecules and TTQDs' surface ligands. Furthermore, our mechanistic study demonstrated that the precise configuration of TTQDs' ligand molecules in cBCC SLs was key to their high structural transformability and unique jelly-like soft mechanical properties. While ligand molecular configurations in nanocrystal SLs are often considered minor features, our findings emphasize their significance in controlling weak van der Waals interactions between nanocrystals within assembled SLs, leading to previously unremarked superstructural transformability and unique mechanical properties. Our findings promote a facile route toward further creation of soft materials, nanorobotics, and out-of-equilibrium assemblies based on nanocrystal building blocks.

Bambus[4,6]urils as Dual Scaffolds for Multivalent Iminosugar Presentation and Ion Transport: Access to Unprecedented Glycosidase-Directed Anion Caging Agents.

Bambusurils, BU[4] and BU[6], were used for the first time as multivalent scaffolds to link glycosidases inhibitors derived from 1-deoxynojirimycin (DNJ). Two linear DNJ ligands having six or nine carbon alkyl azido linkers or a trivalent DNJ dendron were grafted onto octapropargylated BU[4] and dodecapropargylated BU[6] using copper-catalyzed cycloaddition (CuAAC) to yield corresponding neoglycobambus[4] and neoglycobambus[6]urils bearing 8 to 24 iminosugars. The inhibition potencies of neoglycoBU[4], neoglycoBU[6] and neoglycoBU[6] caging anions were evaluated against Jack Bean α-mannosidase and compared to monovalent DNJ derivatives. Strong affinity enhancements per inhibitory head were obtained for the clusters holding trivalent dendrons with inhibitory constants in the nanomolar range (Ki = 24 nM for BU[4] with 24 DNJ units). Interestingly, the anion (bromide or iodide) encapsulated inside the cavity of BU[6] does not modify the inhibition potency of neoglycoBU[6], opening the way to water-soluble glycosidase-directed anion caging agents that may find applications in important fields such as bio(in)organic chemistry or oncology.

Hybrid Multivalent Jack Bean α-Mannosidase Inhibitors: The First Example of Gold Nanoparticles Decorated with Deoxynojirimycin Inhitopes.

Among carbohydrate-processing enzymes, Jack bean α-mannosidase (JBα-man) is the glycosidase with the best responsiveness to the multivalent presentation of iminosugar inhitopes. We report, in this work, the preparation of water dispersible gold nanoparticles simultaneously coated with the iminosugar deoxynojirimycin (DNJ) inhitope and simple monosaccharides (ß-d-gluco- or α-d-mannosides). The display of DNJ at the gold surface has been modulated (i) by using an amphiphilic linker longer than the aliphatic chain used for the monosaccharides and (ii) by presenting the inhitope, not only in monomeric form, but also in a trimeric fashion through combination of a dendron approach with glyconanotechnology. The latter strategy resulted in a strong enhancement of the inhibitory activity towards JBα-man, with a Ki in the nanomolar range (Ki = 84 nM), i.e., more than three orders of magnitude higher than the monovalent reference compound.

Giant Glycosidase Inhibitors: First- and Second-Generation Fullerodendrimers with a Dense Iminosugar Shell.

The multivalent effect in glycosidase inhibition is a new topic in glycoscience that has emerged a few years ago, with the discovery of neoglycoclusters displaying strong binding enhancements over the corresponding monovalent inhibitor. Iminosugar-fullerene conjugates with high valencies have been prepared from iminosugar-terminated dendrons and a clickable fullerene hexa-adduct scaffold. The simultaneous grafting of twelve dendrons allows for a very fast dendritic growth thus limiting the number of synthetic steps required to prepare compounds with a high number of peripheral units. The grafting of first- and second-generation dendrons provided fullerodendrimers surrounded by 36 and 108 peripheral iminosugars, respectively. Inhibition studies have been carried out with a panel of glycosidases. In the particular case of Jack bean α-mannosidase, the 108-valent nanoconstruct displays inhibition in the nanomolar range and an additional binding enhancement of one order of magnitude when compared to the 36-valent analogues.

Expedient synthesis of trifunctional oligoethyleneglycol-amine linkers and their use in the preparation of PEG-based branched platforms.

We designed a convergent synthesis pathway that provides access to trifunctional oligoethyleneglycol-amine (OEG-amine) linkers. By applying the reductive coupling of a primary azide to bifunctional OEG-azide precursors, the corresponding symmetrical dialkylamine bearing two homo-functional end chain groups and a central nitrogen was obtained. These building blocks bear minimal structural perturbation compared to the native OEG backbone which makes them attractive for biomedical applications. The NMR investigations of the mechanism process reveal the formation of nitrile and imine intermediates which can react with the reduced free amine form. Additionally, these trifunctional OEG-amine linkers were employed in a coupling reaction to afford branched multifunctional PEG dendrons which are molecularly defined. These discrete PEG-based dendrons (n = 16, 18 and 36) could be useful for numerous applications where multivalency is required.

One-Pot, Highly Stereoselective Synthesis of Dithioacetal-α,α-Diglycosides.

A one-step access to dithioacetal-α,α-diglycosides is reported. The synthetic strategy is based on the thioacetalization of aldehydes or ketones via highly stereoselective ring-opening of 1,6 anhydrosugars with bis(trimethylsilyl)sulfide.

Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus: report of a case and review of the literature.

Severe bullous eruptions in systemic lupus erythematosus (SLE) patients include bullous SLE, Rowell syndrome, toxic epidermal necrolysis (TEN), and TEN-like eruption of acute cutaneous lupus (TEN-like ACLE). TEN-like ACLE, a rare manifestation of SLE that closely mimics TEN, can be distinguished by characteristic clinical and laboratory findings. A 27-year-old man with SLE who developed TEN-like ACLE after initiating mycophenolate mofetil for active SLE is reported. The reports of 37 women and six men  including our patient with TEN-like ACLE were also reviewed. The diagnosis of SLE or subacute cutaneous lupus erythematosus was either previously confirmed or established at the time of diagnosis of TEN-like ACLE in 41 patients. Fever was present in 59% of patients. The onset of TEN-like ACLE was either subacute (73%) or acute (27%). Thirteen cases did not clarify the nature of disease onset. The skin lesions often presented initially on sun-exposed sites (29 patients) and involved one or more mucous membranes (21 patients). A new medication may have caused the TEN-like ACLE in 67% of the patients. Systemic corticosteroids either alone or combined with hydroxychloroquine, intravenous immunoglobulin, or mycophenolate mofetil were the most commonly used treatment. Patients with TEN-like ACLE patients had an 89% survival.

Structural Basis of Outstanding Multivalent Effects in Jack Bean α-Mannosidase Inhibition.

Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic-level understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first high-resolution crystal structures of the Jack bean α-mannosidase (JBα-man) in apo and inhibited states. The three-dimensional structure of JBα-man in complex with the multimeric cyclopeptoid-based inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition.

The first mite: insect genealogy in Hooke's Micrographia.

What happens when you take the idea of the biblical Adam-the first human - and apply it to insects? You create an origin story for Nature's tiniest creatures, one that gives them 'a Pedigree as ancient as the first creation'. This the naturalist Robert Hooke argued in his treatise, the Micrographia (1665). In what follows, I will retrace how Hooke endeavoured to show that insects-then widely believed to have arisen out of the dirt - were the products of an ancient lineage. These genealogies, while constructed from empirical observation, were conjectures of the imagination. Section 2 shows how Hooke introduced the concept of a 'prime parent' (an Adam-insect) to explain the anatomical similarities between 'mites'. Section 3 demonstrates how Hooke defined the family of "gnats" as tiny machines built from the same components and relates Hookean genealogies to contemporary ideas about Noah's Ark. Section 4 shows how Hooke outlined the morphology of 'insects' (delineating what we now call arthropods). Section 5 explores how Hooke used fossils to study these animals in the distant past. In sum, Hooke was turning natural history - collecting and describing insects - into natural history: reconstructing their origins.

Iminosugar-Cyclopeptoid Conjugates Raise Multivalent Effect in Glycosidase Inhibition at Unprecedented High Levels.

A series of cyclopeptoid-based iminosugar clusters has been evaluated to finely probe the ligand content-dependent increase in α-mannosidase inhibition. This study led to the largest binding enhancement ever reported for an enzyme inhibitor (up to 4700-fold on a valency-corrected basis), which represents a substantial advance over the multivalent glycosidase inhibitors previously reported. Electron microscopy imaging and analytical data support, for the best multivalent effects, the formation of a strong chelate complex in which two mannosidase molecules are cross-linked by one inhibitor.

Toward a Molecular Lego Approach for the Diversity-Oriented Synthesis of Cyclodextrin Analogues Designed as Scaffolds for Multivalent Systems.

A modular strategy has been developed to access a diversity of cyclic and acyclic oligosaccharide analogues designed as prefunctionalized scaffolds for the synthesis of multivalent ligands. This convergent approach is based on bifunctional sugar building blocks with two temporarily masked functionalities that can be orthogonally activated to perform Cu(I)-catalyzed azide-alkyne cycloaddition reactions (CuAAC). The reducing end is activated as a glycosyl azide and masked as a 1,6-anhydro sugar, while the nonreducing end is activated as a free alkyne and masked as a triethylsilyl-alkyne. Following a cyclooligomerization approach, the first examples of close analogues of cyclodextrins composed of d-glucose residues and triazole units bound together through α-(1,4) linkages were obtained. The cycloglucopyranoside analogue containing four sugar units was used as a template to prepare multivalent systems displaying a protected d-mannose derivative or an iminosugar by way of CuAAC. On the other hand, the modular approach led to acyclic alkyne-functionalized scaffolds of a controlled size that were used to synthesize multivalent iminosugars.

A systematic investigation of iminosugar click clusters as pharmacological chaperones for the treatment of Gaucher disease.

A series of 18 mono- to 14-valent iminosugars with different ligands, scaffolds, and alkyl spacer lengths have been synthesized and evaluated as inhibitors and pharmacological chaperones of ß-glucocerebrosidase (GCase). Small but significant multivalent effects in GCase inhibition have been observed for two iminosugar clusters. Our study provides strong confirmation that compounds that display the best affinity for GCase are not necessarily the best chaperones. The best chaperoning effect observed for a deprotected iminosugar cluster has been obtained with a tetravalent 1-deoxynojirimycin (DNJ) analogue (3.3-fold increase at 10 µM). In addition, our study provides the first evidence of the high potential of prodrugs for the development of potent pharmacological chaperones. Acetylation of a trivalent DNJ derivative, to give the corresponding acetate prodrug, leads to a pharmacological chaperone that produces higher enzyme activity increases (3.0-fold instead of 2.4-fold) at a cellular concentration (1 µM) reduced by one order of magnitude.

Cardiovascular and blood glucose parameters in infants during propranolol initiation for treatment of symptomatic infantile hemangiomas.

OBJECTIVES: We sought to determine the effect of propranolol on cardiovascular and blood glucose parameters in infants with symptomatic infantile hemangiomas who were hospitalized for initiation of treatment, and to analyze adverse effects of propranolol throughout the course of inpatient and outpatient treatment. METHODS: A retrospective cohort analysis was performed on 50 infants (age less than 12 months) with symptomatic infantile hemangiomas who were hospitalized for propranolol initiation between 2008 and 2012. Demographic data and disease characteristics were recorded. Systolic and diastolic blood pressures, heart rate, blood glucose values, and adverse events recorded during hospitalization were analyzed. An additional cohort of 200 consecutively treated children was also assessed for adverse events associated with outpatient propranolol use. RESULTS: The median age among the inpatient cohort was 3.4 months (range, 0.8 to 12.0 months). Infants older than 6 months were more likely to exhibit bradycardia than were younger infants (p < 0.001). Hypotensive and/or bradycardic periods were infrequent and were not associated with observable clinical symptoms. The mean systolic and diastolic blood pressures and the mean heart rate decreased significantly from day 1 of hospitalization to day 2 (p = 0.004; p = 0.008; p < 0.001), but not from day 2 to day 3, when the propranolol dose was increased to target. Hypoglycemia was rare (0.3% incidence.) Among the 250 outpatients, 2 infants developed lethargy and hypoglycemia during a viral illness and recovered without sequelae. One infant experienced recurrent bronchospasm with viral illnesses and required concomitant bronchodilator therapy. CONCLUSIONS: Frequent deviations from normal ranges of blood pressure and heart rate occur upon initiation of propranolol, but are clinically asymptomatic. These findings support that outpatient initiation of propranolol in healthy, normotensive infants appears to be a relatively safe alternative to inpatient initiation. Hypoglycemia is rare, but can occur throughout the treatment period; parent counseling is of paramount importance.

Quantum Dot-based Luminescent Solar Concentrators Fabricated through the Ultrasonic Spray-Coating Method.

Luminescent solar concentrators (LSCs) are a class of wave-guiding devices that can harvest solar light and concentrate it to targeted smaller areas. When coupled with photovoltaic devices (PVs), LSCs hold the potential to be integrated into various application setups, especially for building facade integration toward net-zero-energy buildings. Developing reliable LSC fabrication methods with easy scalability, high adaptability, and device controllability has been an important research topic. In this work, we report an ultrasonic nebulization-assisted spray deposition technique to fabricate quantum dot (QD)-based LSCs (QD-LSCs). This method allows for the production of high-performance QD-LSCs with different device dimensions and geometries. In addition, the quality of the QD thin-film coating layer is relatively independent of the concentration and volume of the coating QD ink solution, allowing for deliberate programming and performance optimization of the resulting QD-LSC devices. We anticipate that this ultrasonic spray coating method can be widely applied to the manufacturing of high-quality LSC devices that are integrable to various applications.

Pharmacogenomics of Allopurinol and Sulfamethoxazole/Trimethoprim: Case Series and Review of the Literature.

Severe cutaneous adverse drug reactions (SCAR) such as the Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DIHS) can be induced by a plethora of medications. The field of pharmacogenomics aims to prevent severe adverse drug reactions by using our knowledge of the inherited or acquired genetic risk of drug metabolizing enzymes, drug targets, or the human leukocyte antigen (HLA) genotype. Dermatologists are experts in the diagnosis and management of severe cutaneous adverse drug reactions (SCAR) in both the inpatient and outpatient setting. However, most dermatologists in the US have not focused on the prevention of SCAR. Therefore, this paper presents a case series and review of the literature highlighting salient examples of how dermatologists can apply pharmacogenomics in the diagnosis and especially in the prevention of SCAR induced by allopurinol and sulfamethoxazole/trimethoprim, two commonly prescribed medications.

An Unusual Case of Morphea in the Setting of Aplastic Anemia.

Cutaneous sclerosis occurs in association with a variety of systemic diseases, including hematologic malignancy, plasma cell dyscrasias, solid organ tumors, and other systemic autoimmune conditions. Herein, we present a unique case of morphea/lichen sclerosus overlap arising in association with aplastic anemia. To expand upon this rare case, we also review the literature surrounding paraneoplastic sclerosing skin disorders. A 53-year-old man presented with a 13-month history of progressive and generalized skin changes. Exam revealed irregular, hypopigmented indurated plaques with focal areas of scale on the bilateral axillae and hips, as well as hyperpigmented brown papules and plaques on the back. Laboratory evaluation revealed pancytopenia and positive anti-nuclear antibody (1:160). Bone marrow biopsy demonstrated hypocellular marrow consistent with aplastic anemia. Furthermore, skin biopsies revealed lichen sclerosus overlying superficial morphea, consistent with a paraneoplastic sclerodermoid-like eruption. While preparations for hematologic-directed therapies were made, skin-directed therapy with a combination topical steroids and topical calcineurin inhibitors was initiated. Eosinophilic fasciitis and scleroderma have been linked to aplastic anemia, and herein, we expand upon this phenomenon by presenting our case of generalized plaque morphea/lichen sclerosus overlap arising in the setting of aplastic anemia. Dermatologists must be aware of this rare association in order to identify precocious hematologic disease.

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters.

A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their rigidity but not in their size. The power of multivalency to upgrade the inhibition potency of the weak DNJ inhibitor (monovalent DNJ Ki being at 322 and 188 µM for C6 or C9 linkers, respectively) was evaluated on the model glycosidase Jack Bean α-mannosidase (JBα-man). Although for the clusters with the shorter C6 linker the rigidity of the scaffold was essential, these parameters had no influence for clusters with C9 chains: all of them showed rather good relative affinity enhancements per inhibitory epitopes between 70 and 160 highlighting the sound combination of the calix[8]arene core and the long alkyl arms. Preliminary docking studies were performed to get insights into the preferred binding modes.