Glucose‐Responsive Composite Microneedle Patch for Hypoglycemia‐Triggered Delivery of Native Glucagon

Insulin‐dependent patients with diabetes mellitus require multiple daily injections of exogenous insulin to combat hyperglycemia. However, administration of excess insulin can lead to hypoglycemia, a life‐threatening condition characterized by abnormally low blood glucose levels (BGLs). To prevent hypoglycemia associated with intensive insulin therapy, a “smart” composite microneedle (cMN) patch is developed, which releases native glucagon at low glucose levels. The cMN patch is composed of a photo‐crosslinked methacrylated hyaluronic acid (MeHA) microneedle array with embedded multifunctional microgels. The microgels incorporate zwitterionic moieties that stabilize loaded glucagon and phenylboronic acid moieties that provide glucose‐dependent volume change to facilitate glucagon release. Hypoglycemia‐triggered release of structurally unchanged glucagon from the cMN patch is demonstrated in vitro and in a rat model of type 1 diabetes (T1D). Transdermal application of the patch prevented insulin‐induced hypoglycemia in the diabetic rats. This work is the first demonstration of a glucose‐responsive glucagon‐delivery MN patch for the prevention of hypoglycemia, which has a tremendous potential to reduce the dangers of intensive insulin therapy and improve the quality of life of patients with diabetes and their caregivers.     

Tuning the Hydrophobicity of a Mitochondria‐Targeted NO Photodonor

A few compounds in which the nitric oxide (NO) photodonor N‐[4‐nitro‐3‐(trifluoromethyl)phenyl]propane‐1,3‐diamine is joined to the mitochondria‐targeting alkyltriphenylphosphonium moiety via flexible spacers of variable length were synthesized. The lipophilicity of the products was evaluated by measuring their partition coefficients in n‐octanol/water. The obtained values, markedly lower than those calculated, are consistent with the likely collapsed conformation assumed by the compounds in solution, as suggested by molecular dynamics simulations. The capacity of the compounds to release NO under visible light irradiation was evaluated by measuring nitrite production by means of the Griess reaction. The accumulation of compounds in the mitochondria of human lung adenocarcinoma A549 cells was assessed by UPLC–MS. Interestingly, compound 13 [(9‐((3‐((4‐nitro‐3‐(trifluoromethyl)phenyl)amino)propyl)amino)‐9‐oxononyl) triphenylphosphonium bromide] displayed both the highest accumulation value and high toxicity toward A549 cells upon irradiation‐mediated NO release in mitochondria.     

Predicting hydrogen-bond strengths from acid-base molecular properties. The pK(a) slide rule: toward the solution of a long-lasting problem

Unlike normal chemical bonds, hydrogen bonds (H-bonds) characteristically feature binding energies and contact distances that do not simply depend on the donor (D) and acceptor (:A) nature. Instead, their chemical context can lead to large variations even for a same donor-acceptor couple. As a striking example, the weak HO-H...OH(2) bond in neutral water changes, in acidic or basic medium, to the 6-fold stronger and 15% shorter [H(2)O...H...OH(2)](+) or [HO...H...OH](-) bonds. This surprising behavior, sometimes called the H-bond puzzle, practically prevents prediction of H-bond strengths from the properties of the interacting molecules. Explaining this puzzle has been the main research interest of our laboratory in the last 20 years. Our first contribution was the proposal of RAHB (resonance-assisted H-bond), a new type of strong H-bond where donor and acceptor are linked by a short pi-conjugated fragment. The RAHB discovery prompted new studies on strong H-bonds, finally leading to a general H-bond classification in six classes, called the six chemical leitmotifs, four of which include all known types of strong bonds. These studies attested to the covalent nature of the strong H-bond showing, by a formal valence-bond treatment, that weak H-bonds are basically electrostatic while stronger ones are mixtures of electrostatic and covalent contributions. The covalent component gradually increases as the difference of donor-acceptor proton affinities, DeltaPA, or acidic constants, DeltapK(a), approaches zero. At this limit, the strong and symmetrical D...H...A bonds formed can be viewed as true three-center-four-electron covalent bonds. These results emphasize the role PA/pK(a) equalization plays in strengthening the H-bond, a hypothesis often invoked in the past but never fully verified. In this Account, this hypothesis is reconsidered by using a new instrument, the pK(a) slide rule, a bar chart that reports in separate scales the pK(a)'s of the D-H proton donors and :A proton acceptors most frequently involved in D-H...:A bond formation. Allowing the two scales to shift so to bring selected donor and acceptor molecules into coincidence, the ruler permits graphical evaluation of DeltapK(a) and then empirical appreciation of the D-H...:A bond strength according to the pK(a) equalization principle. Reliability of pK(a) slide rule predictions has been verified by extensive comparison with two classical sources of H-bond strengths: (i) the gas-phase dissociation enthalpies of charged [X...H...X](-) and [X...H...X](+) bonds derived from the thermodynamic NIST Database and (ii) the geometries of more than 9500 H-bonds retrieved from the Cambridge Structural Database. The results attest that the pK(a) slide rule provides a reliable solution for the long-standing problem of H-bond-strength prediction and represents an efficient and practical tool for making such predictions directly accessible to all scientists.     

Ratiometric Organic Fibers for Localized and Reversible Ion Sensing with Micrometer‐Scale Spatial Resolution

A fundamental issue in biomedical and environmental sciences is the development of sensitive and robust sensors able to probe the analyte of interest, under physiological and pathological conditions or in environmental samples, and with very high spatial resolution. In this work, novel hybrid organic fibers that can effectively report the analyte concentration within the local microenvironment are reported. The nanostructured and flexible wires are prepared by embedding fluorescent pH sensors based on seminaphtho‐rhodafluor‐1‐dextran conjugate. By adjusting capsule/polymer ratio and spinning conditions, the diameter of the fibers and the alignment of the reporting capsules are both tuned. The hybrid wires display excellent stability, high sensitivity, as well as reversible response, and their operation relies on effective diffusional kinetic coupling of the sensing regions and the embedding polymer matrix. These devices are believed to be a powerful new sensing platform for clinical diagnostics, bioassays and environmental monitoring.     

Isolation, identification and utilization of thermophilic strains in aerobic digestion of sewage sludge

Two representative thermophilic bacterial strains (T1 and T2) were isolated from a one-stage autothermal thermophilic aerobic digestion pilot-scale reactor. 16S rRNA gene analysis indicated that they were Hydrogenophilaceae and Xanthomonodaceae. These isolated strains were inoculated separately and/or jointly in sewage sludge, to investigate their effects on sludge stabilization under thermophilic aerobic digestion condition. Four digestion conditions were tested for 480 h. Digestion without inoculation and inoculation with strain T2, as well as joint- inoculation with strains T1 and T2, achieved 32.6%, 43.0%, and 38.2% volatile solids (VS) removal, respectively. Removal in a digester inoculated with stain T1 only reached 27.2%. For the first 144 h, the three inoculated digesters all experienced higher VS removal than the digester without inoculations. Both specific thermophilic strains and micro-environment significantly affected the VS removal. DGGE profiles revealed that the isolated strains T1 and T2 can successfully establish in the thermophilic digesters. Other viable bacteria (including anaerobic or facultative microbes) also appeared in the digestion system, enhancing the microbial activity.     

Trace metal concentrations in distilled alcoholic beverages and liquors in Nigeria

The concentrations of 12 metals (Cd, Pb, Ni, Cr, Cu, Co, Fe, Mn, Zn, Ca, Mg and K) in 13 classes of alcoholic beverages were determined by atomic spectrometry after HNO₃/H₂O₂ digestion. The mean concentrations of metals (µg mL^?1) in these alcoholic beverages varied in the ranges 0.01–0.04, 0.02–0.24, 0.04–0.13, 0.01–0.28, 0.01–0.77, <0.001–0.12, 0.28–1.48, 0.004–0.33, 0.10–1.02, 1.43–162.86, 0.26–25.46 and 0.49–322.58 for Cd, Pb, Ni, Cr, Cu, Co, Fe, Mn, Zn, Ca, Mg and K respectively. The concentrations of metals found in these particular alcoholic beverages were below the International Statutory Limits for metals in alcoholic beverages. The estimated daily intake of the metals based on a per capita consumption of 3.6 L per annum pure alcohol was <3% of the tolerable daily intake of each metal. The individual and combined target hazard quotients of the metals were <1, indicating no long‐term health concerns from the consumption of these alcoholic beverages based on their metal content alone. Copyright © 2014 The Institute of Brewing & Distilling     

笔记本简化功能降身价

经济衰退令个人电脑厂商遭受冲击,但这对电脑买家来说是个好消息。专家预测今年年底价格可再降10%。     

电信重组今秋揭晓,盲目投资易栽跟头

日前,在买卖中国电信业巨头股票时,遵循“在传言时买进,在证实时卖出“这一“古训“的投资者们遭受了严重损失. 　　……