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Abstract: Burkholderia mallei, the etiologic agent of glanders, are Category B select agents with biothreat potential, and yet effective therapeutic treatments are lacking. In this study, we showed that CpG administration increased survival, demonstrating protection in the murine glanders model. Bacterial recovery from infected lungs, liver and spleen was significantly reduced in CpG-treated animals as compared with non-treated mice. Reciprocally, lungs of CpG-treated infected animals were infiltrated with higher levels of neutrophils and inflammatory monocytes, as compared to control animals. Employing the B. mallei bioluminescent strain CSM001 and the Neutrophil-Specific Fluorescent Imaging Agent, bacterial dissemination and neutrophil trafficking were monitored in real-time using multimodal in vivo whole body imaging techniques. CpG-treatment increased recruitment of neutrophils to the lungs and reduced bioluminescent bacteria, correlating with decreased bacterial burden and increased protection against acute murine glanders. Our results indicate that protection of CpG-treated animals was associated with recruitment of neutrophils prior to infection and demonstrated, for the first time, simultaneous real time in vivo imaging of neutrophils and bacteria. This study provides experimental evidence supporting the importance of incorporating optimized in vivo imaging methods to monitor disease progression and to evaluate the efficacy of therapeutic treatment during bacterial infections.

Abstract: A new spiro[indole-3,3'-pyrrolizine] derivative is regioselectively synthesized by the straightforward multicomponent reaction of 1-(4-fluorophenyl)-3-phenylprop-2-en-1-one, isatin and L-proline without any catalyst. The structure of the newly synthesized compound is characterized by IR, NMR, UV-visible and mass spectral data. The compound is also screened for its reducing power assay.

Abstract: We introduce and study Clarkson, Dol’nikov-Pichugov, Jacobi and mutual diameter constants reflecting the geometry of a Banach space and Clarkson, Jacobi and Pichugov classes of Banach spaces and their relations with James, self-Jung, Kottman and Schäffer constants in order to establish quantitative versions of Hahn-Banach separability theorem and to characterise the isometric extendability of Hölder-Lipschitz mappings. Abstract results are further applied to the spaces and pairs from the wide classes IG and IG+ and non-commutative Lp-spaces. The intimate relation between the subspaces and quotients of the IG-spaces on one side and various types of anisotropic Besov, Lizorkin-Triebel and Sobolev spaces of functions on open subsets of an Euclidean space defined in terms of differences, local polynomial approximations, wavelet decompositions and other means (as well as the duals and the lp-sums of all these spaces) on the other side, allows us to present the algorithm of extending the main results of the article to the latter spaces and pairs. Special attention is paid to the matter of sharpness. Our approach is quasi-Euclidean in its nature because it relies on the extrapolation of properties of Hilbert spaces and the study of 1-complemented subspaces of the spaces under consideration.

Abstract: The DOCK-AND-LOCK^TM (DNL^TM) method provides a modular approach to develop multivalent, multifunctional complexes of defined structures, of which bispecific hexavalent antibodies (bsHexAbs) are prominent examples with potential applications in targeted therapy for malignant, autoimmune, and infectious diseases. Currently, bsHexAbs are constructed by derivatizing a divalent IgG, at the carboxyl termini of either the heavy chain (the C_H3-format) or the light chain (the C_k-format), to contain two stabilized dimers of Fab having a different specificity from the IgG. In this review, we briefly outline the features of the DNL^TM method and describe key aspects of bsHexAbs examined with diverse preclinical studies, which include binding affinity to target cells, induction of signaling pathways, effector functions, serum stability, pharmacokinetics, and antitumor activity in human tumor xenograft models. Our findings favor the selection of the C_K- over the C_H3-format for further exploration of bsHexAbs in clinical trials.

Abstract: Dihydropyridine Ca²⁺ channel blockers (CCBs) are widely accepted in the treatment of premature labour. Their mechanism of action in tocolysis involves the blockade of L-type Ca²⁺ channels, influenced by the Ca²⁺-activated K⁺ channels, beta-adrenergic receptors (β-ARs) and sexual hormones. In clinical practice, most experience has been gained with the use of nifedipine, whose efficacy is superior or comparable to those of β-agonists and oxytocin antagonists. Additionally, it has a favourable adverse effect profile as compared with the majority of other tocolytics. The most frequent and well-tolerated side-effects of CCBs are tachycardia, headache and hypotension. In tocolytic therapy efforts are currently being made to find combinations of tocolytic agents that yield better therapeutic action. The available human and animal studies suggest that the combination of CCBs with β-AR agonists is beneficial, although such combinations can pose risk of pulmonary oedema in multiple pregnancies and maternal cardiovascular diseases. Preclinical data indicate the potential benefit of combinations of CCBs and oxytocin antagonists. However, the combinations of CCBs with progesterone or cyclooxygenase inhibitors may decrease their efficacy. The CCBs are likely to remain one of the most important groups of drugs for the rapid inhibition of premature uterine contractions. Their significance may be magnified by further clinical studies on their combined use for tocolysis.

Abstract: Earthquake is one of the dominant triggering factors of landslides. Given the wide areas covered by mega earthquake-triggered landslides, their inventory requires development of automatic or semi-automatic methods applied to satellite imagery. A detection method is here proposed for this purpose, to fit with simple datasets; SPOT5 panchromatic images of 5 m resolution coupled with a freely and globally available DEM. The method takes advantage of multi-temporal images to detect changes based on radiometric variations after precise coregistration/orthorectification. Removal of false alarms is then undertaken using shape, orientation and radiometric properties of connected pixels defining objects. 80% of the landslides and 93% of the landslide area are detected indicating small omission errors but 50% of false alarms remain. They are removed using expert based analysis of the inventory. The method is applied to realize the first comprehensive inventory of landslides triggered by the Pisco earthquake (Peru, 15/08/2007, Mw 8.0) over an area of 27,000 km2. 866 landslides larger than 100 m2 are detected covering a total area of 1.29 km2. The area/number distribution follows a power-law with an exponent of 1.63, showing a very particular regime of triggering in this arid environment compared to other areas in the world. This specific triggering can be explained by the little soil cover in the coastal and forearc regions of Peru. Analysis of this database finally shows a major control of the topography (both orientation and inclination) on the repartition of the Pisco-triggered landslides.

Abstract: Rainfall intensity plays an important role in landslide prediction especially in mountain areas. However, the rainfall intensity of a location is usually interpolated from rainfall recorded at nearby gauges without considering any possible effects of topographic slopes. In order to obtain reliable rainfall intensity for disaster mitigation, this study proposes a rainfall-vector projection method for topographic-corrected rainfall. The topographic-corrected rainfall is derived from wind speed, terminal velocity of raindrops, and topographical factors from digital terrain model. In addition, scatter plot was used to present landslide distribution with two triggering factors and kernel density analysis is adopted to enhance the perception of the distribution. Numerical analysis is conducted for a historic event, typhoon Mindulle, which occurred in 2004, in a location in central Taiwan. The largest correction reaches 11%, which indicates that topographic correction is significant. The corrected rainfall distribution is then applied to the analysis of landslide triggering factors. The result with corrected rainfall distribution provides better agreement with the actual landslide occurrence than the result without correction.

Abstract: A new 8,4¢-oxyneolignane glucoside 1 has been isolated from the stems of Dendrobium aurantiacum var. denneanum together with six known phenolic glucosides 2-7. The structure of the new compound, including its absolute configuration, was determined by spectroscopic and chemical methods as (–)-(7S,8R,7¢E)-4-hydroxy-3,3¢,5,5¢-tetramethoxy-8,4¢-oxyneolign-7¢-ene-7,9,9¢-triol 7,9¢-bis-O-β-D-glucopyranoside (1). In the in vitro assays, compound 1 and (-)-syringaresinol-4,4¢-bis-O-β-D-glucopyranoside (2) showed evident activity against glutamate-induced neurotoxicity in PC12 cells. Shashenoside I (4) showed a selective cytotoxic activity with the IC₅₀ value of 4.17 μM against the acute myeloid leukemia cell line MV4-11, while it was inactive against 10 other human tumor cell lines.

Abstract: An efficient one-pot synthesis of novel β-amino acid derivatives containing a thiadiazole moiety was developed using a chiral squaramide cinchona alkaloid as organocatalyst. The reactions afforded chiral β-amino acid derivatives in moderate yields and with moderate to excellent enantioselectivities. The present study demonstrated for the first time the use of a Mannich reaction catalyzed by a chiral bifunctional organocatalyst for the one-pot synthesis of novel β-amino acid derivatives bearing a 1,3,4-thiadiazole moiety on nitrogen.

Abstract: Novel antioxidants have been synthesized and characterized by their chemical properties as antioxidants with high superoxide scavenging activity. (2R,3R)-diphenylethylenediamine is a spacer in antioxidants, and we synthesized targets 11a and 11b by conjugation with o-hydroquinone and p-hydroquinone at the two N-termini, respectively. Superoxide scavenging activities of the plant flavonoid-like 11a and 11b were compared with those of known antioxidants, and shown to increase in the following order: curcumin << ascorbic acid < Trolox < (+)-epicatechin < 11a < quercetin £ 11b. Compound 11a also formed a solvated 11a–metal complex with metal ions. The 11a–Cu²⁺ complex was shown to have higher superoxide scavenging activity than that of 11a, 11b, Cu²⁺, and the 11a–Al³⁺ and 11a–La³⁺ complexes, whereas the 11a–Al³⁺ complex increased rather than decreased superoxide levels. The 11a–Al³⁺ complex did not abstract one electron from the SOMO of O₂^−. since the HOMO and LUMO phases of Al³⁺ do not exist in the center of the 11a–Al³⁺ complex. However, the SOMO of the 11a–Cu²⁺ complex distributed in the center of Cu²⁺ may abstract one electron from the SOMO of O₂^−.. These results suggest that 11a and 11b are powerful antioxidants.