The rapid synthesis of bicyclom.n.1alkanone cores possessing quaternary carbon centers adjacent to a bridged ketone represents a significant synthetic challenge. This type of architectural feature is ...embedded in various complex biologically active compounds such as hyperforin and garsubellin A. Herein, we report a highly diastereoselective one-pot Diels-Alder reaction/Au(I)-catalyzed carbocyclization to generate bicyclo3.3.1alkanones in yields ranging from 48-93%.
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A class of substituted 1-thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives was found to have potent anti-proliferative activity against a broad range of tumor cell ...lines. A compound from this class (14) was profiled across a broad panel of hematologic and solid tumor cancer cell lines demonstrating cell cycle arrest at the G0/G1 interphase and has potent anti-proliferative activity against a distinct and select set of cancer cell types with no observed effects on normal human cells. An example is the selective inhibition of human B-cell lymphoma cell line (BJAB). Compound 14 was orally bioavailable and tolerated well in mice. Synthesis and structure activity relationships (SAR) in this series of compounds are discussed.
A main goal of cancer immunology research is the formation of Ag-specific memory T cell immunity capable of activation upon tumor re-encounter. The requirements necessary to overcome the inhibitory ...signals present in the tumor microenvironment and form such memory T cell responses are unknown. In contrast to previous studies targeting tumors expressing highly immunogenic model Ags, we demonstrate that alleviating tumor-induced suppression along with vaccination against authentic Ags during the perioperative period provides long-lasting protection against a highly suppressive and poorly immunogenic melanoma. In this study, we employed DNA vaccination with an immunologically optimized mouse melanoma-shared Ag, Trp1ee/ng, combined with systemic TGF-β blockade during the perioperative period of primary tumor resection, to confer protection against B16 melanoma, and against JBRH, an independently derived melanoma unrelated to B16. Importantly, we demonstrate that correlative to memory responses, perioperative immunotherapy increases the formation of tumor-infiltrating and tumor-reactive CD8(+) T cells expressing low levels of the transcription factor T-bet, defined as memory precursor effector cells. We show that conditions for an immunologically fertile environment are met when TGF-β blockade and vaccination are applied during the perioperative period of primary tumor resection. These findings address limitations of current CD8(+) T cell immunotherapies against cancer by generating effective CD8(+) T cell memory recall responses.
Several plant species of wetland habitats expand through clonal growth, often forming dense, nearly monospecific stands. Adjoining interspecific colonies represent an ideal model for testing ...hypotheses about competitive interactions between clonal species and developing predictive theories on plant competition for space. In this study, we evaluated the outcome of competition between colonies of Phragmites and Typha. First, we compared the progression and density of colonies in roadside ditches 1) at the zone of contact of two well-established monospecific colonies, and 2) in zones where the progression fronts are free from competition. Second, we used an experimental mesocosm approach to simulate competition for space between two plant colonies. The experiment was done under three salinity levels in order to better understand how deicing salt may influence interspecific competition. In roadside ditches, Typha did not slow down Phragmites progression. In the mesocosm experiment, both species showed optimal growth in low salinity, but Phragmites was superior at all salinity levels. In opposition to previous classical pair-wise experiments, the results of our experiments on Phragmites - Typha interactions concur with field evidence of dynamics between neighboring colonies. Our experiment approach succeeds in better simulating competitive interactions for space between plants with clonal growth.
Analysis of multiple electromyographic activities suggests that central and peripheral neurological structures modulate the relative amplitude and time course of specific muscle groups during gait. ...Following neurological insult such as stroke, spatiotemporal characteristics of the four muscular modules or synergies identified during gait (C1, C2, C3 and C4) are impaired. The objective of the present work is to develop a new methodology to recruit synergies involved in gait.
The subject is seated with his trunk leaning back and his foot fixed on a multidirectional force transducer, interfaced to a laboratory computer. The centers of rotation of the hip, knee and ankle joints are determined to estimate the lengths of the different segments of the lower limb. In addition, the relative angles between these segments are measured using a goniometer. In order to recruit different muscle synergies during progressive effort, a visual feedback was provided to the subject allowing him to control the direction and magnitude of the static force vector exerted in the sagittal plane of the foot. By measuring the location of the center of pressure exerted and the direction of the force vector applied at the extremity of the lower limb, it is possible to calculate the different moments of force exerted at the hip, knee and ankle using morphometric values of the subject.
Seven healthy subjects were asked to exert progressive static efforts in eight sagittal directions while the activities of eight muscles of the lower extremity were recorded using surface electrodes. The muscle synergies elicited in specific directions during these efforts were highly similar to three of the four modules previously identified during gait (C1, C2 and C4).
It is suggested that this methodology can provide a basis to establish a training program re-educating muscle synergies of the lower limb that are specifically recruited during gait.
The impact of congenital visual deprivation on speech production in adults was examined in an ultrasound study of compensation strategies for lip-tube perturbation. Acoustic and articulatory analyses ...of the rounded vowel /u/ produced by 12 congenitally blind adult French speakers and 11 sighted adult French speakers were conducted under two conditions: normal and perturbed (with a 25-mm diameter tube inserted between the lips). Vowels were produced with auditory feedback and without auditory feedback (masked noise) to evaluate the extent to which both groups relied on this type of feedback to control speech movements. The acoustic analyses revealed that all participants mainly altered F2 and F0 and, to a lesser extent, F1 in the perturbed condition -- only when auditory feedback was available. There were group differences in the articulatory strategies recruited to compensate; while all speakers moved their tongues more backward in the perturbed condition, blind speakers modified tongue-shape parameters to a greater extent than sighted speakers.
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