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961.
Martin Siegemund Oliver Seifert Tamara Džinić Valentino De Leo Doris Göttsch 《MABS-AUSTIN》2016,8(5):879-891
Fusion proteins combining oligomeric assemblies of a genetically obtained single-chain (sc) variant of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with antibodies directed against tumor-associated antigens represent a promising strategy to overcome the limited therapeutic activity of conventional soluble TRAIL. To further improve the scTRAIL module in order to obtain a robust, thermostable molecule of high activity, we performed a comprehensive analysis of the minimal TNF homology domain (THD) and optimized linkers between the 3 TRAIL subunits constituting a scTRAIL. Through a stepwise mutagenesis of the N- and C-terminal region and the joining linker sequences, we generated bioactive scTRAIL molecules comprising a covalent linkage of the C-terminal Val280 and the N-terminal position 122 by only 2 amino acid residues in combination with conservative exchanges at positions 122 and 279. The increased thermal stability and solubility of such optimized scTRAIL molecules translated into increased bioactivity in the diabody-scTRAIL (Db-scTRAIL) format, exemplified here for an epidermal growth factor receptor-specific Db-scTRAIL. Additional modifications within the diabody linkers resulted in a fusion protein exerting high, target-dependent apoptosis induction in tumor cell lines in vitro and potent antitumor activity in vivo. Our results illustrate that protein engineering of scTRAIL and associated peptide linkers provides a promising strategy to develop antibody-scTRAIL fusion proteins as effective antitumor therapeutics. 相似文献
962.
The human opposable thumb enables the hand to perform dexterous manipulation of objects, which requires well-coordinated digit force vectors. This study investigated the directional coordination of force vectors generated by the thumb and index finger during precision pinch. Fourteen right-handed, healthy subjects were instructed to exert pinch force on an externally stabilized apparatus with the pulps of the thumb and index finger. Subjects applied forces to follow a force-ramp profile that linearly increased from 0 to 12 N and then decreased to 0 N, at a rate of ±3 N/s. Directional relationships between the thumb and index finger force vectors were quantified using the coordination angle (CA) between the force vectors. Individual force vectors were further analyzed according to their projection angles (PAs) with respect to the pinch surface planes and the shear angles (SAs) within those planes. Results demonstrated that fingertip force directions were dependent on pinch force magnitude, especially at forces below 2 N. Hysteresis was observed in the force-CA relationship for increasing and decreasing forces and fitted with exponential models. The fitted asymptotic values were 156.0±6.6° and 150.8±9.3° for increasing and decreasing force ramps, respectively. The PA of the thumb force vector deviated further from the direction perpendicular to the pinching surface planes than that of the index finger. The SA showed that the index finger force vector deviated in the ulnar-proximal direction, whereas the thumb switched its force between the ulnar-proximal and radial-proximal directions. The findings shed light on the effects of anatomical composition, biomechanical function, and neuromuscular control in coordinating digit forces during precision pinch, and provided insight into the magnitude-dependent force directional control which potentially affects a range of dexterous manipulations. 相似文献
963.
Kathrin Thedieck Birgit HolzwarthMirja Tamara Prentzell Christopher BoehlkeKathrin Kläsener Stefanie RufAnnika Gwendolin Sonntag Lars MaerzSushma-Nagaraja Grellscheid Elisabeth KremmerRoland Nitschke E. Wolfgang KuehnJohan W. Jonker Albert K. GroenMichael Reth Michael N. HallRalf Baumeister 《Cell》2013
964.
965.
Ana Maria Arbeláez Yi Su Jewell B. Thomas Amy C. Hauch Tamara Hershey Beau M. Ances 《PloS one》2013,8(3)
Different brain regions sense and modulate the counterregulatory responses that can occur in response to declining plasma glucose levels. The aim of this study was to determine if changes in regional cerebral blood flow (rCBF) during hypoglycemia relative to euglycemia are similar for two imaging modalities–pulsed arterial spin labeling magnetic resonance imaging (PASL-MRI) and positron emission tomography (PET). Nine healthy non-diabetic participants underwent a hyperinsulinemic euglycemic (92±3 mg/dL) – hypoglycemic (53±1 mg/dL) clamp. Counterregulatory hormone levels were collected at each of these glycemic levels and rCBF measurements within the previously described network of hypoglycemia-responsive regions (thalamus, medial prefrontal cortex and globus pallidum) were obtained using PASL-MRI and [15O] water PET. In response to hypoglycemia, rCBF was significantly increased in the thalamus, medial prefrontal cortex, and globus pallidum compared to euglycemia for both PASL-MRI and PET methodologies. Both imaging techniques found similar increases in rCBF in the thalamus, medial prefrontal cortex, and globus pallidum in response to hypoglycemia. These brain regions may be involved in the physiologic and symptom responses to hypoglycemia. Compared to PET, PASL-MRI may provide a less invasive, less expensive method for assessing changes in rCBF during hypoglycemia without radiation exposure. 相似文献
966.
Santiago Martín‐Bravo Pedro Jimnez‐Mejías Tamara Villaverde Marcial Escudero Marlene Hahn Daniel Spalink Eric H. Roalson Andrew L. Hipp Carmen Benítez‐Benítez Leo P. Bruederle Elisabeth Fitzek Bruce A. Ford Kerry A. Ford Mira Garner Sebastian Gebauer Matthias H. Hoffmann Xiao‐Feng Jin Isabel Larridon tienne Lveill‐Bourret Yi‐Fei Lu Modesto Luceo Enrique Maguilla Jose Ignacio Mrquez‐Corro Mnica Míguez Robert Naczi Anton A. Reznicek Julian R. Starr 《植物分类学报:英文版》2019,57(6):695-718
The megadiverse genus Carex (c. 2000 species, Cyperaceae) has a nearly cosmopolitan distribution, displaying an inverted latitudinal richness gradient with higher species diversity in cold‐temperate areas of the Northern Hemisphere. Despite great expansion in our knowledge of the phylogenetic history of the genus and many molecular studies focusing on the biogeography of particular groups during the last few decades, a global analysis of Carex biogeography and diversification is still lacking. For this purpose, we built the hitherto most comprehensive Carex‐dated phylogeny based on three markers (ETS–ITS–matK), using a previous phylogenomic Hyb‐Seq framework, and a sampling of two‐thirds of its species and all recognized sections. Ancestral area reconstruction, biogeographic stochastic mapping, and diversification rate analyses were conducted to elucidate macroevolutionary biogeographic and diversification patterns. Our results reveal that Carex originated in the late Eocene in E Asia, where it probably remained until the synchronous diversification of its main subgeneric lineages during the late Oligocene. E Asia is supported as the cradle of Carex diversification, as well as a “museum” of extant species diversity. Subsequent “out‐of‐Asia” colonization patterns feature multiple asymmetric dispersals clustered toward present times among the Northern Hemisphere regions, with major regions acting both as source and sink (especially Asia and North America), as well as several independent colonization events of the Southern Hemisphere. We detected 13 notable diversification rate shifts during the last 10 My, including remarkable radiations in North America and New Zealand, which occurred concurrently with the late Neogene global cooling, which suggests that diversification involved the colonization of new areas and expansion into novel areas of niche space. 相似文献
967.
968.
969.
Elisa Bellucci Orlando Mario Aguilar Saleh Alseekh Kirstin Bett Creola Brezeanu Douglas Cook Lucía De la Rosa Massimo Delledonne Denise F. Dostatny Juan J. Ferreira Valérie Geffroy Sofia Ghitarrini Magdalena Kroc Shiv Kumar Agrawal Giuseppina Logozzo Mario Marino Tristan Mary-Huard Phil McClean Vladimir Meglič Tamara Messer Frédéric Muel Laura Nanni Kerstin Neumann Filippo Servalli Silvia Străjeru Rajeev K. Varshney Marta W. Vasconcelos Massimo Zaccardelli Aleksei Zavarzin Elena Bitocchi Emanuele Frontoni Alisdair R. Fernie Tania Gioia Andreas Graner Luis Guasch Lena Prochnow Markus Oppermann Karolina Susek Maud Tenaillon Roberto Papa 《The Plant journal : for cell and molecular biology》2021,108(3):646-660
970.