scholarly journals Synthetic inhibitor leads of human tropomyosin receptor kinase A (hTrkA)

2020 ◽  
Vol 11 (3) ◽  
pp. 370-377
Author(s):  
Govindan Subramanian ◽  
Rajendran Vairagoundar ◽  
Scott J. Bowen ◽  
Nicole Roush ◽  
Theresa Zachary ◽  
...  
Keyword(s):  
Mixed Type ◽  
Kinase Domain ◽  
Receptor Kinase ◽  
Synthetic Inhibitor ◽  
Domain Type ◽  
Starting Point ◽  
Kinase A

New hTrkA kinase domain type 2 inhibitors and mixed type 1/type 2 inhibitor leads disclosed here offers a differential starting point to investigate the disease pathophysiology.

Plural marking on noun-associated forms

2020 ◽  
Vol 73 (3) ◽  
pp. 363-401
Author(s):  
Francesca Di Garbo
Keyword(s):  
Mixed Type ◽  
Lexical Semantics ◽  
Number Marking ◽  
Number Systems ◽  
Plural Marking ◽  
Type 3 ◽  
Semantic Properties

AbstractNumber systems can be morphosemantic or morphosyntactic, based on whether number marking is restricted to nouns or also extends to noun-associated forms, such as adnominal modifiers, predicates, and pronouns. While it is well-known that asymmetries in the distribution of plural marking on nouns can be due to lexico-semantic properties such as animacy and/or inherent number, the question of whether these properties also affect patterns of plural agreement has been less broadly investigated. This paper examines the distribution of plural agreement in 24 Cushitic (Afro-Asiatic) languages. The number systems of the languages of the sample are classified into three types, ranging from radically morphosemantic (Type 1) to radically morphosyntactic (Type 2). A subset of languages displays a combination of morphosemantic and morphosyntactic strategies, and thus qualifies as a mixed type (Type 3). In these languages, the distribution of plural agreement is largely lexically-specified: nouns denoting groups, masses, and collections are more likely to trigger plural agreement than other types of nouns. These results thus show that, similarly to the nominal domain, the lexical semantics of nouns may also affect plural marking on noun-associated forms. Furthermore, in Cushitic, radically morphosemantic and radically morphosyntactic number systems appear to be diachronically connected to each other, with the latter seemingly evolving from the former, as testified by ongoing variation and change in some of the sampled languages. The relevance of these findings for understanding the typology and evolution of number systems is discussed.

scholarly journals A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding

2020 ◽  
Vol 477 (22) ◽  
pp. 4443-4452
Author(s):  
Alexander Pflug ◽  
Marianne Schimpl ◽  
J. Willem M. Nissink ◽  
Ross C. Overman ◽  
Philip B. Rawlins ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Crystal Structures ◽  
Residence Time ◽  
Kinase Inhibitor ◽  
Structural Information ◽  
Kinase Domain ◽  
Phosphoryl Transfer ◽  
Mer Tyrosine Kinase

The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases, where it collapses onto the protein surface and blocks substrate binding when unphosphorylated. Due to its flexible nature, the A-loop is usually disordered and untraceable in kinase domain crystal structures. The resulting lack of structural information is regrettable as it impedes the design of drug A-loop contacts, which have proven favourable in multiple cases. Here, we characterize the binding with A-loop engagement between type 1.5 kinase inhibitor ‘example 172’ (EX172) and Mer tyrosine kinase (MerTK). With the help of crystal structures and binding kinetics, we portray how the recruitment of the A-loop elicits a two-step binding mechanism which results in a drug-target complex characterized by high affinity and long residence time. In addition, the type 1.5 compound possesses excellent kinome selectivity and a remarkable preference for the phosphorylated over the dephosphorylated form of MerTK. We discuss these unique characteristics in the context of known type 1 and type 2 inhibitors and highlight opportunities for future kinase inhibitor design.

Lesional skin in atopic dogs shows a mixed Type-1 and Type-2 immune responsiveness

2011 ◽  
Vol 143 (1-2) ◽  
pp. 20-26 ◽  
Author(s):  
Yvette M. Schlotter ◽  
Victor P.M.G. Rutten ◽  
Frank M. Riemers ◽  
Edward F. Knol ◽  
Ton Willemse
Keyword(s):  
Mixed Type ◽  
Immune Responsiveness ◽  
Lesional Skin

Correlation between VEGFR-2 receptor kinase domain-containing receptor (KDR) mRNA and angiotensin II receptor type 1 (AT1-R) mRNA in endometrial cancer

Cytokine ◽  
2013 ◽  
Vol 61 (2) ◽  
pp. 639-644 ◽  
Author(s):  
Agnieszka W. Piastowska-Ciesielska ◽  
Elżbieta Płuciennik ◽  
Katarzyna Wójcik-Krowiranda ◽  
Andrzej Bieńkiewicz ◽  
Magdalena Nowakowska ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Angiotensin Ii ◽  
Kinase Domain ◽  
Receptor Type ◽  
Receptor Kinase ◽  
Angiotensin Ii Receptor

scholarly journals Vaccination with Toxoplasma gondii SAG-1 Protein Is Protective against Congenital Toxoplasmosis in BALB/c Mice but Not in CBA/J Mice

2003 ◽  
Vol 71 (11) ◽  
pp. 6615-6619 ◽  
Author(s):  
Valerie Letscher-Bru ◽  
Alexander W. Pfaff ◽  
Ahmed Abou-Bacar ◽  
Denis Filisetti ◽  
Elisabeth Antoni ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Genetic Background ◽  
Mixed Type ◽  
Congenital Toxoplasmosis ◽  
Type 2 Immunity ◽  
Predominant Type

ABSTRACT We evaluated the effect of vaccination with the SAG1 protein of Toxoplasma gondii against congenital toxoplasmosis in mice with different genetic backgrounds. In BALB/c mice (H-2d ), vaccination reduced the number of infected fetuses by 50% and was associated with a mixed type 1 and type 2 immunity. In CBA/J mice (H-2k ), vaccination increased the number of infected fetuses by 50% and was associated with a predominant type 2 response. Our results indicate that the effect of vaccination with SAG1 is controlled by the genetic background of the mouse.

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