Late Miocene to present day structural development of the Polish segment of the Outer Carpathians

This paper presents a few pieces of evidence on neotectonic structural evolution of the Polish segment of the Outer Carpathians. During the Late Neogene, structural development was largely controlled by normal faulting and block uplift. However, there are also indications of compressional stress setting, at least during the Pliocene and particularly within the medial and eastern parts of the belt. In the Quaternary, in turn, structural development has been mainly controlled by compressional stress arrangement, with \sigma _{1} orientated roughly perpendicular to the belt. The Pliocene-Quaternary tectonic mobility of the Polish Outer Carpathians has been relatively weak and mostly of thin-skinned character. Normal faults were formed on the margins of intramontane basins and in the western part of the belt. Rates of uplift of individual structures were variable and the amount of uplift was the greatest in the Late Pliocene and Early Quaternary times. Geomorphologically-detected zones of uplift are relatively narrow and arranged subparallel or under small angle in respect to the strike of principal thrusts and frontal parts of large slices. Such an arrangement is interpreted as resulting from the steepening of frontal thrusts due to horizontal compression within the overthrust flysch nappes. This hypothesis is confirmed by the results of recent break-out and GPS studies, as well as by focal solutions of some Outer Carpathian earthquakes

Quaternary exhumation of the Carpathians: a record from the Orava-Nowy Targ intramontane basin, Western Carpathians, Polish Galicia and Slovakia

Quaternary exhumation of the Carpathians: a record from the Orava-Nowy Targ Intramontane Basin, Western Carpathians (Poland and Slovakia)The Neogene-Quaternary infill of the Orava-Nowy Targ Intramontane Basin comprises two tiers showing contrasting lithologies. The Neogene tier is largely composed of claystones and siltstones, whereas the Quaternary tier is dominated by gravels. The two sequences are separated by an erosional surface underlain by a regolith. Deposition of the Neogene sequence took place during subsidence of the basin. No prominent relief existed in the area of the present-day mountains actually surrounding the basin at that time. The regolith started to form at the onset of basin inversion. Still, no prominent relief existed in the present-day mountains. The onset of deposition of Quaternary gravels in the basin corresponds to acceleration of uplift of the surrounding mountains, which has been continuing until now. The Pieniny Klippen Belt has been subject to erosion, at least locally, from the deposition of the basal part of the Neogene sequence filling the Orava-Nowy Targ Basin until present times. In contrast, the Paleogene cover of the Tatra Mts was removed only during the Quaternary.</jats:p

Novel insights into host-fungal pathogen interactions derived from live-cell imaging

Acknowledgments The authors acknowledge funding from the Wellcome Trust (080088, 086827, 075470 and 099215) including a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377 and FP7-2007–2013 grant agreement HEALTH-F2-2010-260338–ALLFUN to NARG.Peer reviewedPublisher PD

Crystal Structures of ABL-Related Gene (ABL2) in Complex with Imatinib, Tozasertib (VX-680), and a Type I Inhibitor of the Triazole Carbothioamide Class†

ABL2 (also known as ARG (ABL related gene)) is closely related to the well-studied Abelson kinase cABL. ABL2 is involved in human neoplastic diseases and is deregulated in solid tumors. Oncogenic gene translocations occur in acute leukemia. So far no structural information for ABL2 has been reported. To elucidate structural determinants for inhibitor interaction, we determined the cocrystal structure of ABL2 with the oncology drug imatinib. Interestingly, imatinib not only interacted with the ATP binding site of the inactive kinase but was also bound to the regulatory myristate binding site. This structure may therefore serve as a tool for the development of allosteric ABL inhibitors. In addition, we determined the structures of ABL2 in complex with VX-680 and with an ATP-mimetic type I inhibitor, which revealed an interesting position of the DFG motif intermediate between active and inactive conformations, that may also serve as a template for future inhibitor design

Inhibiting ex-vivo Th17 responses in Ankylosing Spondylitis by targeting Janus kinases

Treatment options for Ankylosing Spondylitis (AS) are still limited. The T helper cell 17 (Th17) pathway has emerged as a major driver of disease pathogenesis and a good treatment target. Janus kinases (JAK) are key transducers of cytokine signals in Th17 cells and therefore promising targets for the treatment of AS. Here we investigate the therapeutic potential of four different JAK inhibitors on cells derived from AS patients and healthy controls, cultured in-vitro under Th17-promoting conditions. Levels of IL-17A, IL-17F, IL-22, GM-CSF and IFN gamma were assessed by ELISA and inhibitory effects were investigated with Phosphoflow. JAK1/2/3 and TYK2 were silenced in CD4+ T cells with siRNA and effects analyzed by ELISA (IL-17A, IL-17F and IL-22), Western Blot, qPCR and Phosphoflow. In-vitro inhibition of CD4+ T lymphocyte production of multiple Th17 cytokines (IL-17A, IL-17F and IL-22) was achieved with JAK inhibitors of differing specificity, as well as by silencing of JAK1-3 and Tyk2, without impacting on cell viability or proliferation. Our preclinical data suggest JAK inhibitors as promising candidates for therapeutic trials in AS, since they can inhibit multiple Th17 cytokines simultaneously. Improved targeting of TYK2 or other JAK isoforms may confer tailored effects on Th17 responses in AS

Allosteric Interactions between the Myristate- and ATP-Site of the Abl Kinase

Abl kinase inhibitors targeting the ATP binding pocket are currently employed as potent anti-leukemogenic agents but drug resistance has become a significant clinical limitation. Recently, a compound that binds to the myristate pocket of Abl (GNF-5) was shown to act cooperatively with nilotinib, an ATP-competitive inhibitor to target the recalcitrant “T315I” gatekeeper mutant of Bcr-Abl. To uncover an explanation for how drug binding at a distance from the kinase active site could lead to inhibition and how inhibitors could combine their effects, hydrogen exchange mass spectrometry (HX MS) was employed to monitor conformational effects in the presence of both dasatinib, a clinically approved ATP-site inhibitor, and GNF-5. While dasatinib binding to wild type Abl clearly influenced Abl conformation, no binding was detected between dasatinib and T315I. GNF-5, however, elicited the same conformational changes in both wild type and T315I, including changes to dynamics within the ATP site located approximately 25 Å from the site of GNF-5 interaction. Simultaneous binding of dasatinib and GNF-5 to T315I caused conformational and/or dynamics changes in Abl such that effects of dasatinib on T315I were the same as when it bound to wild type Abl. These results provide strong biophysical evidence that allosteric interactions play a role in Abl kinase downregulation and that targeting sites outside the ATP binding site can provide an important pharmacological tool to overcome mutations that cause resistance to ATP-competitive inhibitors

The Energy Landscape Analysis of Cancer Mutations in Protein Kinases

The growing interest in quantifying the molecular basis of protein kinase activation and allosteric regulation by cancer mutations has fueled computational studies of allosteric signaling in protein kinases. In the present study, we combined computer simulations and the energy landscape analysis of protein kinases to characterize the interplay between oncogenic mutations and locally frustrated sites as important catalysts of allostetric kinase activation. While structurally rigid kinase core constitutes a minimally frustrated hub of the catalytic domain, locally frustrated residue clusters, whose interaction networks are not energetically optimized, are prone to dynamic modulation and could enable allosteric conformational transitions. The results of this study have shown that the energy landscape effect of oncogenic mutations may be allosteric eliciting global changes in the spatial distribution of highly frustrated residues. We have found that mutation-induced allosteric signaling may involve a dynamic coupling between structurally rigid (minimally frustrated) and plastic (locally frustrated) clusters of residues. The presented study has demonstrated that activation cancer mutations may affect the thermodynamic equilibrium between kinase states by allosterically altering the distribution of locally frustrated sites and increasing the local frustration in the inactive form, while eliminating locally frustrated sites and restoring structural rigidity of the active form. The energy landsape analysis of protein kinases and the proposed role of locally frustrated sites in activation mechanisms may have useful implications for bioinformatics-based screening and detection of functional sites critical for allosteric regulation in complex biomolecular systems