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The Alpha Ridge-Mendeleev Rise (AMR) is the major bathymetric feature in the Amerasia Basin of the Arctic Ocean. Its tectonic history is controversial due to its remote location in ice covered waters making data acquisition difficult, resulting in the lack of diagnostic data. Analysis of the wide-angle reflection/refraction data based on the compressional waves (P-waves) from the AMR indicates that its velocity/depth structure is typical of large igneous provinces (LIPs). LIPs can form on either oceanic or continental crust and can exhibit complex history of development. Here converted shear waves (S-wave) on the Alpha Ridge have been used to calculate Poisson's ratios and many of measured values are within the felsic range in the upper crust. They are comparable to published S-waves from the Mendeleev Rise. They are also consistent with the results of Rayleigh-wave group-velocity analysis that indicate the Alpha Ridge in adjacent northern Canada has an intermediate composition. Based on magnetics, pseudogravity and volumetric considerations the High Arctic Large Igneous Province (HALIP) most closely resembles the Kerguelen Plateau, a LIP with a continental component. The geophysical characteristics of the AMR are compatible with a number of other LIPs that have continental affinities. A variety of offshore information from dredges and cores and onshore geological data support continental fragments incorporated in the AMR. [ABSTRACT FROM AUTHOR]

Synthesis of seismic velocity, potential field, and geological data from Canada Basin and its surrounding continental margins suggests that a northeast-trending structural fabric has influenced the origin, evolution, and current tectonics of the basin. This structural fabric has a crustal origin, based on the persistence of these trends in upward continuation of total magnetic intensity data and vertical derivative analysis of free-air gravity data. Three subparallel northeast-trending features are described. Northwind Escarpment, bounding the east side of the Chukchi Borderland, extends ∼600 km and separates continental crust of Northwind Ridge from high-velocity transitional crust in Canada Basin. A second, shorter northeast-trending zone extends ∼300 km in northern Canada Basin and separates inferred continental crust of Sever Spur from magmatically intruded crust of the High Arctic Large Igneous Province. A third northeast-trending feature, here called the Alaska-Prince Patrick magnetic lineament (APPL) is inferred from magnetic data and its larger regional geologic setting. Analysis of these three features suggests strike slip or transtensional deformation played a role in the opening of Canada Basin. These features can be explained by initial Jurassic-Early Cretaceous strike slip deformation (phase 1) followed in the Early Cretaceous (∼134 to ∼124 Ma) by rotation of Arctic Alaska with seafloor spreading orthogonal to the fossil spreading axis preserved in the central Canada Basin (phase 2). In this model, the Chukchi Borderland is part of Arctic Alaska. [ABSTRACT FROM AUTHOR]

Seismic velocities determined from 70 sonobuoys widely distributed in Canada Basin were used to discriminate crustal types. Velocities of oceanic layer 3 (6.7–7.1 km/s), transitional (7.2–7.6 km/s) and continental crust (5.5–6.6 km/s) were used to distinguish crustal types. Potential field data supports the distribution of oceanic crust as a polygon with maximum dimensions of ~ 340 km (east–west) by ~ 590 km (north–south) and identification of the ocean–continent boundary (OCB). Paired magnetic anomalies are associated only with crust that has oceanic velocities. Furthermore, the interpreted top of oceanic crust on seismic reflection profiles is more irregular and sometimes shallower than adjacent transitional crust. The northern segment of the narrow Canada Basin Gravity Low (CBGL), often interpreted as a spreading center, bisects this zone of oceanic crust and coincides with the location of a prominent valley in seismic reflection profiles. Data coverage near the southern segment of CBGL is sparse. Velocities typical of transitional crust are determined east of it. Extension in this region, close to the inferred pole of rotation, may have been amagmatic. Offshore Alaska is a wide zone of thinned continental crust up to 300 km across. Published longer offset refraction experiments in the Basin confirm the depth to Moho and the lack of oceanic layer 3 velocities. Further north, toward Alpha Ridge and along Northwind Ridge, transitional crust is interpreted to be underplated or intruded by magmatism related to the emplacement of the High Arctic Large Igneous Province (HALIP). Although a rotational plate tectonic model is consistent with the extent of the conjugate magnetic anomalies that occupy only a portion of Canada Basin, it does not explain the asymmetrical configuration of the oceanic crust in the deep water portion of Canada Basin, and the unequal distribution of transitional and continental crust around the basin. [ABSTRACT FROM AUTHOR]

Presents information on results ascertained from a seismic and magnetic study, relating to the acoustic basement beneath the Southern Iberia Abyssal Plain. Acquisition of the wide-angle seismic data; Reference to the seaward change in basement morphology coinciding with the changes in seismic velocity structure; Consistency of the absence of a magmatic crust in the ocean-continent transition zone (OCT).

Background: Checkpoint inhibitors (CPIs) such as anti-PD(L)-1 and anti-CTLA-4 antibodies have resulted in unprecedented rates of antitumor responses and extension of survival of patients with a variety of cancers. But some patients fail to respond or initially respond but later relapse as they develop resistance to immune therapy. One of the tumor-extrinsic mechanisms for resistance to immune therapy is the accumulation of regulatory T cells (T reg ) in tumors. In preclinical and clinical studies, it has been suggested that tumor trafficking of T reg is mediated by CC chemokine receptor 4 (CCR4). Over 90% of human T reg express CCR4 and migrate toward CCL17 and CCL22, two major CCR4 ligands that are either high at baseline or upregulated in tumors on CPI treatment. Hence, CCR4 antagonism has the potential to be an effective antitumor treatment by reducing the accumulation of T reg into the tumor microenvironment (TME)., Methods: We developed in vitro and in vivo models to assess T reg migration and antitumor efficacy using a potent and selective CCR4 antagonist, CCR4-351. We used two separate tumor models, Pan02 and CT26 mouse tumors, that have high and low CCR4 ligand expression, respectively. Tumor growth inhibition as well as the frequency of tumor-infiltrating T reg and effector T cells was assessed following the treatment with CCR4 antagonist alone or in combination with CPI., Results: Using a selective and highly potent, novel small molecule inhibitor of CCR4, we demonstrate that migration of CCR4 + T reg into the tumor drives tumor progression and resistance to CPI treatment. In tumor models with high baseline levels of CCR4 ligands, blockade of CCR4 reduced the number of T reg and enhanced antitumor immune activity. Notably, in tumor models with low baseline level of CCR4 ligands, treatment with immune CPIs resulted in significant increases of CCR4 ligands and T reg numbers. Inhibition of CCR4 reduced T reg frequency and potentiated the antitumor effects of CPIs., Conclusion: Taken together, we demonstrate that CCR4-dependent T reg recruitment into the tumor is an important tumor-extrinsic mechanism for immune resistance. Blockade of CCR4 led to reduced frequency of T reg and resulted in increased antitumor activity, supporting the clinical development of CCR4 inhibitors in combination with CPI for the treatment of cancer., Statement of Significance: CPI upregulates CCL17 and CCL22 expression in tumors and increases T reg migration into the TME. Pharmacological antagonism of the CCR4 receptor effectively inhibits T reg recruitment and results in enhanced antitumor efficacy either as single agent in CCR4 ligand high tumors or in combination with CPIs in CCR4 ligand low tumors., Competing Interests: Competing interests: LAM, AJ, SJ, MZ, OR, JJJ, DP, JS, MB, AW, DW, PDK, GC, BW, DGB and OT are employees and stockholders of RAPT Therapeutics., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (T reg ) as well as other circulating and tissue-resident T cells. T reg can be recruited to the tumor microenvironment (TME) through the C-C chemokines CCL17 and CCL22. T reg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the T reg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of T reg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.

Recruitment of suppressive CD4 + FOXP3 + regulatory T cells (T reg ) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human T reg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, T reg accumulation correlates with poor patient prognosis. Preclinical data suggests that preventing the recruitment of T reg and increasing the population of activated effector T cells (T eff ) in the TME can potentiate antitumor immune responses. We developed a novel series of potent, orally bioavailable small molecule antagonists of CCR4. From this series, several compounds exhibited high potency in distinct functional assays in addition to good in vitro and in vivo ADME properties. The design, synthesis, and SAR of this series and confirmation of its in vivo activity are reported.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Several neurological diseases, including Parkinson disease and dementia with Lewy bodies, are characterized by the accumulation of alpha-synuclein phosphorylated at Ser-129 (p-Ser-129). The kinase or kinases responsible for this phosphorylation have been the subject of intense investigation. Here we submit evidence that polo-like kinase 2 (PLK2, also known as serum-inducible kinase or SNK) is a principle contributor to alpha-synuclein phosphorylation at Ser-129 in neurons. PLK2 directly phosphorylates alpha-synuclein at Ser-129 in an in vitro biochemical assay. Inhibitors of PLK kinases inhibited alpha-synuclein phosphorylation both in primary cortical cell cultures and in mouse brain in vivo. Finally, specific knockdown of PLK2 expression by transduction with short hairpin RNA constructs or by knock-out of the plk2 gene reduced p-Ser-129 levels. These results indicate that PLK2 plays a critical role in alpha-synuclein phosphorylation in central nervous system.