bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR02: Structural and functional analyses of GATOR1, a negative regulator of the mTORC1 pathway
Authors: Shen Kuang , Huang Rick , Yu Zhiheng , Sabatini David M. 
Published: December 2020

Abstract
mTORC1 is a major regulator for cell growth and proliferation that coordinates nutrient inputs, such as amino acids, glucose, and growth factor, with anabolic and catabolic processes in cells. Amino acid signals are transmitted towards mTORC1 through the Rag GTPases, which directly recruit mTORC1 onto the lysosomal membrane. The Rag GTPase heterodimer has a unique architecture that consists of two GTPase subunits, RagA or RagB bound to RagC or RagD. Their nucleotide loading states are strictly controlled by several lysosomal or cytosolic protein complexes that directly process the amino acid signal. One such complex is GATOR1, a negative regulator on the cytosolic branch of the amino acid sensing pathway. GATOR1 comprises three subunits, Depdc5, Nprl2, and Nprl3, and is a GTPase Activating Protein (GAP) for RagA. It functions through a noncanonical GAP mechanism in which GATOR1 binds the Rag GTPases with two modes, an inhibitory mode that holds the Rag GTPase heterodimer and has been captured by structural determination, and a GAP mode that actually stimulates GTP hydrolysis by RagA but remains elusive. Here, we used biochemical approaches to probe the GAP mode of GATOR1 and found that a critical arginine finger on Nprl2, Arg78, is the catalytic residue, while a loop localized close to it provides the binding site for the Rag GTPases. Furthermore, we used cryo-EM to resolve the structure of the GATOR1-Rag-Ragulator complex at 4.1A resolution, which represents the architecture of the mTORC1-inhibiting complex on the lysosomal surface. Our results revealed the molecular bases for mTORC1 inactivation in human cells.
This abstract is also being presented as Poster B10.
Citation Format: Kuang Shen, Rick Huang, Zhiheng Yu, David M. Sabatini. Structural and functional analyses of GATOR1, a negative regulator of the mTORC1 pathway [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR02.
Abstract PR03: Selective degradation of mutant PIK3CA promotes increased mutant specificity in a subset of PI3K ATP-competitive inhibitors
Authors: Nguyen Lan , Edgar Kyle , Song Kyung , Schmidt Stephen , Schutz Victorai , Ishisoko Noriko , Torres Eric , Das Akash , Murali Divya , Sideris Steve , Wendorff Timothy , Saabye Matt , Purkey Hans , Sudhamsu Jawahar , Staben Steven , Hanan Emily , Hatzivassiliou Georgia , Friedman Lori , Endres Nicholas F. 
Published: December 2020

Abstract
Activating mutations in PIK3CA are among the most significant oncogenic events across all cancers, making it an important target for drug development. Yet the application of PI3K inhibitors in the clinic has been limited by the difficulty of achieving an adequate therapeutic window, due to the critical role that PI3K signaling plays in normal physiologic processes, such as glucose homeostasis. In theory, the therapeutic window could be improved if it were possible to design mutant selective inhibitors, as has been demonstrated with other oncogenes such as EGFR. However, unlike EGFR, the most predominant PIK3CA activating mutations do not reside in the kinase active site, presenting a major challenge for rational structure-based design. Nevertheless, it was recently shown that the PI3K inhibitor taselisib is able to achieve modest levels of mutant selectivity both across cancer lines as well as in cell lines that were engineered to express mutant or wild-type PIK3CA. Taselisib was also shown to selectively induce degradation of mutant versus wild-type PIK3CA, leading to the speculation that this degradation may be responsible for the observed selectivity. In order to better understand the origins of mutant selectivity for taselisib and several other PIK3CA inhibitors, we assessed these inhibitors in a variety of biophysical and biochemical assays under conditions designed to mimic physiologic settings. In parallel, we also investigated the mechanistic basis of this selectivity in our engineered cell lines. Our results are consistent with the hypothesis that selective degradation of mutant PIK3CA is the predominant mechanism underlying mutant selectivity for this class of PIK3CA active site inhibitors.
This abstract is also being presented as Poster B03.
Citation Format: Lan Nguyen, Kyle Edgar, Kyung Song, Stephen Schmidt, Victorai Schutz, Noriko Ishisoko, Eric Torres, Akash Das, Divya Murali, Steve Sideris, Timothy Wendorff, Matt Saabye, Hans Purkey, Jawahar Sudhamsu, Steven Staben, Emily Hanan, Georgia Hatzivassiliou, Lori Friedman, Nicholas F. Endres. Selective degradation of mutant PIK3CA promotes increased mutant specificity in a subset of PI3K ATP-competitive inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR03.
BMP9 and BMP10 Act Directly on Vascular Smooth Muscle Cells for Generation and Maintenance of the Contractile State
Authors: Wang Lei , Rice Megan , Swist Sandra , Kubin Thomas , Wu Fan , Wang Shengpeng , Kraut Simone , Weissmann Norbert , Böttger Thomas , Wheeler Matthew , Schneider Andre , Braun Thomas 
Published: December 2020

Background:
Vascular smooth muscle cells (VSMCs) show a remarkable phenotypic plasticity, allowing acquisition of contractile or synthetic states, but critical information is missing about the physiologic signals, promoting formation, and maintenance of contractile VSMCs in vivo. BMP9 and BMP10 (bone morphogenetic protein) are known to regulate endothelial quiescence after secretion from the liver and right atrium, whereas a direct role in the regulation of VSMCs was not investigated. We studied the role of BMP9 and BMP10 for controlling formation of contractile VSMCs.

Methods:
We generated several cell type–specific loss- and gain-of-function transgenic mouse models to investigate the physiologic role of BMP9, BMP10, ALK1 (activin receptor-like kinase 1), and SMAD7 in vivo. Morphometric assessments, expression analysis, blood pressure measurements, and single molecule fluorescence in situ hybridization were performed together with analysis of isolated pulmonary VSMCs to unravel phenotypic and transcriptomic changes in response to absence or presence of BMP9 and BMP10.

Results:

Concomitant genetic inactivation of
Bmp9
in the germ line and
Bmp10
in the right atrium led to dramatic changes in vascular tone and diminution of the VSMC layer with attenuated contractility and decreased systemic as well as right ventricular systolic pressure. On the contrary, overexpression of
Bmp10
in endothelial cells of adult mice dramatically enhanced formation of contractile VSMCs and increased systemic blood pressure as well as right ventricular systolic pressure. Likewise, BMP9/10 treatment induced an ALK1-dependent phenotypic switch from synthetic to contractile in pulmonary VSMCs. Smooth muscle cell–specific overexpression of
Smad7
completely suppressed differentiation and proliferation of VSMCs and reiterated defects observed in adult
Bmp9/10
double mutants. Deletion of
Alk1
in VSMCs recapitulated the
Bmp9/10
phenotype in pulmonary but not in aortic and coronary arteries. Bulk expression analysis and single molecule RNA–fluorescence in situ hybridization uncovered vessel bed–specific, heterogeneous expression of BMP type 1 receptors, explaining phenotypic differences in different
Alk1
mutant vessel beds.

Conclusions:
Our study demonstrates that BMP9 and BMP10 act directly on VSMCs for induction and maintenance of their contractile state. The effects of BMP9/10 in VSMCs are mediated by different combinations of BMP type 1 receptors in a vessel bed–specific manner, offering new opportunities to manipulate blood pressure in the pulmonary circulation.
The High Tide of Anticolonial Legalism
Authors: Moyn Samuel 
Published: December 2020

Abstract
For a time in the 1960s it seemed as if one domain in which the global south’s enthusiastic struggle to arrogate the mantle of universalism as an exercise in “worldmaking” was the transformation of international law. Though this struggle was ultimately circumvented by great power politics and newer forms of international law and organization, it was a crucial moment. The introductory prosopographical survey that follows seeks to recapture the consensus of a set of northern and southern international lawyers in the 1960s who saw potential in the project of transforming their field to register the aims of a new epoch – the aims of postcolonial states.
Building the Nation: Sovereignty and International Law in the Decolonisation of South Asia
Authors: Saksena Priyasha 
Published: December 2020

Abstract
The position of the territorially sovereign nation-state as the fundamental building block of the contemporary world order has come under increasing challenge. Historians have long focused on social, cultural, economic, and technological factors to examine the constructed nature of the nation-state. In this article, I explore the role of law, and specifically the concept of sovereignty, in the creation of the unified spatial entity constituting the nation-state. I focus in particular on the decolonisation of South Asia and analyse legal arguments made in two international disputes (over Hyderabad and the river Indus) to understand the process through which the Indian nation-state came into being.
“Paved with Good Intentions:” Best Practices in the Ethics of Track Two Interventions
Authors: Jones Peter 
Published: December 2020

Abstract
This article unpacks the development of key ideas and debates which surround the ethical issues of Track Two. It defines what is meant by ‘Track Two’ and discusses how ethics might best be applied in practice to these dialogues. The ethical dimensions of four key issues are explored: accountability; the basis on which third parties feel they are entitled to intervene; the problem of dealing with actors who have committed atrocities; and ethical questions surrounding secrecy or confidentiality which is often required. The article suggests several ways forward in terms of creating a mechanism to enable practitioners to assist each other with the challenges they face. The article takes the view that a ‘hard and fast’ set of ethics may not be appropriate for the field, as each intervention is quite different, but rather that a set of ‘reflective questions’ should be developed to help practitioners confront ethical issues.
Towards an Inclusive Conception of Best Practices in Peace and Conflict Initiatives: The Case of the South Caucasus
Authors: Gamaghelyan Philip 
Published: December 2020

Abstract
The field of peace and conflict studies has been maturing over the past few decades, not least thanks to the continual epistemological contestation between its philosophy and methodology. As a consequence, the methods of conflict resolution practice have been evolving. Dominated by realist approaches of conflict management during the Cold War, the field in the 1990s relied heavily on neo-liberal theories of economic interdependence, democracy building, and interest-based negotiations that can bring win-win outcomes. By the late 2000s, as the constructivist paradigm and critical theory started gaining ground in academia, the conceptual conversation shifted toward the possibilities of building inclusive societies and achieving structural and cultural peace via conflict transformation, rather than resolution, as the respective methodology.
Incorporating Best Practices into Design and Facilitation of Track Two Initiatives
Authors: d’Estrée Tamra Pearson , Fox Benjamin B. 
Published: December 2020

Abstract
Track Two processes were developed to facilitate movement in difficult international conflicts. Since Montville first coined the term, Track Two processes have considered deliberate and strategic ways to bring together adversaries in unofficial, private face-to-face interactions that allow for joint analysis and mutual learning. Such processes create the conditions for more nuanced problem definition and solution exploration. Ideally, these insights are then transferred into official peace processes, policymaking and decision-making. Transfer acknowledges a strategic dimension to planning for change; Track Two approaches abridge and accelerate the long-term accumulation approach by the strategic choice of participants, agenda and goals. This article reviews and summarizes our knowledge to date about how best to encourage Track Two inputs into negotiation and other Track One diplomatic efforts. It then offers a checklist for designing initiatives to best promote both intergroup learning and timely transfer to generate effective change.
Family Life for Children in State Care
Authors: Breen Clarie , Krutzinna Jenny , Luhamaa Katre , Skivenes Marit 
Published: December 2020

Abstract
This paper examines what set of familial circumstances allow for the justifiable interference with the right to respect for family life under Article 8, echr. We analyse all the Courts’ judgments on adoptions from care to find out what the Court means by a “family unit” and the “child´s best interest”. Our analysis show that the status and respect of the child’s de facto family life is changing. This resonates with a view that children do not only have formal rights, but that they are recognised as individuals within the family unit that states and courts must address directly. Family is both biological parents and child relationships, as well between children and foster parents, and to a more limited extent between siblings themselves. The Court’s understanding of family is in line with the theoretical literature, wherein the concept of family reflects the bonds created by personal, caring relationships and activities.
Child Support and the Government’s Children’s Socio-economic Rights Obligations
Authors: Walker Lara 
Published: December 2020

Abstract
This article argues that the recovery of child support is a vital aspect of ensuring children’s socio-economic rights. The UK Government has a legal responsibility to assist parents to meet the needs of their children, whether by providing specialist support or through welfare payments. The Government cannot fulfil this responsibility by requiring parents to reach private agreements and failing to provide suitable additional support. The current law and policy focus purely on the duty to maintain. It is assumed that each parent has the responsibility to provide for their children, and there is no back up support under the Child Support Act where the parents are unable to do this. This fails to acknowledge and resolve wider social issues which are crucial to ensuring that child support is received, and children are not living in unnecessary poverty. The article argues that by taking this approach the Government is failing to fulfil its responsibility to protect children’s socio-economic rights. This article sets out a socio-economic rights framework for amending child support legislation and policy, highlighting the bare minimum Government obligations.
Barriers to Effective, Equitable and Quality Education
Authors: MacKenzie Alison , Bower Christine , Owaineh Mohammed 
Published: December 2020

Abstract
The Israeli occupation has had a considerable negative impact on the lives of Palestinians, such that achieving an effective, equitable, quality education for all children is far from being realised. Palestinian children are not only adversely affected by the occupation, but also by an educational system that fails fully and systematically to accord them their rights. Using rights-based participatory methods informed by human rights protocols, we explored the experiences of children with disabilities’ inclusion in schools. Our findings show that there is continuing failure to understand or implement the provisions of the uncrc or uncrpd, and that these children are systematically excluded or marginalised from education. We suggest that children’s rights to educational inclusion can be achieved by means of a whole system, whole educational and whole person approach, along with a consideration of a rights-based policy framework.
Reclaiming Progressive Realisation: A Children’s Rights Analysis
Authors: Byrne Seamus 
Published: December 2020

Abstract
Any discussion on children’s socio-economic rights should not overlook their means of fulfilment; namely, the principle of progressive realisation and the legal duties arising therefrom. This article argues that from a children’s rights perspective, this principle has remained legally and operationally underdeveloped by the Committee on the Rights of the Child. This can be seen from their failure sufficiently to engage with, and address, the obligations imposed by progressive realisation in their General Comments and in their Concluding Observations on state practice issued under the Convention’s reporting process. This article argues that the cumulative consequence of these failings is that the Committee has peripheralised this important legal obligation within children’s rights scholarship and has ultimately undermined its ability to achieve its full legal potential in enhancing children’s socio-economic rights. In advocating for the promulgation of a revised General Comment on the General Measures of Implementation, it demonstrates how children’s rights can meaningfully reconnect with the principle in a more consequential way.
A Reflection on “Divinatory Conventions in Late Shang China” and the Grammar of the Oracle-Bone Inscriptions
Authors: Takashima Ken-ichi 
Published: December 2020

Abstract
This paper questions Keightley’s claim that the divinatory conventions followed in the Diviner Li 歷-Group charges were different from those followed in the Diviner Bin 賓-Group charges. The paper relies in part on what may be shown as an objective guideline, i.e., what is commonly referred to as “presupposition”, a supposition made prior to any utterance or sentence. The paper also addresses the problem of qi 其 and the negatives used with or without it.
Snowfall-Rate Retrieval for K- and W-Band Radar Measurements Designed in Hyytiälä, Finland, and Tested at Ny-Ålesund, Svalbard, Norway
Authors: Schoger Sybille Y. , Moisseev Dmitri , von Lerber Annakaisa , Crewell Susanne , Ebell Kerstin 
Published: December 2020

AbstractTwo power-law relations linking equivalent radar reflectivity factor Ze and snowfall rate S are derived for a K-band Micro Rain Radar (MRR) and for a W-band cloud radar. For the development of these Ze–S relationships, a dataset of calculated and measured variables is used. Surface-based video-disdrometer measurements were collected during snowfall events over five winters at the high-latitude site in Hyytiälä, Finland. The data from 2014 to 2018 include particle size distributions (PSD) and their fall velocities, from which snowflake masses were derived. The K- and W-band Ze values are computed using these surface-based observations and snowflake scattering properties as provided by T-matrix and single-particle scattering tables, respectively. The uncertainty analysis shows that the K-band snowfall-rate estimation is significantly improved by including the intercept parameter N0 of the PSD calculated from concurrent disdrometer measurements. If N0 is used to adjust the prefactor of the Ze–S relationship, the RMSE of the snowfall-rate estimate can be reduced from 0.37 to around 0.11 mm h−1. For W-band radar, a Ze–S relationship with constant parameters for all available snow events shows a similar uncertainty when compared with the method that includes the PSD intercept parameter. To demonstrate the performance of the proposed Ze–S relationships, they are applied to measurements of the MRR and the W-band microwave radar for Arctic clouds at the Arctic research base operated by the German Alfred Wegener Institute Helmholtz Centre for Polar and Marine Research (AWI) and the French Polar Institute Paul Emile Victor (IPEV) (AWIPEV) in Ny-Ålesund, Svalbard, Norway. The resulting snowfall-rate estimates show good agreement with in situ snowfall observations while other Ze–S relationships from literature reveal larger differences.
Crown Lengthening for Mandibular and Maxillary Canine Teeth in the Dog
Authors: Hale Fraser A. 
Published: December 2020

Crown lengthening is the exposure of root structure to function as clinical crown for restorative coverage.1 Indications for crown lengthening include increasing the amount of clinical crown available for attachment of a prosthesis (crown or bridge) following crown fracture, and exposure of a malerupted tooth crown allowing management of any pathologic changes. Types of crown lengthening procedures include simple gingivectomy [type I], apically repositioned flap(s) following bone recontouring [type II], or orthodontic extrusion [type III]. Type I and II crown lengthening procedures involve periodontal surgery requiring maintenance of the biological width of the gingiva composed of the gingival sulcus, junctional epithelium, and connective tissue attachment (Fig. 1). Each of these zones is approximately 1-mm wide in humans, and may be 2 to 3-mm wide in large dogs. In type II crown lengthening procedures in dogs, the apically repositioned flap should maintain a minimum 3-mm biological width of the gingiva coronal to the newly formed alveolar crest to provide space for the three zones to reestablish. Failure to maintain gingival biological width physiology may cause an inflammatory response that results in crestal bone resorption and apical migration of periodontal soft tissues.1 Advanced periodontal disease resulting in the formation of infrabony pockets may jeopardize tooth maintenance.1 Crown preparation may be performed acutely, however a 2 to 3-week interval is recommended between crown lengthening and preparation to allow for accurate assessment of gingival margin location following wound healing. Type II crown lengthening of the mandibular and maxillary canine teeth is described step-by-step.