OBJECTIVES/GOALS: LSD1 is a histone demethylase important in GBM regulation. Our goal is to design a therapeutic strategy for LSD1 inhibitors to meet clinical needs in GBM. Despite the abundance of LSD1 inhibitors, resistance emerges in GBM mouse models. We aim to understand the relevance of proliferative signaling pathways, such as MAPK, in LSD1 inhibitor resistance. METHODS/STUDY POPULATION: Following LSD1 knockdown in GBM cells, we determined differentially expressed genes using RNA-seq and gene set enrichment analysis (GSEA). Kinase signaling processes enriched for LSD1 expression were identified. Utilizing western blot, we assessed LSD1’s impact on MAPK signaling in patient-derived GBM stem cells (GSCs) and pediatric high-grade glioma cell models. Pharmacological evaluation of LSD1 involved five inhibitor candidates. Additionally, we explored LSD1 inhibition in combination with brain penetrant kinase inhibitors, osimertinib and ulixertinib, directed against the epidermal growth factor receptor (EGFR) and MAPK, respectively. The treatment combinations were assessed at multiple concentrations and analyzed using SynergyFinder. RESULTS/ANTICIPATED RESULTS: Pharmacological LSD1 inhibition after 24 hours induced increased phosphorylated ERK1/2 across multiple glioma cell lines. Concurrent LSD1 and EGFR/MAPK inhibition demonstrated improvedin vitro efficacy compared to individual agents. Notably, the combination of Iadademstat (ORY-1001) and osimertinib demonstrated the highest synergy score of 37.2 using the bliss synergy model in the GSC17s. Furthermore, 11 out of the 12 combination treatments tested had a synergistic relationship, with bliss synergy scores greater than 10. DISCUSSION/SIGNIFICANCE: Our study addresses the pressing need for novel therapeutic strategies in GBM. We leveraged pharmacological tools of LSD1 inhibition to determine how they could be used most effectively, revealing kinase inhibition as a promising strategy with demonstrated in vitro efficacy. Future efforts will focus on validating these findingsin vivo.

Brochuchus is a small crocodylid originally based on specimens from the early Miocene of Rusinga Island, Lake Victoria, Kenya. Here, we report occurrences of Brochuchus from several early and middle Miocene sites. Some are from the Lake Victoria region, and others are in the Lake Turkana Basin. Specimens from the middle Miocene Maboko locality form the basis of a new species, Brochuchus parvidens, which has comparatively smaller maxillary alveoli. Because of the smaller alveoli, the teeth appear to be more widely spaced in the new species. We also provide a revised diagnosis for Brochuchus and its type species, B. pigotti. A phylogenetic analysis supports a close relationship between Brochuchus and tube-snouted Euthecodon, but although relationships among crocodylids appear poorly resolved in the set of optimal trees, this is because Brochuchus and Euthecodon, along with early Miocene “Crocodylus” gariepensis from the early Miocene of Namibia, jointly adopt two distinct positions—either closely related to the living sharp-nosed crocodile (Mecistops) or to a group including the living dwarf crocodiles (Osteolaemus). Character support for a close relationship with Mecistops is problematic, and we suspect a closer relationship to Osteolaemus will be recovered with improved sampling, but the results here are ambiguous. In either case, Brochuchus is more closely related to living groups not currently found in East Africa. This material helps constrain the timing of crocodylian faunal turnover in the East African Rift Valley System, with endemic lineages largely being replaced by Crocodylus in the middle or late Miocene possibly in response to regional xerification and the replacement of continuous rainforest cover with open grasslands and savannas.

UUID: http://zoobank.org/e6f0b219-5f3e-44e5-bdb9-60a4fae8d126

Radiocarbon (14C) ages cannot provide absolutely dated chronologies for archaeological or paleoenvironmental studies directly but must be converted to calendar age equivalents using a calibration curve compensating for fluctuations in atmospheric 14C concentration. Although calibration curves are constructed from independently dated archives, they invariably require revision as new data become available and our understanding of the Earth system improves. In this volume the international 14C calibration curves for both the Northern and Southern Hemispheres, as well as for the ocean surface layer, have been updated to include a wealth of new data and extended to 55,000 cal BP. Based on tree rings, IntCal20 now extends as a fully atmospheric record to ca. 13,900 cal BP. For the older part of the timescale, IntCal20 comprises statistically integrated evidence from floating tree-ring chronologies, lacustrine and marine sediments, speleothems, and corals. We utilized improved evaluation of the timescales and location variable 14C offsets from the atmosphere (reservoir age, dead carbon fraction) for each dataset. New statistical methods have refined the structure of the calibration curves while maintaining a robust treatment of uncertainties in the 14C ages, the calendar ages and other corrections. The inclusion of modeled marine reservoir ages derived from a three-dimensional ocean circulation model has allowed us to apply more appropriate reservoir corrections to the marine 14C data rather than the previous use of constant regional offsets from the atmosphere. Here we provide an overview of the new and revised datasets and the associated methods used for the construction of the IntCal20 curve and explore potential regional offsets for tree-ring data. We discuss the main differences with respect to the previous calibration curve, IntCal13, and some of the implications for archaeology and geosciences ranging from the recent past to the time of the extinction of the Neanderthals.

As the worldwide standard for radiocarbon (14C) dating over the past ca. 50,000 years, the International Calibration Curve (IntCal) is continuously improving towards higher resolution and replication. Tree-ring-based 14C measurements provide absolute dating throughout most of the Holocene, although high-precision data are limited for the Younger Dryas interval and farther back in time. Here, we describe the dendrochronological characteristics of 1448 new 14C dates, between ~11,950 and 13,160 cal BP, from 13 pines that were growing in Switzerland. Significantly enhancing the ongoing IntCal update (IntCal20), this Late Glacial (LG) compilation contains more annually precise 14C dates than any other contribution during any other period of time. Thus, our results now provide unique geochronological dating into the Younger Dryas, a pivotal period of climate and environmental change at the transition from LG into Early Holocene conditions.

The analysis of function-ascribing statements, such as “the function of x is y”, is proving to be a difficult matter. It is difficult because we are only beginning to see the complexity which is involved in ascribing functions. The process of discovery has been slow and tedious, with each newly constructed analysis of the meaning of functional ascriptions yielding insights into the structure of functional analysis and functional explanation. However, as each analysis is, in turn, dismantled, we seem to see our insights slip away. In the wake of each exchange, a new member is added to the list of desiderata for an analysis of function-ascribing statements. Thus, the matter of finding a proper analysis of function attributions becomes more and more complex.

What is the relationship between trying, desire, and desiring to try? Is it necessary to desire to do something in order to try to do it? Must Dave desire to quit smoking in order to try to quit? I shall defend the view that desiring to do A is necessary for trying to do A. First, Dave needs motivation to quit smoking and motivation comes in the form of desire. So it seems straightforward that when one tries to do something A, one’s desire to do that thing A is one’s motivation. Second, when Dave throws out a pack of cigarettes, this may or may not be part of an attempt to quit smoking. It may be a political protest against R.J.R. Nabisco (Dave may be changing brands, not lifestyles). Dave’s throwing out the cigarettes only counts as part of his attempt to quit smoking, if it is done for the right reason, out of the right motivation. Again, the right motivation seems to be the desire to quit smoking. Thus, the desire to do A appears to play important roles in the attempt to do A. At the very least, it helps to motivate, guide, and constitute the attempt as the attempt to do A. It is because Dave wants to quit smoking that his throwing out his cigarettes counts as part of his attempt to quit smoking, not as a political protest.

There is a venerable and thoroughly entrenched tradition of regarding epistemic justification as playing an essential cognitive role in the acquisition, maintenance, or even loss of knowledge. Hold fixed that p is true and that S believes that p. Given this, whether S comes to know that p, still knows that p, or no longer knows that p essentially depends upon whether S has acquired, sustained, or lost justification for believing that p. I shall call any theory which regards epistemic justification as playing this essential epistemological function in cognition a Jn-theory. To simplify, we will say that a Jn-theorist is one who holds that - when the truth of p is held constant and S's belief that p is held constant - S's knowledge that p varies directly with the victory of S's justification and indirectly with its defeat.

People intend to do things, try to do things, and do things. Do they also will to do things? More precisely, if people will to do things and their willing bears upon what they do, is willing, or volition, something distinct from intending and trying? This question is central to the intention/volition debate, a debate about the ingredients of the best theory of the nature and explanation of human action. A variety of competing conceptions of volition, intention, and trying have been advanced in the literature; it would be impossible to examine each thoroughly in a single paper. We can show, however, that the major functional roles ascribed to volition are nicely filled by a triad composed of intention, trying, and information feedback. Sections I and II below develop an account of the connection between intention and trying. Section III examines leading arguments for the existence of volitions and decomposes volitions into members of the triad just identified.

A great deal of attention has been paid in recent years to the functional roles of intentions in intentional action. In this paper we sketch and defend a position on this issue while attacking a provocative alternative. Our position has its roots in a cybernetic theory of purposive behavior and is only part of the larger task of understanding all goal-directed behavior. Indeed, a unified model of goal-directed behavior, with appropriate modifications for different types of systems, is a long-range ambition.

I am pleased to be able to respond to Al Mele’s reply to my paper on trying and desire (‘Desiring to Try: Reply to Adams’ and ‘Trying, Desire, and Desiring to Try,’ respectively, both this volume). My remarks will bebriet.

First, it is not thesis T (as stated in Mele’s reply) that I find objectionable. It may be possible for me to want TO TRY to quit smoking (prior to trying), while currently not wanting TO QUIT smoking (nor trying to quit). I may want to try because I want to ACQUIRE the desire to quit, since people persist in nagging me to quit. So I accept thesis T because it is not the issue. The issue is whether one can PERFORM THE ATTEMPT to quit smoking WHILE one lacks the desire to quit smoking. THAT is what I find objectionable and impossible. Mele accepts that it is possible. I believe such an attempt to be merely ‘going through the motions’ in bad faith and not a genuine attempt at all. I believe this for the controltheoretic reasons that I outlined in my original paper and elsewhere.

Advances in accelerator mass spectrometry have resulted in an unprecedented amount of new high-precision radiocarbon (14C) -dates, some of which will redefine the international 14C calibration curves (IntCal and SHCal). Often these datasets are unaccompanied by detailed quality insurances in place at the laboratory, questioning whether the 14C structure is real, a result of a laboratory variation or measurement-scatter. A handful of intercomparison studies attempt to elucidate laboratory offsets but may fail to identify measurement-scatter and are often financially constrained. Here we introduce a protocol, called Quality Dating, implemented at ETH-Zürich to ensure reproducible and accurate high-precision 14C-dates. The protocol highlights the importance of the continuous measurements and evaluation of blanks, standards, references and replicates. This protocol is tested on an absolutely dated German Late Glacial tree-ring chronology, part of which is intercompared with the Curt Engelhorn-Center for Archaeometry, Mannheim, Germany (CEZA). The combined dataset contains 170 highly resolved, highly precise 14C-dates that supplement three decadal dates spanning 280 cal. years in IntCal, and provides detailed 14C structure for this interval.

No discipline has been impacted more by war and armed conflict than health care has. Health systems and health care providers are often the first victims, suffering increasingly heinous acts that cripple the essential health delivery and public health infrastructure necessary for the protection of civilian and military victims of the state at war. This commentary argues that current instructional opportunities to prepare health care providers fall short in both content and preparation, especially in those operational skill sets necessary to manage multiple challenges, threats, and violations under international humanitarian law and to perform triage management in a resource-poor medical setting. Utilizing a historical framework, the commentary addresses the transformation of the education and training of humanitarian health professionals from the Cold War to today followed by recommendations for the future. (Disaster Med Public Health Preparedness. 2019;13:383-396)

Since 1945, the reason for humanitarian crises and the way in which the world responds to them has dramatically changed every 10 to 15 years or less. Planning, response, and recovery for these tragic events have often been ad hoc, inconsistent, and insufficient, largely because of the complexity of global humanitarian demands and their corresponding response system capabilities. This historical perspective chronicles the transformation of war and armed conflicts from the Cold War to today, emphasizing the impact these events have had on humanitarian professionals and their struggle to adapt to increasing humanitarian, operational, and political challenges. An unprecedented independent United Nations–World Health Organization decision in the Battle for Mosul in Iraq to deploy to combat zones emergency medical teams unprepared in the skills of decades-tested war and armed conflict preparation and response afforded to health care providers and dictated by International Humanitarian Law and Geneva Convention protections has abruptly challenged future decision-making and deployments. (Disaster Med Public Health Preparedness. 2019;13:109–115)

Radiocarbon measurements in tree rings can be used to estimate atmospheric 14C concentration and thereby used to create a 14C calibration curve. When wood is discovered in construction sites, rivers, buildings, and lake sediments, it is unclear if the wood could fill gaps in the 14C calibration curve or if the wood is of historical interest until the age is determined by dendrochronology or 14C dating. However, dendrochronological dating is subjected to many requirements and 14C dating is costly and time consuming, both of which can be frivolous endeavors if the samples are not in the age range of interest. A simplified 14C dating technique, called Speed Dating, was thus developed. It can be used to quickly obtain 14C ages as wood samples are neither chemically treated nor graphitized. Instead, wood is combusted in an elemental analyzer (EA) and the CO2 produced is carried into an accelerator mass spectrometer (AMS) with a gas ion source. Within a day, 75 samples can be measured with uncertainties between 0.5–2% depending on the age, preservation, and contaminants on the material and Speed Dating costs about one-third of conventional AMS dates.

Dominant users of Lake Okeechobee water resources are agricultural producers and recreational anglers These uses will be directly affected, should the lake become infested with zebra mussels. We employ a probabilistic bioeconomic simulation model to estimate the potential impact of zebra mussels on consumptive water uses, recreational angling, and wetland ecosystem services under alternative public management scenarios. Without public management, the expected net economic impact from zebra mussels is –$244.1 million over 20 years. Public investment in prevention and eradication will yield a net expected gain of +$188.7 million, a superior strategy to either prevention or eradication alone.

The collaborative London based non-governmental organization network ELRHA (Enhancing Learning and Research for Humanitarian Assistance) supports partnerships between higher education institutions and humanitarian organizations worldwide with the objective to enhance the professionalization of the humanitarian sector. While coordination and control of the humanitarian sector has plagued the response to every major crisis, concerns highlighted by the 2010 Haitian earthquake response further catalyzed and accelerated the need to ensure competency-based professionalization of the humanitarian health care work force. The Harvard Humanitarian Initiative sponsored an independent survey of established academically affiliated training centers in North America that train humanitarian health care workers to determine their individual training center characteristics and preferences in the potential professionalization process. The survey revealed that a common thread of profession-specific skills and core humanitarian competencies were being offered in both residential and online programs with additional programs offering opportunities for field simulation experiences and more advanced degree programs. This study supports the potential for the development of like-minded academic affiliated and competency-based humanitarian health programs to organize themselves under ELRHA's regional “consultation hubs” worldwide that can assist and advocate for improved education and training opportunities in less served developing countries.

Burkle Jr FM, WallsAE, HeckJP, SorensenBS, CranmerHH, JohnsonK, LevineAC, KaydenS, CahillB, VanRooyenMJ. Academic Affiliated Training Centers in Humanitarian Health, Part I: Program Characteristics and Professionalization Preferences of Centers in North America. Prehosp Disaster Med. 2013:28(2):1-8.