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Commercialization of autonomous vehicle technology is a major goal of the automotive industry, thus research in this space is rapidly expanding across the world. However, despite this high level of research activity, literature detailing a straightforward and cost-effective approach to the development of an AV research platform is sparse. To address this need, we present the methodology and results regarding the AV instrumentation and controls of a 2019 Kia Niro which was developed for a local AV pilot program. This platform includes a drive-by-wire actuation kit, Aptiv electronically scanning radar, stereo camera, MobilEye computer vision system, LiDAR, inertial measurement unit, two global positioning system receivers to provide heading information, and an in-vehicle computer for driving environment perception and path planning. Robotic Operating System software is used as the system middleware between the instruments and the autonomous application algorithms. After selection, installation, and integration of these components, our results show successful utilization of all sensors, drive-by-wire functionality, a total additional power* consumption of 242.8 Watts (*Typical), and an overall cost of $118,189 USD, which is a significant saving compared to other commercially available systems with similar functionality. This vehicle continues to serve as our primary AV research and development platform.

This article focuses on the ways that threatened heritage sites are caught up in complex deliberations of UNESCO's World Heritage Committee around inscription to the List of World Heritage in Danger. Through quantitative and qualitative analyses of Committee decision-making from 1979-2018, we observe geopolitical inequity and bureaucratic inefficacy characterizing the implementation of the List in Danger that prevent the realization of its envisioned purpose as a collaborative tool for garnering international investment in preservation. We argue that this situation stems from the development of diplomatic practices used by powerful States Parties to ensure their sites are only ever \"considered\" rather than \"inscribed\" on the List in Danger. The proliferation of \"consideration\" for the List in Danger effectively erases situations of danger rather than resolving threats in any real sense, subjecting endangered sites on the World Heritage List to further peril.

The impact of first-generation covalent KRAS G12C inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS G12C inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS G12C -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS G12C even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS G12C inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS G12C mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically. The success of KRAS G12C mutation specific inhibitors in patients with KRAS-driven tumours is limited by the emergence of acquired resistance. Here, the authors characterise olomorasib, a next-generation covalent KRAS G12C-mutant inhibitor, demonstrating efficacy in the presence of clinically relevant resistance mutations in preclinical KRAS-driven cancer models.

TGFβ (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGFβ acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream signalling within the TGFβ pathway, and in established tumours, TGFβ then acts as a tumour promotor through multiple mechanisms including inducing epithelial-to-mesenchymal transition (EMT), promoting formation of cancer-associated fibroblasts (CAFs) and increasing angiogenesis. TGFβ is secrereted as a large latent complex and is embedded in the extracellular matrix or held on the surface of cells and must be activated before mediating its multiple functions. Thus, whilst TGFβ is abundant in the tumour microenvironment (TME), its functionality is regulated by local activation. The αv-integrins are major activators of latent-TGFβ. The potential benefits of manipulating the immune TME have been highlighted by the clinical success of immune-checkpoint inhibitors in a number of solid tumour types. TGFβ is a potent suppressor of T-cell-mediated immune surveillance and a key cause of resistance to checkpoint inhibitors. Therefore, as certain integrins locally activate TGFβ, they are likely to have a role in the immunosuppressive TME, although this remains to be confirmed. In this review, we discussed the role of TGFβ in cancer, the role of integrins in activating TGFβ in the TME, and the potential benefits of targeting integrins to augment immunotherapies.

This article introduces the archaeological site of Chawin Punta, located in the Chaupihuaranga Basin of Pasco, Peru. Surface investigations there have identified a late Initial Period civic-ceremonial center with large-scale public architecture and carved stone art that show stylistic links to Chavín de Huántar, Pacopampa, and Pampa de las Llamas-Moxeke. Surface ceramics from the nearby site of Condorai reveal additional connections to Kotosh and San Blas. The evidence for interregional interaction involving the Chaupihuaranga Basin challenges long-held assumptions that the Peruvian central highlands were marginal to the development of social complexity during the second and first millennia BC.

The majority of states have passed legislation or have signed an executive order enacting safe testing, development, and deployment of level 4 and level 5 autonomous vehicles (AVs) in accordance with SAE standard J3016, which has led to an increase in the frequency of AV testing. The major driving force behind the push for AVs on public roads appears to be the increases the number of AVs on the road to decrease the chances of fatalities from distracted drivers. There are reports of disengagement from companies, which are required to report them to operate within California. The continuance of disengagements from AV companies within California show that there is a need for further research and development to advance AV technology. This study focuses on development and evaluation of sensor technology for an AV perception subsystem. This was accomplished by addressing three separate research questions with various focuses to identify (1) instrumentation for AV applications focusing on development of a low-cost energy-efficient research platform (2) develop and evaluate high-accuracy, low-computational sensor fusion algorithms for a perception subsystem (3) and develop and evaluate the feasibility of passive infrastructure sensors for efficient AV operations. The first study provides a better understanding of how AV technology works and what is necessary for safe AV operation. The second study explores a novel algorithm for reducing the amount of detection from radar and LiDAR to improve computational efficiency in the perception subsystem. Finally, the third study purposes how a retroreflector can be used for a passive-infrastructure sensor which has the capability to detect lane lines using radar to detect lane markers. This collection of studies demonstrate AV sensor technology and perception subsystems can improve the AV operation and energy efficiency.

This dissertation studies the dynamic relationship between interaction and innovation in ancient Peru, where archipelagos of social movement developed among groups of people living in distant regions of the Central Andes and Amazon. The early development of these archipelagic societies can be traced to the rise of the Chavin phenomenon in the 2nd and 1st millennia B.C.E., when monumental platforms and plazas were built across the Andes to accommodate large gatherings of people who interacted in civic and ceremonial events. Although the people who gathered at Chavin monuments had different historical backgrounds and geographic origins, their collective experiences forged new kinds of shared social identities that they brought back to their far-flung homelands. In this way, participants in the Chavin phenomenon created unprecedented, pan-Andean social movements that were materially visible in their artwork inspired by the idiosyncratic styles and symbols of Chavin monuments. The present investigation focuses on the dual case study of Chawin Punta and Kunturay as neighboring mountaintop monuments overlooking the Chaupihuaranga Canyon in the east-central highlands of Pasco, Peru. Here, abundant archaeological evidence suggests the Chaupihuaranga Canyon played a key role in Chavin social movements. Archaeological excavations, pedestrian surveys, and satellite remote sensing have all generated data on ancient patterns of human interaction involving the Chaupihuaranga Canyon during pre-Hispanic times. This fieldwork revealed that Chawin Punta and Kunturay were particularly important ceremonial centers during 2nd and 1st millennia B.C.E. when massive stone monuments were built into their bedrock peaks.Stylistic data from bas-relief and tenon head stone sculptures, carved bone ritual objects, and decorated ceramic vessels revealed that ancient people at Chawin Punta and Kunturay possessed dynamic, interregional social ties with many distant sites: down the Andean slopes with eastern midland sites like Kotosh, Shillacoto, Jancao, and Cave of the Owls (Huánuco); into the Amazon lowlands of Tutishcainyo (Ucayali); along the western Pacific lowlands with north coast Cupisnique (La Libertad), north-central coast Casma (Áncash), central coast Ancon-Supe (Lima), and south coast Paracas (Ica); and along the Andean plateaus with north-central highland sites like Chavín de Huántar, Huaricoto (Áncash), and Pacopampa (Cajamarca), as well as south-central highland sites like San Blas (Junín), Atalla (Huancavelica) and Campanayuq Rumi (Ayacucho). An integrated chronological scheme of ceramic phases, architectural sequences, and radiocarbon data from the excavations at Chawin Punta and Kunturay allowed for a detailed characterization of the sociohistorical trajectory of the Chaupihuaranga Canyon through time. This regional chronology includes: Chaka I (early Initial Period, early 2nd mil. B.C.E), Chaka II (middle Initial Period, mid 2nd mil. B.C.E.), Wayra (late Initial Period, late 2nd & early 1st mil. B.C.E.), Willka (beginning of the Early Horizon, mid 1st mil. B.C.E.), Patak (end of the Early Horizon, late 1st mil B.C.E.), Rinri (Early Intermediate Period, early 1st mil. C.E.), Huertas (Middle Horizon, late 1st mil. C.E.), and Waranqa (Late Intermediate Period & Late Horizon, early to mid 2nd mil. C.E.).Social innovation in the Chaupihuaranga Canyon was assessed through the remains of ceramics found at Chawin Punta and Kunturay. A chaîne operatoire analysis of the techniques and style choices involved in ancient pottery production revealed the changing pace of innovation through time. Human interaction was characterized at Chawin Punta and Kunturay using the novel conceptual apparatus of the “material archipelago,” in which the distribution of similar material remains at coeval archaeological sites in different regions are hypothesized to correspond to an interactive social group. Based on Andean social theories from ethnohistory, the material archipelago framework allowed for a more precise description of the range of ancient interregional interactions involving the Chaupihuaranga Canyon. This research has illustrated how new styles of ceramic, stone, and bone artworks were widely shared across many regions, suggesting that human interaction and social innovation were closely related in the early Andean past.Application of the “material archipelago” framework to study ancient Chawin Punta and Kunturay has confirmed the enduring importance of vertical complementarity between the central Andean highlands, eastern slope midlands and Amazonian lowlands, supporting the pre-Hispanic application of Murra’s (1972) “vertical archipelago” model to explain sociohistorical dynamics in east-central Peru. Moreover, the diversity range of interactions between the Chaupihuaranga Canyon and other highland and coastal regions during the 2nd and 1st mil. B.C.E. supports Burger’s (1988) “religious archipelago” model to explain the development of the Chavin phenomenon. These findings suggest that the material archipelago framework has the potential to clarify other pre-Hispanic cases of pan-Andean interaction, such as the Wari phenomenon or Inca Tawantinsuyu.

The impact of first-generation covalent KRAS inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.

Approximately 14% of all men will be diagnosed with prostate cancer. Not only is prostate cancer very prevalent, but as the second leading cause of cancer related deaths in men, it is also very deadly. Many of these deaths result from resistance to androgen deprivation therapy (ADT), defined as Castration Resistant Prostate Cancer (CRPC). The majority of men with CRPC die within 5 years of diagnosis, emphasizing the need for further research for novel CRPC therapeutics. Many prostate cancers become resistant to ADT through reactivation of the Androgen Receptor (AR). Within this dissertation, we demonstrate that the cell surface receptor Ron tyrosine kinase is important in activating AR in prostate cancer under conditions of androgen deprivation, leading to resistance to ADT. Previous studies established the Ron receptor and its ligand (HGFL) as critical players in prostate cancer, with Ron expression levels in prostate cancer correlating with disease severity and loss of Ron or HGFL in the Transgenic Adenocarcinoma of Mouse Prostate model of prostate cancer severely reducing primary tumor growth. These previous studies were critical in demonstrating the importance of Ron in prostate cancer, but had yet to address the potential role of Ron in regulating CRPC. We observed that Ron overexpression was sufficient to drive resistance to castration therapy by overexpressing Ron in androgen sensitive murine and human cell lines for allograft and xenograft models of CRPC. Prostate tumors derived from Ron overexpressing prostate cancer cells display elevated AR activation and require AR to provide growth in androgen depleted conditions. Further, Ron was shown to activate AR in an epithelial cell specific manner through activation of NF-κB and β-Catenin. As we further analyzed the consequences of Ron overexpression in prostate cancer, we discovered increased macrophage recruitment into Ron overexpressing tumors. We show that macrophage infiltration into Ron overexpressing tumors enhances AR, Ron, and Axl activation in prostate cancer cells through the secretion of Gas6, demonstrating a non-cell autonomous role for macrophages in promoting Ron mediated castration resistant growth. Excitingly, as we pursued the role of macrophage secreted Gas6 to drive growth of Ron overexpressing tumors we made the novel discovery that Gas6 binds to and induces activation of Ron. Discovery of this interaction has the potential to provide clarity to a number of questions that have remained unanswered regarding the role of Ron in the absence of HGFL. As we further investigated roles for Ron in prostate cancer we made the observation that Ron signaling is important for enhancing the effects of diet-induced obesity on prostate cancer. Obese patients have a higher incidence of developing aggressive metastatic prostate cancer compared to lean patients. Herein we provide evidence that adipocyte specific Ron signaling is essential for obesity to enhance prostate cancer growth and metastatic potential. Taken together, this work demonstrates several novel functions for the Ron receptor in driving prostate cancer and provides rationale for targeting this signaling pathway for the treatment of men with aggressive disease.

Honey bee colonies maintain viable queens in part through communication with Queen Mandibular Pheromone (QMP), a mixture that signals the queen’s presence and reproductive quality to workers. In turn, workers are thought to provide retinue queen care or replace queens partially based on QMP profiles. We examined the effects of seasonal dearth (overwintering in a warm subtropical location) on queen-worker interactions. Retinue worker responses to continuously ovipositing queens were considered in view of QMP signaling and queen reproductive quality. QMP signaling was estimated from QMP residues recovered from nest worker bodies, which is the primary mode of QMP transfer from the queen to the colony at large. QMP residues varied seasonally but not at all with queen reproductive quality (spermatheca sperm storage, ovary protein and lipid contents). 9-HDA and 9-ODA were lower in January than other months. HOB decreased from July to January, while HVA, a component associated with mated queens, increased sharply in January. Despite these seasonal signaling differences, retinue workers attended queens at similar levels through the months. In terms of reproductive quality, queens did not differ over the months in matedness (spermatheca sperm storage) or physiological age (protein carbonyl content), but varied in nutrient allocation to reproductive and non-reproductive tissues. Queen ovaries contained more protein in September than in November, and more lipid in July and September than in November and January. Queen fat bodies had more protein in July than September or November, but less lipid in July and September than November or January. Retinue worker responses did not vary with seasonal QMP changes, but reflected overall continuous brood rearing efforts and queen matedness throughout the year. The absence of seasonal differences in worker responses to QMP should be considered in the broader context of continuous reproductive efforts in warm subtropical colonies.