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The recent development of portable X-ray fluorescence spectrometers (PXRF) has created new avenues for rapid plant elemental concentration determination at reduced cost while avoiding hazardous chemicals. A few studies have indicated the potential use of PXRF for homogenous plant tissue analysis. However, there is a lack of information for analysis of heterogeneous plant samples like livestock forage, which consists of a mixture of several species and plant parts, each varying in elemental concentration. Our objective was to evaluate PXRF for forage analysis, specifically the effect of forage particle size and scan time on important elements including P, K, Ca, and Fe determination. Hay samples ( = 42) were oven dried (60°C for 3 days) and ground into three particle sizes (≤0.5 mm, 0.25-0.5 mm and 1-2 mm). Prepared samples were scanned by PXRF using a vacuum (<10 torr) without a filter. Samples were placed in cups over thin prolene X-ray film and scanned for 180 s. A subset ( = 29) were also scanned for 60 and 120 s. PXRF counts for P, K, Ca, and Fe were compared with laboratory Inductively Coupled Plasma Optical Emission Spectroscopy (ICP) determinations, using regression models. Results indicated that these elements could potentially be determined with PXRF ( ≥ 0.70) in heterogeneous forage samples. Relationship strength increased with decreasing particle size, however, the relationship was still strong ( ≥ 0.57) at the largest particle size. Scanning time did not affect the relationship with ICP concentration for any of the particle sizes evaluated. This work demonstrated that with the right sample preparation PXRF can obtain results comparable to acid digestion and ICP regardless of sample composition, and suggests the potential for determinations.

Strontium isotope sourcing has become a common and useful method for assigning sources to archaeological artifacts.In Chaco Canyon, an Ancestral Pueblo regional center in New Mexico, previous studiesusing these methods have suggested that significant portion of maize and wood originate in the Chuska Mountains region, 75 km to the West [corrected]. In the present manuscript, these results were tested using both frequentist methods (to determine if geochemical sources can truly be differentiated) and Bayesian methods (to address uncertainty in geochemical source attribution). It was found that Chaco Canyon and the Chuska Mountain region are not easily distinguishable based on radiogenic strontium isotope values. The strontium profiles of many geochemical sources in the region overlap, making it difficult to definitively identify any one particular geochemical source for the canyon's pre-historic maize. Bayesian mixing models support the argument that some spruce and fir wood originated in the San Mateo Mountains, but that this cannot explain all 87Sr/86Sr values in Chaco timber. Overall radiogenic strontium isotope data do not clearly identify a single major geochemical source for maize, ponderosa, and most spruce/fir timber. As such, the degree to which Chaco Canyon relied upon outside support for both food and construction material is still ambiguous.

This dissertation develops new techniques of analysis that make existing archaeological data more useful for understanding past climate change. These techniques are introduced through three key case studies in the San Juan Basin of New Mexico, the Lower Alentejo of Portugal, and the Eastern Mediterranean. A 12,000 year record of pollen collected from packrat middens across Chaco Canyon were analyzed using a new normalization procedure to produce a Holocene record of piñon and ponderosa pine abundance. The normalization procedure, species occurrence, enabled statistical analysis of the data. Simple linear models indicated that piñon and ponderosa pollen were strongly correlated with each other. Bayesian change-point analysis was run, and a period between 5,440 and 5,102 cal. yr BP was identified as a point of expansion of piñon. This expansion of piñon was contemporaneous with increased storage and territoriality of populations in the San Juan Basin around the same time period. In the Lower Alentejo of Portugal, a series of δ13C values from radiocarbon-dated pollen were used to calculate rates of 13C discrimination (Δ13C). These Δ13C values indicated a period of stability from AD 600 - 1000, increased arid conditions during the first half of the Medieval Warm Period (AD 1000 - 1100), and a return to normal conditions from AD 1100 - 1150. Following this, the rural Lower Alentejo was abandoned for almost two centuries. The data suggest a climate that was stable during a period of population growth followed by heightened variability during the Medieval Warm Period. This would have caused some drying out of soil, potentially contributing to later soil erosion as wetter conditions returned prior to the rural abandonment. Importantly, the study paired modern observations of Δ13C with archaeological data, establishing an approach to the study of data commonly available to archaeologists. Finally, in the Eastern Mediterranean, a set of regional paleoclimate records were used to better understand climatic conditions during the time of the Late Bronze Age Collapse (1200 - 1000 BC). At this time, most urban centers in the region were destroyed and abandoned during a period of depopulation. Alkenone-derived sea surface temperature records and warm species dinocyst/formainifera ratios indicate a cooling of Mediterranean waters at the time. Terrestrial paleoclimate records, including a biome-wide measure of Δ13C derived from radiocarbon-dated bulk pollen, indicate that conditions may have been more arid at this time. This study of paleoclimate reconstruction includes new techniques developed to make use of under-utilized data gathered by archaeologists. These techniques include the use of of radiocarbon-derived Δ13C as a local indicator of aridity, the use of biome-wide Δ13C from pollen as a regional paleoclimate record, a new normalization technique for pollen records, and the use of Bayesian change-point analysis to assess the significance of changes in a paleoclimate record. These new techniques can compliment archaeological research questions that require information about paleoclimate.

Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we demonstrate that inhibition of p38α MAPK reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. We establish that p38α MAPK phosphorylates TDP-43 at pathological serine 409/410 (S409/S410) and serine 292 (S292), which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we show that protein arginine methyltransferase 1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we demonstrate that inhibition of p38α MAPK reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. We establish that p38α MAPK phosphorylates TDP-43 at pathological serine 409/410 (S409/S410) and serine 292 (S292), which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we show that protein arginine methyltransferase 1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies. Competing Interest Statement HJW, DGB, and NJB were all full-time employees and shareholders of AstraZeneca at the time these studies were conducted. SJM serves as a consultant for SAGE Therapeutics and AstraZeneca, relationships that are regulated by Tufts University. JS is a consultant for Dewpoint Therapeutics, Maze Therapeutics, Vivid Sciences, Korro Bio, and ADRx.