Structures in the Dog River Fault Zone between Northfield and Montpelier, Vermont

Guidebook for field trips in Vermont: New England Intercollegiate Geological Conference, 79th annual meeting, October 16, 17 and 18, 1987: Trips A-

The Northwest Boundary Fault of the Boundary Mountain Anticlinorium

New England Intercollegiate Geological Conference Guidebook for field trips in The Greenville - Millinocket Regions, North Central Maine, October 7-9, 1983: Trip B-

Confronting Global Warming: Maine’s Multi-Sector Initiatives, 2003–2008

David Littell, Gary Westerman and Malcolm Burson describe Maine’s pioneering efforts in reducing greenhouse gas emissions, promoting energy efficiency, and developing less carbon-intensive and more sustainable energy sources. They discuss in particular the goals and accomplishments of the state’s Climate Action Plan and Maine’s participation in several multi-state and regional efforts, including the Regional Greenhouse Gas Initiative (RGGI)

Guidebook for field trips in Vermont: New England Intercollegiate Geological Conference, 79th annual meeting, October 16, 17 and 18, 1987

Geologic fieldtrips in Vermon

Guidebook for field trips in Vermont: New England Intercollegiate Geological Conference, 79th annual meeting, October 16, 17 and 18, 1987: title pages, table of contents, introduction

front matte

Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defects

Many neurodegenerative diseases exhibit axonal pathology, transport defects, and aberrant phosphorylation and aggregation of the microtubule binding protein tau. While mutant tau protein in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP17) causes aberrant microtubule binding and assembly of tau into filaments, the pathways leading to tau-mediated neurotoxicity in Alzheimer's disease and other neurodegenerative disorders in which tau protein is not genetically modified remain unknown. To test the hypothesis that axonal transport defects alone can cause pathological abnormalities in tau protein and neurodegeneration in the absence of mutant tau or amyloid β deposits, we induced transport defects by deletion of the kinesin light chain 1 (KLC1) subunit of the anterograde motor kinesin-1. We found that upon aging, early selective axonal transport defects in mice lacking the KLC1 protein (KLC1-/-) led to axonopathies with cytoskeletal disorganization and abnormal cargo accumulation. In addition, increased c-jun N-terminal stress kinase activation colocalized with aberrant tau in dystrophic axons. Surprisingly, swollen dystrophic axons exhibited abnormal tau hyperphosphorylation and accumulation. Thus, directly interfering with axonal transport is sufficient to activate stress kinase pathways initiating a biochemical cascade that drives normal tau protein into a pathological state found in a variety of neurodegenerative disorders including Alzheimer's disease.Fil: Falzone, Tomas Luis. Howard Hughes Medical Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Stokin, Gorazd B.. University Psychiatric Hospital; EsloveniaFil: Lillo, Concepción. University of California at San Diego; Estados UnidosFil: Rodrigues, Elizabeth M.. Howard Hughes Medical Institute; Estados UnidosFil: Westerman, Eileen L.. Howard Hughes Medical Institute; Estados UnidosFil: Williams, David S.. University of California at San Diego; Estados UnidosFil: Goldstein, Lawrence S. B.. Howard Hughes Medical Institute; Estados Unido

Agronomic and Economic Performance Characteristics of Conventional and Low-External-Input Cropping Systems in the Central Corn Belt

We conducted a 9-ha field experiment near Boone, IA, to test the hypothesis that yield, weed suppression, and profit characteristics of low-external-input (LEI) cropping systems can match or exceed those of conventional systems. Over a 4-yr period, we compared a conventionally managed 2-yr rotation system {corn (Zea mays L.)/soybean [Glycine max (L.) Merr.]} with two LEI systems: a 3-yr corn/soybean/small grain + red clover (Trifolium pratense L.) rotation, and a 4-yr corn/soybean/small grain + alfalfa (Medicago sativa L.)/alfalfa rotation. Synthetic N fertilizer use was 59 and 74% lower in the 3- and 4-yr systems, respectively, than in the 2-yr system; similarly, herbicide use was reduced 76 and 82% in the 3- and 4-yr systems. Corn and soybean yields were as high or higher in the LEI systems as in the conventional system, and weed biomass in corn and soybean was low (≤4.2 g m−2) in all systems. Experimentally supplemented giant foxtail (Setaria faberi Herrm.) seed densities in the surface 20 cm of soil declined in all systems; supplemented velvetleaf (Abutilon theophrasti Medik.) seed densities declined in the 2- and 4-yr systems and remained unchanged in the 3-yr system. Without subsidy payments, net returns were highest for the 4-yr system ($540 ha−1 yr−1), lowest for the 3-yr system ($475 ha−1 yr−1), and intermediate for the 2-yr system ($504 ha−1 yr−1). With subsidies, differences among systems in net returns were smaller, as subsidies favored the 2-yr system, but rank order of the systems was maintained

Systematic In Vivo Analysis of the Intrinsic Determinants of Amyloid β Pathogenicity

Protein aggregation into amyloid fibrils and protofibrillar aggregates is associated with a number of the most common neurodegenerative diseases. We have established, using a computational approach, that knowledge of the primary sequences of proteins is sufficient to predict their in vitro aggregation propensities. Here we demonstrate, using rational mutagenesis of the Aβ42 peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of Aβ42 to form protofibrils and its effect on neuronal dysfunction and degeneration in a Drosophila model of Alzheimer disease. Our findings provide a quantitative description of the molecular basis for the pathogenicity of Aβ and link directly and systematically the intrinsic properties of biomolecules, predicted in silico and confirmed in vitro, to pathogenic events taking place in a living organism

A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities.

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value

Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma:an open-label phase 2 trial

Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.</p