Oligodeoxynucleotides ODN 2006 and M362 Exert Potent Adjuvant Effect through TLR-9/-6 Synergy to Exaggerate Mammaglobin-A Peptide Specific Cytotoxic CD8+T Lymphocyte Responses against Breast Cancer Cells

Mammaglobin-A (MamA) is overexpressed in 40–80% of all human breast cancers. Recent phase I clinical trials of the MamA DNA vaccine showed encouraging safety outcomes. However, this vaccine elicited only a modest increase in MamA specific CD8+T lymphocyte (CTL) activation. As vaccine adjuvants play a critical role in enhancing the immunotherapeutic efficiency of vaccines, we tested the potential role of three synthetic CpG oligodeoxynucleotides (ODN2216—class A ODN, ODN2006—class B ODN, and ODN M362—class C ODN) to further enhance MamA specific CTL responses. Towards this, naïve CD8+T cells were obtained from healthy HLA-A2+ human donors. The HLA-A2 specific immunodominant epitope of MamA, MamA2.1 (LIYDSSLCDL), was utilized to activate naïve CD8+T cells. The THP-1 (HLA-A2+) cells were used as antigen presenting cells to stimulate naïve CD8+T cells along with (or without) co-treatment of various ODNs mentioned above. Activation of naïve CD8+T cells with the MamA2.1 peptide along with ODNs demonstrated enhanced MamA specific CTL mediated cytotoxicity on AU565 (HLA-A+/MamA+) breast cancer cells following co-treatment with ODN2006 and M362 compared to ODN2216 or MamA2.1 peptide alone. However, no significant cytotoxicity was noted upon treatment of MamA2.1 activated CTLs on MCF7 (HLA-A+/MamA−) cells, suggesting that the activation of CTLs is specific to the MamA antigen. Functional characterization studies demonstrated specific IL-12 mediated cross-talk between TLR-6 and -9 in THP-1 cells following stimulation with ODN2006 and M362, which was critical for the final cytotoxic activation of CD8+T lymphocytes. Based on these data, we conclude that ODN2006 and ODN M362 exerted a strong adjuvant effect through induction of the initial innate immune response through TLR9 upregulation followed by enhanced MamA specific CTL dependent adaptive immune responses. Our current data provide evidence for the application of Class-B/-C-CpG-ODNs as potential vaccine adjuvants towards enhancing the success of MamA based breast cancer vaccination

Implications of the differing roles of the beta 1 and beta 3 transmembrane and cytosplasmic domains for integrin function

Integrins are transmembrane receptors composed of alpha and beta subunits. Although most integrins contain beta 1, canonical activation mechanisms are based on studies of the platelet integrin, allb beta 3. Its inactive conformation is characterized by the association of the alpha llb transmembrane and cytosolic domain (TM/CT) with a tilted beta 3 TM/CT that leads to activation when disrupted. We show significant structural differences between beta 1 and beta 3 TM/CT in bicelles. Moreover, the 'snorkeling' lysine at the TM/CT interface of beta subunits, previously proposed to regulate alpha llb beta 3 activation by ion pairing with nearby lipids, plays opposite roles in beta 1 and beta 3 integrin function and in neither case is responsible for TM tilt. A range of affinities from almost no interaction to the relatively high avidity that characterizes alpha llb beta 3 is seen between various alpha subunits and beta 1 TM/CTs. The alpha llb beta 3-based canonical model for the roles of the TM/CT in integrin activation and function clearly does not extend to all mammalian integrins

The Thermal Electrical Conductivity Probe (TECP) for Phoenix

The Thermal and Electrical Conductivity Probe (TECP) is a component of the Microscopy, Electrochemistry, and Conductivity Analyzer (MECA) payload on the Phoenix Lander. TECP will measure the temperature, thermal conductivity and volumetric heat capacity of the regolith. It will also detect and quantify the population of mobile H2O molecules in the regolith, if any, throughout the polar summer, by measuring the electrical conductivity of the regolith, as well as the dielectric permittivity. In the vapor phase, TECP is capable of measuring the atmospheric H2O vapor abundance, as well as augment the wind velocity measurements from the meteorology instrumentation. TECP is mounted near the end of the 2.3 m Robotic Arm, and can be placed either in the regolith material or held aloft in the atmosphere. This paper describes the development and calibration of the TECP. In addition, substantial characterization of the instrument has been conducted to identify behavioral characteristics that might affect landed surface operations. The greatest potential issue identified in characterization tests is the extraordinary sensitivity of the TECP to placement. Small gaps alter the contact between the TECP and regolith, complicating data interpretation. Testing with the Phoenix Robotic Arm identified mitigation techniques that will be implemented during flight. A flight model of the instrument was also field tested in the Antarctic Dry Valleys during the 2007-2008 International Polar year.

Chemistry and Mineralogy of Antarctica Dry Valley Soils: Implications for Mars

The Antarctic Dry Valleys (ADV) comprise the largest ice-free region of Antarctica. Precipitation almost always occurs as snow, relative humidity is frequently low, and mean annual temperatures are about -20 C. The ADV soils have previously been categorized into three soil moisture regimes: subxerous, xerous and ultraxerous, based on elevation and climate influences. The subxerous regime is predominately a coastal zone soil, and has the highest average temperature and precipitation, while the ultraxerous regime occurs at high elevation (>1000 m) and have very low temperature and precipitation. The amounts and types of salts present in the soils vary between regions. The nature, origin and significance of salts in the ADV have been previously investigated. Substantial work has focused on soil formation in the ADVs, however, little work has focused on the mineralogy of secondary alteration phases. The dominant weathering process in the ADV region is physical weathering, however, chemical weathering has been well documented. The objective of this study was to characterize the chemistry and mineralogy, including the alteration mineralogy, of soils from two sites, a subxerous soil in Taylor Valley, and an ultraxerous soil in University Valley. The style of aqueous alteration in the ADVs may have implications for pedogenic processes on Mars

Integrin-linked kinase in muscle is necessary for the development of insulin resistance in diet-induced obese mice

Diet-induced muscle insulin resistance is associated with expansion of extracellular matrix (ECM) components, such as collagens, and the expression of collagen-binding integrin, α2β1. Integrins transduce signals from ECM via their cytoplasmic domains, which bind to intracellular integrin-binding proteins. The integrin-linked kinase (ILK)-PINCH-parvin (IPP) complex interacts with the cytoplasmic domain of β-integrin subunits and is critical for integrin signaling. In this study we defined the role of ILK, a key component of the IPP complex, in diet-induced muscle insulin resistance. Wild-type (ILK(lox/lox)) and muscle-specific ILK-deficient (ILK(lox/lox)HSAcre) mice were fed chow or a high-fat (HF) diet for 16 weeks. Body weight was not different between ILK(lox/lox) and ILK(lox/lox)HSAcre mice. However, HF-fed ILK(lox/lox)HSAcre mice had improved muscle insulin sensitivity relative to HF-fed ILK(lox/lox) mice, as shown by increased rates of glucose infusion, glucose disappearance, and muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. Improved muscle insulin action in the HF-fed ILK(lox/lox)HSAcre mice was associated with increased insulin-stimulated phosphorylation of Akt and increased muscle capillarization. These results suggest that ILK expression in muscle is a critical component of diet-induced insulin resistance, which possibly acts by impairing insulin signaling and insulin perfusion through capillaries

McMurdo Dry Valleys, Antarctica - A Mars Phoenix Mission Analog

The Phoenix mission (PHX; May 25 - Nov. 2, 2008) studied the north polar region of Mars (68deg N) to understand the history of water and potential for habitability. Phoenix carried with it a wet chemistry lab (WCL) capable of determining the basic solution chemistry of the soil and the pH value, a thermal and evolved-gas analyzer capable of determining the mineralogy of the soil and detecting ice, microscopes capable of seeing soil particle shapes, sizes and colors at very high resolution, and a soil probe (TECP) capable of detecting unfrozen water in the soil. PHX coincided with an international effort to study the Earth s polar regions named the International Polar Year (IPY; 2007-2008). The best known Earth analog to the Martian high-northern plains, where Phoenix landed, are the McMurdo Dry Valleys (MDV), Antarctica (Fig. 1). Thus, the IPY afforded a unique opportunity to study the MDV with the same foci - history of water and habitability - as PHX. In austral summer 2007, our team took engineering models of WCL and TECP into the MDV and performed analgous measurements. We also collected sterile samples and analyzed them in our home laboratories using state-of-the-art tools. While PHX was not designed to perform biologic analyses, we were able to do so with the MDV analog samples collected

Mineralogy of Antarctica Dry Valley Soils: Implications for Pedogenic Processes on Mars

The Antarctic Dry Valleys (ADVs) located in the Transantarctic Mountains are the coldest and driest locations on Earth. The mean annual air temperature is -20 C or less and the ADVs receive 100mm or less of precipitation annually in the form of snow. The cold and dry climate in the ADVs is one of the best terrestrial analogs for the climatic conditions on Mars [2]. The soils in the ADVs have been categorized into three soil moisture zones: subxerous, xerous and ultraxerous. The subxerous zone is a coastal region in which soils have ice-cemented permafrost relatively close to the surface. Moisture is available in relatively large amounts and soil temperatures are above freezing throughout the soil profile (above ice permafrost) in summer months. The xerous zone, the most widespread of the three zones, is an inland region with a climate midway between the subxerous and ultraxerous. The soils from this zone have dry permafrost at moderate depths (30-75cm) but have sufficient water in the upper soil horizons to allow leaching of soluble materials. The ultraxerous zone is a high elevation zone, where both temperature and precipitation amounts are very low resulting in dry permafrost throughout the soil profile. The three moisture regime regions are similar to the three microclimatic zones (coastal thaw, inland mixed, stable upland) defined by Marchant and Head

Why nature matters: A systematic review of intrinsic, instrumental, and relational values

\ua9 2023 The Author(s). Published by Oxford University Press on behalf of the American Institute of Biological Sciences. In this article, we present results from a literature review of intrinsic, instrumental, and relational values of nature conducted for the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, as part of the Methodological Assessment of the Diverse Values and Valuations of Nature. We identify the most frequently recurring meanings in the heterogeneous use of different value types and their association with worldviews and other key concepts. From frequent uses, we determine a core meaning for each value type, which is sufficiently inclusive to serve as an umbrella over different understandings in the literature and specific enough to help highlight its difference from the other types of values. Finally, we discuss convergences, overlapping areas, and fuzzy boundaries between different value types to facilitate dialogue, reduce misunderstandings, and improve the methods for valuation of nature\u27s contributions to people, including ecosystem services, to inform policy and direct future research

Development of a distributed international patient data registry for hairy cell leukemia

Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE’s to expand access to patients across the globe. This international PDR will enable researchers to study outcomes in HCL in ways not previously possible due to the rarity of the disease and will serve as a platform for future prospective research

Foodways in transition: food plants, diet and local perceptions of change in a Costa Rican Ngäbe community

Background Indigenous populations are undergoing rapid ethnobiological, nutritional and socioeconomic transitions while being increasingly integrated into modernizing societies. To better understand the dynamics of these transitions, this article aims to characterize the cultural domain of food plants and analyze its relation with current day diets, and the local perceptions of changes given amongst the Ngäbe people of Southern Conte-Burica, Costa Rica, as production of food plants by its residents is hypothesized to be drastically in recession with an decreased local production in the area and new conservation and development paradigms being implemented. Methods Extensive freelisting, interviews and workshops were used to collect the data from 72 participants on their knowledge of food plants, their current dietary practices and their perceptions of change in local foodways, while cultural domain analysis, descriptive statistical analyses and development of fundamental explanatory themes were employed to analyze the data. Results Results show a food plants domain composed of 140 species, of which 85 % grow in the area, with a medium level of cultural consensus, and some age-based variation. Although many plants still grow in the area, in many key species a decrease on local production–even abandonment–was found, with much reduced cultivation areas. Yet, the domain appears to be largely theoretical, with little evidence of use; and the diet today is predominantly dependent on foods bought from the store (more than 50 % of basic ingredients), many of which were not salient or not even recognized as ‘food plants’ in freelists exercises. While changes in the importance of food plants were largely deemed a result of changes in cultural preferences for store bought processed food stuffs and changing values associated with farming and being food self-sufficient, Ngäbe were also aware of how changing household livelihood activities, and the subsequent loss of knowledge and use of food plants, were in fact being driven by changes in social and political policies, despite increases in forest cover and biodiversity. Conclusions Ngäbe foodways are changing in different and somewhat disconnected ways: knowledge of food plants is varied, reflecting most relevant changes in dietary practices such as lower cultivation areas and greater dependence on food from stores by all families. We attribute dietary shifts to socioeconomic and political changes in recent decades, in particular to a reduction of local production of food, new economic structures and agents related to the State and globalization