Toward an Overall Analytical Framework for the Integrated Sustainability Assessment of the Production and Supply of Raw Materials and Primary Energy Carriers

The sustainable production and supply of raw materials (“nonenergy raw materials”) and primary energy carriers (“energy raw materials”) is a core element of many policies. The natural resource base for their production and supply, and the access thereto, are limited. Moreover, raw material supply is high on environmental and social impact agendas as well. A broad, quantitative framework that supports decision makers is recommended so as to make use of raw materials and primary energy carriers more sustainably. First, this article proposes a holistic classification of raw materials and primary energy carriers. This is an essential prerequisite for developing an integrated sustainability assessment framework (ISAF). Indeed, frequently, only a subset of raw materials and primary energy carriers are considered in terms of their source, sector, or final application. Here, 85 raw materials and 30 primary energy carriers overall are identified and grouped into seven and five subgroups, respectively. Next, this article proposes a quantitative ISAF for the production and supply of raw materials and primary energy carriers, covering all the sustainability pillars. With the goal of comprehensiveness, the proposed ISAF integrates sustainability issues that have been covered and modeled in quite different quantitative frameworks: ecosystem services; classical life cycle assessment (LCA); social LCA; resource criticality assessment; and particular international concerns (e.g., conflict minerals assessment). The resulting four areas of concerns (i.e., environmental, technical, economic, and social/societal) are grouped into ten specific sustainability concerns. Finally, these concerns are quantified through 15 indicators, enabling the quantitative sustainability assessment of the production and supply of raw materials and primary energy carriers.     

Hydroxyethylamine-based inhibitors of BACE1: P1–P3 macrocyclization can improve potency,selectivity, and cell activity

We describe a systematic study of how macrocyclization in the P₁–P₃ region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APP_SW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.     

Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma.

Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting.     

Mitogen-stimulated activation of the Na+/H+ antiporter does not regulate S6 phosphorylation or protein synthesis in murine thymocytes or Swiss 3T3 fibroblasts

The activation of protein synthesis by mitogens in quiescent (G0) mammalian cells is obligatory for progression from G0 through G1 to DNA synthesis in S phase. When the activation of the Na+/H+ antiporter which occurs in mitogen-stimulated Swiss 3T3 fibroblasts or murine fibroblasts is completely blocked by dimethylamiloride, there is little or no effect on the phosphorylation of the ribosomal protein S6 or the activation of protein synthesis assayed by [35S]methionine incorporation. Furthermore, the accumulation of the protein product of the activated c-myc gene is unaffected by dimethylamiloride in 3T3 fibroblasts. The data show that there is no requirement for activation of the Na+/H+ antiporter for the activation of S6 phosphorylation or protein synthesis by mitogens but do not preclude the possibility that activation of the antiporter is necessary for some other response(s) obligatory for DNA synthesis. These data are contrasted with previous reports for Chinese hamster lung fibroblasts that the increase in intracellular pH which results from activation of the Na+/H+ antiporter in bicarbonate-free media is necessary for S6 phosphorylation, protein synthesis, and hence, for subsequent DNA synthesis (Pouyssegur, J., Chambard, J. C., Franchi, A., Paris, S., and Van Obberghen-Schilling, E. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 3935-3939; Chambard, J.C., and Pouyssegur, J. (1986) Exp. Cell Res. 164, 282-294).     

Biotic homogeneity of putative biogeographic units in the Neotropics: A test with Sapotaceae

Aim

To evaluate Morrone's (2001, Biogeografia de America Latina y el Caribe. Zaragoza, Spain: CYTED, ORCYT‐UNESCO, Sociedad Entomológica Aragonesa (SEA)) Neotropical regionalization by testing the prediction that biotas are more homogeneous within than among biogeographic units.

Location

Neotropics.

Methods

We conducted pairwise comparisons of beta diversity of Sapotaceae species within and between biogeographic units in the hierarchical regionalization proposed by Morrone (2001, Biogeografia de America Latina y el Caribe. Zaragoza, Spain: CYTED, ORCYT‐UNESCO, Sociedad Entomológica Aragonesa (SEA)), at a spatial resolution of 1‐degree cells. We used a null model to control differences in sampling effort across 1‐degree cells and performed beta‐diversity comparisons conditional on geographic distance to control for distance decay of biotic similarity.

Results

None of the biogeographic units proposed by Morrone (2001, Biogeografia de America Latina y el Caribe. Zaragoza, Spain: CYTED, ORCYT‐UNESCO, Sociedad Entomológica Aragonesa (SEA)) was biotically homogeneous with respect to all other units at the same hierarchical level. This was the case even for units commonly reported to be isolated and to host distinctive taxa like “Choco.” However, five of 45 biogeographic units were biotically homogenous relative to several other units. These units were “Cuba,” “Chaco,” “Varzea,” “Cauca” and “Costa Pacífica Mexicana.” Also, beta diversity within units was often lower than beta diversity between units at relatively short geographic distances.

Main conclusions

The distribution of Sapotaceae species showed generally low biotic homogeneity within Morrone's (2001, Biogeografia de America Latina y el Caribe. Zaragoza, Spain: CYTED, ORCYT‐UNESCO, Sociedad Entomológica Aragonesa (SEA)) biogeographic units and did not support his biogeographic regionalization. This result suggests a strong role for dispersal and biotic interchange among biogeographic units and across barriers like the Andes. It also casts doubt on the usefulness of Morrone's (2001, Biogeografia de America Latina y el Caribe. Zaragoza, Spain: CYTED, ORCYT‐UNESCO, Sociedad Entomológica Aragonesa (SEA)) biogeographic units as tools for the identification of priority areas for the conservation of biodiversity. However, relatively high biotic homogeneity within some biogeographic units suggests that they capture significant spatial patterns. In particular, noteworthy biotic homogeneity within “Cuba,” “Cauca” and “Costa Pacifica Mexicana” could be explained by isolation. Also, in “Costa Pacifica Mexicana,” patterns of biotic homogeneity could reflect closer affinities to humid lowland montane forest in Central America than to lowland rain forest in South America. Finally, substantial biotic homogeneity within “Varzea” could result from common adaptation to edaphic environments near the Amazon River.

     

Targeting the cell cycle in breast cancer: towards the next phase

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.     

Secondary structure of ShK toxin, a potassium-channel-blocking peptide

Summary Sea anemones possess small K-channel-blocking peptides about the same size as the scorpion K-channel toxins. We have estimated the secondary structure content (33% helix, 26% -sheet) of one of these toxins, ShK toxin, using CD, Raman, and FTIR spectroscopy. A hypothetical 3D structure of the peptide core has been constructed using secondary structure and disulfide-linkage constraints; a single helical segment running from Ala¹⁴ through Leu²⁵ is predicted.     

Mass spectral analysis of peptides containing nitrobenzyl moieties

Summary By means of MALDI-TOF analysis of peptides containing a nitrobenzyl moiety, we have observed that the predominant signal often corresponds to ions that have eliminated multiple oxygen atoms, [M–O_n+H]⁺, and not to the protonated molecular ion, [M+H]⁺. Matrix selection for handling these types of molecules appears to be important. The MALDI-TOF matrices, such as sinapinic acid (3,5-dimethoxy-4-hydroxycinnamic acid) and -cyano-4-hydroxycinnamic acid, resulted in the appearance of significant levels of the photodeoxygenated species, whereas 4-hydroxyazobenzene-2-carboxylic acid appeared to moderately and in some cases completely suppress the photodeoxygenation reaction. This phenomenon was independent of laser intensity. Photodeoxygenation was not observed with electrospray or fast atom bombardment ionization techniques. Therefore, use of MALDI should be avoided with peptides containing a nitrobenzyl moiety and similar moieties that are prone to reactive photochemistry.