Sustainable transportation and order quantity: insights from multiobjective optimization

This article applies multiobjective optimization to show how the tradeoffs between cost and carbon emissions may be obtained in the context of sustainable operations. We formulate a model where transportation mode selection and order quantity decisions are considered jointly. We derive structural properties of the model and develop several insights. First, we show that switching to a greener mode of transportation while continuing to optimize the total logistics costs function may lead to a dominated solution. Second, we prove that the modal shift occurs only under strong carbon emissions reduction requirements. Third, we show that the efficient frontier is non-convex and we analyze some implications. Finally, we analyze the impacts of an increase in truck capacity. The results are illustrated through an example of a French retailer.     

Quantitative proteomics suggests metabolic reprogramming during ETHE1 deficiency

Deficiency of mitochondrial sulfur dioxygenase (ETHE1) causes the severe metabolic disorder ethylmalonic encephalopathy, which is characterized by early‐onset encephalopathy and defective cytochrome C oxidase because of hydrogen sulfide accumulation. Although the severe systemic consequences of the disorder are becoming clear, the molecular effects are not well defined. Therefore, for further elucidating the effects of ETHE1‐deficiency, we performed a large scale quantitative proteomics study on liver tissue from ETHE1‐deficient mice. Our results demonstrated a clear link between ETHE1‐deficiency and redox active proteins, as reflected by downregulation of several proteins related to oxidation‐reduction, such as different dehydrogenases and cytochrome P450 (CYP450) members. Furthermore, the protein data indicated impact of the ETHE1‐deficiency on metabolic reprogramming through upregulation of glycolytic enzymes and by altering several heterogeneous ribonucleoproteins, indicating novel link between ETHE1 and gene expression regulation. We also found increase in total protein acetylation level, pointing out the link between ETHE1 and acetylation, which is likely controlled by both redox state and cellular metabolites. These findings are relevant for understanding the complexity of the disease and may shed light on important functions influenced by ETHE1 deficiency and by the concomitant increase in the gaseous mediator hydrogen sulfide. All MS data have been deposited in the ProteomeXchange with the dataset identifiers PXD002741 ( http://proteomecentral.proteomexchange.org/dataset/PXD002741 ) and PXD002742 ( http://proteomecentral.proteomexchange.org/dataset/PXD002741 ).     

Heavy chain variable region gene families evolved early in phylogeny. Ig complexity in fish

The V regions of channel catfish H chain cDNA clones have been analyzed. Based upon sequence relationships and hybridization analyses, five different groups of VH genes are identified whose definition is consistent with that of five different VH families. Genomic Southern blots indicate that as many as 100 different germ-line VH genes are likely represented by these families. The sequence diversity between identified members of these different families is similar in magnitude to the divergence represented between members of different human or mouse VH families. The FR regions are the most conserved regions when members of different catfish VH families are compared; specific amino acid positions appear to be highly conserved in phylogeny. Equally important is that diversity is represented in complementarity-determining regions CDR1 and CDR2 in members of the different families as well as in members of the same VH family. These results suggest that an extensive repertoire of VH genes can contribute to antibody diversity in this lower vertebrate. Sequence comparisons indicate that one of the catfish VH families shares considerable structural similarity to several higher vertebrate VH gene families--a relationship which suggests that this VH family may be ancestral to some VH gene families of higher vertebrates. Characteristic of the genomic organization of higher vertebrate H chains, catfish appear to have different VH families wherein a VH gene likely undergoes functional recombination with putative DH gene segments and one of apparently several different JH segments. The recombined V region is expressed with the same C region gene. These combined results suggest that bony fishes are the earliest known phylogenetic representatives to have evolved extensive V region gene families.     

Reaction of thiol nucleophiles with 1,2-epoxy- and 4,5-epoxy-estrene-3-one-17 beta-ols

Four ring A steroidal epoxyenones as probable intermediate in the formation of catechol estrogens were synthesized. The isomeric 1 alpha,2 alpha-epoxy-17 beta-hydroxyestr-4-en-3-one (9) and 1 beta,2 beta-epoxy-17 beta-hydroxyestr-4-en-3-one (8) were synthesized from 17 beta-hydroxy-5 alpha-estra-3-one. The isomeric 4 alpha,5 alpha-epoxy-17 beta-hydroxyestr-1-en-3-one (11) and 4 beta,5 beta-epoxy-17 beta-hydroxyestr-1-en-3-one (10) were prepared from 19-nortestosterone. The reaction of 9 and 10 with sodium/ethanethiol resulted in the formation of three types of reactions leading to multiple products: 1,4-addition, opening of epoxide, and epoxide opening followed by dehydration. Reaction of 8 with ethanethiol gave only one compound identified as 2-ethanethio-1,4-estradien-17 beta-ol-3-one, while reaction of 9 with ethanethiol gave an unusual product identified as 4-estren-1 alpha,17 beta-diol-3-one. Unlike reaction of ethanethiol with 9 and 10, reaction with N-acetylecysteine or glutathione results in epoxide opening followed by dehydration leading to the formation of estradiol-4-thioethers.     

Two-Electron Aromatics with Classical and Non-Classical Homobridges

Bishomotriborirane anions with a B-H-B bridge, 7, have been synthesized by a) protonation and b) methylation of bishomodianions, 3, as well as by c) hydride addition to 1,2,4-triboracyclopentanes, 15. Compounds 7 were characterized by ¹H, ¹³C and ¹¹B NMR spectroscopy and X-ray diffraction analyses. The suggested mechanism for the formation of 7 is supported by MP4SDTQ/6-311++G**//MP2(fc)/6-31+G* computations on [C₂B₃H₈]^- model compounds. Classical 1,2-dibora-4-borata-cyclopentane intermediates 16 undergo an intramolecular hydrogen shift to the B-B unit in their envelope conformation to give intermediates 17, which easily isomerize to 7. Relative energies for the parent compounds, 16u, 17u, 7u and the transition structures, TS-16/17u and TS-7/17u are predicted to be 30.7, 14.5, 0.0, 32.6 and 23.5 kcal mol^-1, respectively. The terms classical and non-classical homobridges are suggested for methylene and hydrogen bridges in 7 and in related compounds on the grounds of common building principles. The strength of homoaromaticity in 7u was estimated to be at least 23.5 kcal mol^-1, neglecting the much higher strain in 7u compared to TS-7/17u without a 3c2e bond.Electronic Supplementary Material available.     

The statistical power of genome-wide association studies for threshold traits with different frequencies of causal variants

Genetica - This study aimed to investigate the effects of incidence rate, heritability, and polygenic variance on the statistical power of genome-wide association studies (GWAS) for threshold...     

Thymoquinone reduces intracytoplasmic oxidative stress and improves epigenetic modification in polycystic ovary syndrome mice oocytes,during in‐vitro maturation

Although in‐vitro maturation (IVM) of oocytes has been presented as an alternative treatment to traditional stimulated in‐vitro fertilization, the culture condition can be improved by natural antioxidants. Thus, we investigated the protective effect of Thymoquinone (TQ) during IVM in the polycystic ovary syndrome (PCOS) mice model. The induction of PCOS was made by dehydroepiandrosterone via subcutaneous injection, in prepubertal female B6D2F1‐mice. After 21 days later, germinal vesicle (GV)‐stage‐oocytes were extracted and incubated in IVM media containing 0, 1.0, 10.0, and 100.0 μM of TQ. To assess fertilization and blastulation rates, after 22–24 hr, the treated oocytes were fertilized in‐vitro with epididymal spermatozoa. Some other oocytes were evaluated for maturation, epigenetic, and oxidative stress markers. Similarly, the mRNA expression of epigenetic enzymes genes (Dnmt1 and Hdac1), three maternally derived genes (Mapk, CyclinB, and Cdk1) and apoptosis‐related genes (Bax and Bcl2) were assessed. Our results showed that the maturation, fertilization, and blastulation rates were significantly higher in the 10.0 μM TQ‐treated group compared with the untreated group and likewise with in‐vivo matured oocytes. The Bax expression was reduced in 10.0 μM TQ matured oocytes, but Bcl2, Dnmt1, Hdac1, Cdk1, and Mapk were upregulated in this group compared to other groups. Furthermore, dimethylation of histone‐3 at lysine‐9 (H3K9m2) and DNA methylation were significantly increased whereas H4K12 acetylation (H4K12ac) was decreased in the 10.0 μM TQ‐treated group in comparison with control and in‐vivo matured oocytes. Therefore, our results are suggesting that 10.0 μM TQ may enhance the developmental competence of PCOS oocytes via the modulation of oxidative stress and epigenetic alterations.     

Microfluidic tissue model for live cell screening

We have developed a microfluidic platform modeled after the physiologic microcirculation for multiplexed tissue-like culture and high-throughput analysis. Each microfabricated culture unit consisted of three functional components: a 50 microm wide cell culture pocket, an artificial endothelial barrier with 2 microm pores, and a nutrient transport channel. This configuration enabled a high density of cancer cells to be maintained for over 1 week in a solid tumor-like morphology when fed with continuous flow. The microfluidic chip contained 16 parallel units for "flow cell" based experiments where live cells were exposed to a soluble factor and analyzed via fluorescence microscopy or flow-through biochemistry. Each fluidically independent tissue unit contained approximately 500 cells fed with a continuous flow of 10 nL/min. As a demonstration, the toxicity profile of the anti-cancer drug paclitaxel was collected on HeLa cells cultured in the microfluidic format and compared with a 384-well dish for up to 5 days of continuous drug exposure.     

Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120

NBD-556 and the chemically and structurally similar NBD-557 are two low-molecular weight compounds that reportedly block the interaction between the HIV-1 envelope glycoprotein gp120 and its receptor, CD4. NBD-556 binds to gp120 with a binding affinity of 2.7 x 10(5) M(-1) (K(d) = 3.7 muM) in a process characterized by a large favorable change in enthalpy partially compensated by a large unfavorable entropy change, a thermodynamic signature similar to that observed for binding of sCD4 to gp120. NBD-556 binding is associated with a large structuring of the gp120 molecule, as also demonstrated by CD spectroscopy. NBD-556, like CD4, activates the binding of gp120 to the HIV-1 coreceptor, CCR5, and to the 17b monoclonal antibody, which recognizes the coreceptor binding site of gp120. NBD-556 stimulates HIV-1 infection of CD4-negative, CCR5-expressing cells. The thermodynamic signature of the binding of NBD-556 to gp120 is very different from that of another viral entry inhibitor, BMS-378806. Whereas NBD-556 binds gp120 with a large favorable enthalpy and compensating unfavorable entropy changes, BMS-378806 does so with a small binding enthalpy change in a mostly entropy-driven process. NBD-556 is a competitive inhibitor of sCD4 and elicits a similar structuring of the coreceptor binding site, whereas BMS-378806 does not compete with sCD4 and does not induce coreceptor binding. These studies demonstrate that low-molecular-weight compounds can induce conformational changes in the HIV-1 gp120 glycoprotein similar to those observed upon CD4 binding, revealing distinct strategies for inhibiting the function of the HIV-1 gp120 envelope glycoprotein. Furthermore, competitive and noncompetitive compounds have characteristic thermodynamic signatures that can be used to guide the design of more potent and effective viral entry inhibitors.