bluuebunny/crossref_metadata_2025 huggingface dataset:
Specific binding of protein kinase CK2 catalytic subunits to tubulin
Authors: Faust Michael , Schuster Norbert , Montenarh Mathias
Published: July 2002

Protein kinase CK2 is composed of two regulatory β‐subunits and two catalytic α‐ or α′‐subunits. To analyse these subunits individually we generated antibodies against unique peptides derived from the α‐, α′‐ and β‐subunit. Immunofluorescence studies with these antibodies revealed the presence of all three CK2 subunits in the cytoplasm and weakly in the nucleus with strong signals around the nuclear membrane. Double staining experiments revealed a co‐localisation of all three subunits with tubulin. A direct association between the CK2 α‐ and the α′‐subunit and tubulin was confirmed by co‐immunoprecipitation experiments as well as by Far Western analysis. There was no binding of the CK2 β‐subunit to tubulin. Thus, with tubulin we have identified a new binding partner specific for the catalytic subunits of CK2.
Inhibitory effect of phosphate on in vitro development of 2‐cell rat embryos is overcome by a factor(s) in oviductal extracts
Authors: Yamada Masayasu , Nishikimi Akihiko
Published: July 2002

It has been found that inorganic phosphate (P) at concentrations as low as 10 μM markedly inhibits in vitro development of early rat embryos at the 1‐cell or 2‐cell stage to the blastocyst stage, although P is present at concentrations of 0.37–1.19 mM in oviductal fluid, in which the development of early embryos occurs. We show here that fractions (PTF, 50–250 μg/ml) of rat oviductal extracts (OVEs) passed through a Blue CL6B affinity column have the ability to overcome the inhibitory effects of P on the development of 2‐cell rat embryos in a dose‐dependent manner, whereas 250 μg/ml OVE or 250 μg/ml of the bound fractions (BF) induced degenerative changes in the embryos at the 2‐cell stage. Moreover, PTF at concentrations of ≥100 μg/ml stimulated the hatching of blastocysts both in medium with and without P, although none of the blastocysts in medium without PTF hatched from their zona pellucida.
Synergy of importin α recognition and DNA binding by the yeast transcriptional activator GAL4
Authors: Chan Chee-Kai , Jans David A
Published: July 2002

The N‐terminus of the yeast transcriptional activator GAL4 contains partially overlapping nuclear targeting and DNA binding functions. We have previously shown that GAL4 is recognised with high affinity by importin β and not by the conventional nuclear localisation sequence binding importin α subunit of the importin α/β heterodimer. The present study uses ELISA‐based binding and electrophoretic mobility shift assays to show that recognition of GAL4 by importin α can occur, but only when GAL4 is bound to its specific DNA recognition sequence. Intriguingly, binding by importin α enhances DNA binding on the part of GAL4, implying a synergistic co‐operation between these two functions. The results implicate a possible role for importin α in the nucleus additional to its established role in nuclear transport, as well as having implications for the use of GAL4 as a DNA carrier in gene therapy applications.
Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho family
Authors: Vayssière Béatrice , Zalcman Gérard , Mahé Yannick , Mirey Gladys , Ligensa Tanja , Weidner K.Michael , Chardin Pierre , Camonis Jacques
Published: July 2002

Grb7 is a member of a family of molecular adapters which are able to contribute positively but also negatively to signal transduction and whose precise roles remain obscure. Rnd1 is a member of the Rho family, but, as opposed to usual GTPases, it is constitutively bound to GTP. We show here that Rnd1 and Grb7 interact, in two‐hybrid assays, in vitro, and in pull‐down experiments performed with SK‐BR3, a breast cancer cell line that overexpresses Grb7. This interaction involves switch II loop of Rnd1, a region crucial for guanine nucleotide exchange in all GTPases, and a Grb7 SH2 domain, a region crucial for Grb7 interaction with several activated receptors. The contribution of the interaction between Rnd1 and Grb7 to their respective functions and properties is discussed.
Expression, purification and charaterization of recombinant mouse MT5‐MMP protein products
Authors: Wang Xing , Yi Jun , Lei Jianxun , Pei Duanqing
Published: July 2002

We have recently identified the fifth member of the membrane‐type matrix metalloproteinase subfamily, MT5‐MMP/MMP24, which is expressed in a brain specific manner (Duanqing Pei (1999) J. Biol. Chem. 274, 8925–8932). To further characterize its enzymic properties, an expression construct was engineered to produce MT5‐MMP as a soluble and active form by truncating its transmembrane domain. Stable expression cell lines were subsequently established from MDCK cells transfected with this construct. Unfortunately, purification of MT5‐MMP from the culture media in large quantity proves to be difficult initially due to its rapid turnover via a mechanism which can be inhibited by a broad spectrum metalloproteinase inhibitor, BB94. Thus, BB94 was included in the cell culture medium and throughout the purification process except the final step of chromatography to protect MT5‐MMP from destruction. Purified to homogeneity and free of the synthetic inhibitor, MT5‐MMP can activate progelatinase A efficiently in a TIMP2 sensitive fashion. A preliminary screen for its potential substrates among extracellular matrix components identified the proteoglycans as the preferred substrates for MT5‐MMP. Furthermore, it is determined that the stability of purified MT5‐MMP is temperature dependent with rapid destruction at 37°C, but being relatively stable at temperatures 4°C or lower. These observations establish MT5‐MMP as a proteoglycanase with a short half‐life at body temperature, which may be critical for tightly controlled turnover of ECM components such as those in the brain.
Conformationally controlled pK‐switching in membrane proteins: One more mechanism specific to the enzyme catalysis?
Authors: Mulkidjanian Armen Y.
Published: July 2002

Internal proton displacements in several membrane photosynthetic enzymes are analyzed in relation to general mechanisms of enzymatic catalysis. In the bacterial photosynthetic reaction center (RC) and in bacteriorhodopsin (BR), carboxy residues (Glu‐212 in the RC L‐subunit and Asp‐96 in BR) serve as indispensable intrinsic proton donors. Both carboxyls are protonated prior to the proton‐donation step, because their pK values are shifted to ≥12.0 by the interaction with the protein and/or substrate. In both cases, the proton transfer reactions are preceded by conformational changes that, supposedly, let water interact with the carboxyls. These changes switch over the pK values of the carboxyls to ≤6.0 and 7.1 in the RC and BR, respectively. The sharp increase in the proton‐donating ability of the carboxyls drives the reaction cycles. This kind of catalytic mechanism, where a strong general acid or base emerges, when needed, as a result of a conformational change can be denoted as a conformationally controlled pK‐switching. Generally, the ability of enzymes to go between isoenergetic conformations that differ widely in the reactivity of the catalytic group(s) may be of crucial importance to the understanding of enzymatic catalysis. Particularly, the pK‐switching concept could help to reconcile the contradictory views on the functional protonation state of the redox‐active tyrosine YZ in the oxygen‐evolving photosystem II. It is conceivable that YZ switches its pK from ∼4.5 to ≥10.0 upon the last, rate‐limiting step of water oxidation. By turning into a strong base, tyrosine assists then in abstracting a proton from the bound substrate water and helps to drive the dioxygen formation.
UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged
Authors: Cadenas Susana , Buckingham Julie A. , Samec Sonia , Seydoux Josiane , Din Nanni , Dulloo Abdul G. , Brand Martin D.
Published: July 2002

The relationship between UCP2 and UCP3 expression and mitochondrial proton conductance of rat skeletal muscle was examined. Rats were starved for 24 h and the levels of UCP2 and UCP3 mRNA and UCP3 protein were determined by Northern and Western blots. Proton conductance was measured by titrating mitochondrial respiration rate and membrane potential with malonate. Starvation increased UCP2 and UCP3 mRNA levels more than 5‐fold and 4‐fold, respectively, and UCP3 protein levels by 2‐fold. However, proton conductance remained unchanged. These results suggest either that Northern and Western blots do not reflect the levels of active protein or that these UCPs do not catalyse the basal proton conductance in skeletal muscle mitochondria.
Isolation and characterization of a calendic acid producing (8,11)‐linoleoyl desaturase1
Authors: Fritsche Kathrin , Hornung Ellen , Peitzsch Nicola , Renz Andreas , Feussner Ivo
Published: July 2002

For the biosynthesis of calendic acid a (8,11)‐linoleoyl desaturase activity has been proposed. To isolate this desaturase, PCR‐based cloning was used. The open reading frame of the isolated full‐length cDNA is a 1131 bp sequence encoding a protein of 377 amino acids. For functional identification the cDNA was expressed in Saccharomyces cerevisiae, and formation of calendic acid was analyzed by RP‐HPLC. The expression of the heterologous enzyme resulted in a significant amount of calendic acid presumably esterified within phospholipids. The results presented here identify a gene encoding a new type of (1,4)‐acyl lipid desaturase.
Quercetin and anti‐CD95(Fas/Apo1) enhance apoptosis in HPB‐ALL cell line
Authors: Russo Maria , Palumbo Rosanna , Tedesco Idolo , Mazzarella Giuseppe , Russo Paola , Iacomino Giuseppe , Russo Gian Luigi
Published: July 2002

Several malignant cell lines are resistant to CD95(Apo1/Fas)‐mediated apoptosis, even when the CD95 receptor is highly expressed. Sensitivity to CD95‐induced apoptosis can be restored using different molecules. In this study, we showed that quercetin, a naturally occurring flavonoid, in association with the agonistic anti‐CD95 monoclonal antibody, increases DNA fragmentation and caspase‐3 activity in HPB‐ALL cells. These cells have been selected for their known resistance to CD95‐induced apoptosis. At molecular level, quercetin lowers the level of intracellular reactive oxygen species, reduces mitochondrial transmembrane potential, thereby leaving the expression of CD95 receptor unchanged.
α1,3‐Fucosyltransferase 9 (FUT9; Fuc‐TIX) preferentially fucosylates the distal GlcNAc residue of polylactosamine chain while the other four α1,3FUT members preferentially fucosylate the inner GlcNAc residue
Authors: Nishihara Shoko , Iwasaki Hiroko , Kaneko Mika , Tawada Akira , Ito Masato , Narimatsu Hisashi
Published: July 2002

We analyzed the substrate specificity of six human α1,3‐fucosyltransferases (α1,3FUTs) for the 2‐aminobenzamide (2AB)‐labelled polylactosamine acceptor, Galβ1‐4GlcNAcβ1‐3Galβ1‐4GlcNAcβ1‐3Galβ1‐4GlcNAc‐2AB (3LN‐2AB). FUT9 preferentially fucosylated the distal GlcNAc residue of the polylactosamine chain while the other four α1,3FUT members, FUT3, FUT4, FUT5 and FUT6, preferentially fucosylated the inner GlcNAc residue. This indicated that FUT9 exhibits more efficient activity for the synthesis of Lewis x carbohydrate epitope (Lex; CD15; stage‐specific embryonal antigen‐1 (SSEA‐1)). In contrast, the other four members synthesize more effectively the internal Lex epitope. FUT7 could not transfer a fucose to an acceptor which is non‐sialylated.
Expression and characterization of human foamy virus proteinase
Authors: Fenyöfalvi György , Bagossi Péter , Copeland Terry D. , Oroszlan Stephen , Boross Péter , Tözsér József
Published: July 2002

The human foamy virus proteinase was expressed in fusion with maltose binding protein in Escherichia coli and purified. The specific activity of the fusion protein was similar to that of the processed enzyme. The kinetic constants on foamy virus cleavage site substrates were very low but comparable to those obtained with the gag‐encoded avian proteinase on its own substrates. The proteinase showed preference for high ionic strength and a pH optimum of 6.6. None of the tested retroviral cleavage site peptides were substrates, however, some peptides representing cleavage sites in retrotransposons were properly processed by the enzyme.
Exploring the open pore of the potassium channel from Streptomyces lividans
Authors: Meuser D. , Splitt H. , Wagner R. , Schrempf H.
Published: July 2002

The tetrameric potassium channel from Streptomyces lividans (KcsA) embedded in planar bilayers exhibits the following electrophysiological characteristics: (i) K+ ions can cross the pore in a highly hydrated state (n
H2O≳6), (ii) the selectivity for K+ exceeds that for Na+ ions by 11 times, and both Ca2+ and Mg2+ are permeant, (iii) the internal side is blocked by Ba2+ ions in a voltage‐dependent manner, (iv) intrinsic rectification is due to gating, depending on the direction of the electric field, (v) the internal side is pH‐sensitive, and (vi) the open pore has a diameter of ∼5.8 Å. In conclusion, our results show that ion conduction and selectivity of KcsA cannot easily be reconciled with the properties deduced from the rigid crystal structure [Doyle et al., Science 280 (1998) 69–77], which must be concluded to have the pore trapped in its closed state.
Sarcoplasmic reticulum vesicles embedded in agarose gel exhibit propagating calcium waves
Authors: Wussling M.H.P. , Krannich K. , Landgraf G. , Herrmann-Frank A. , Wiedenmann D. , Gellerich F.N. , Podhaisky H.
Published: July 2002

In different cell types, activation of signal transduction pathways leads to the generation of calcium oscillations and/or waves. Due to this important impact for cellular function, calcium waves are the subject of intensive investigations. To study interactions of cell organelles with no influence of the cell membrane, sarcoplasmic reticulum (SR) vesicles and well‐coupled mitochondria were reconstituted. For the first time, we demonstrate the generation and propagation of calcium waves in a suspension of sarcoplasmic reticulum vesicles, embedded in an agarose gel. The propagation dynamics resemble those of calcium waves in living cells. Moreover, the addition of well‐coupled mitochondria leads to more pronounced and significantly faster propagating waves, demonstrating the importance of the mitochondrial Ca2+ transport. The experimental and simulation results indicate the resemblance of the in vitro system to an excitable medium.
Purification and two‐dimensional crystallization of highly active cytochromeb6fcomplex from spinach
Authors: Dietrich Jens , Kühlbrandt Werner
Published: July 2002

The purification and two‐dimensional crystallization of highly active cytochromeb6fcomplex from spinach is described. The preparation shows all spectroscopic characteristics of the pure complex. The electron transfer activity of 450±60 electrons per s is the highest in vitro activity reported to date. Using dimethyl sulfoxide (DMSO) as a solvent for the electron donor enhanced the performance and reproducibility of the assay. The high yield and the high activity of the protein make it an ideal candidate for biophysical and structural studies. Preliminary two‐dimensional crystallization experiments yielded several different forms of two‐dimensional and thin three‐dimensional crystals, exhibiting varying degrees of order.
Detection and regulation of leptin receptor mRNA in ovine mammary epithelial cells during pregnancy and lactation
Authors: Laud Karine , Gourdou Isabelle , Bélair Lucette , Keisler Duane H. , Djiane Jean
Published: July 2002

Adipocyte‐epithelial cell interactions and their secretions are critical determinants of mammary gland development. In this present study, we examined the possible involvement of leptin and its receptors in the process of mammogenesis/lactogenesis. We demonstrated by reverse transcription and polymerase chain reaction analysis that long and short forms of leptin receptors were expressed in the ovine mammary gland during pregnancy and lactation. Furthermore, quantitative determinations, via ribonuclease protection assays, provided evidence that the level of leptin receptor expression was greatest during mid‐pregnancy when active growth of the mammary gland is initiated. Location of the leptin receptors, as determined by in situ hybridization analysis, revealed that leptin receptor transcripts were expressed specifically in mammary epithelial cells. These data provide evidence that leptin, with its receptors, could be an important mediator in regulating mammary gland growth and development.
Forssman pentasaccharide and polyvalent Galβ1→4GlcNAc as major ligands with affinity for Caragana arborescens agglutinin
Authors: Wu Albert M. , Wu June H. , Chen Yuen-Yuen , Tsai Ming-Sung , Herp Anthony
Published: July 2002

The binding properties of Caragana arborescens agglutinin (CAA, pea tree agglutinin) were studied by enzyme linked lectinosorbent assay (ELLSA) and by inhibition of CAA‐glycan interaction. Among glycoproteins (gps) tested, CAA reacted strongly with asialo bird nest gp, asialo rat sublingual gp, human Tamm‐Horsfall Sd(a+) urinary gp (THGP) and asialo THGP that are rich in GalNAcα1→, GalNAcβ1→ and/or Galβ1→4GlcNAc residues. CAA also bound tightly with multi‐valent Galβ1→4GlcNAc (mII) containing glycoproteins (human blood group precursor gps, asialo fetuin) and asialo ovine salivary glycoprotein (Tn, GalNAcα1→Ser/Thr), but CAA reacted poorly or not at all with sialylated glycoproteins tested. Of the sugars tested for inhibition of binding, Forssman pentasaccharide (Fp, GalNAcα1→3GalNAcβ1→3Galα1→4Galβ1→4Glc) was the best. It was about 2.3, 9.5 and 52.6 times more active than Galβ1→4GlcNAc, GalNAc and Gal, respectively, and about 1.9 times more active than tri‐antennary Galβ1→4GlcNAc (Tri‐II). These results suggest that this agglutinin is mainly specific for Fp, mII and Tn clusters. This property can be used to detect human abnormal glycotopes related to Fp and unmasked mII/Tn clusters and to study cell growth and differentiation given the lack of toxicity of this lectin toward mouse fibroblast cells.
Binding of IL‐4 to the IL‐13Rα1/IL‐4Rα receptor complex leads to STAT3 phosphorylation but not to its nuclear translocation
Authors: Wery-Zennaro Sandrine , Letourneur Martine , David Muriel , Bertoglio Jacques , Pierre Josiane
Published: July 2002

Interleukin‐4 (IL‐4) is a pleiotropic cytokine, which acts on both hematopoietic and non‐hematopoietic cells, through different types of receptor complexes. In this study, we report that in human B cells, IL‐4 caused rapid phosphorylation of Janus kinase (JAK) 1 and JAK3 tyrosine kinases. In keratinocytes, the hematopoietic‐specific receptor common γc chain is not expressed and the IL‐13 receptor α1 (IL‐13Rα1) participates in IL‐4 signal transduction. In keratinocytes, IL‐4 induced JAK1 and JAK2 phosphorylation but, unlike in immune cells, IL‐4 did not involve JAK3 activation for its signaling. In both cell types, IL‐4 induced phosphorylation and DNA binding activation of the signal transducer and activator of transcription (STAT) 6 protein. Furthermore, IL‐4 stimulation of keratinocytes also induced tyrosine phosphorylation of STAT3 which was found to bind to the phosphorylated IL‐13Rα1. STAT3 however did not significantly translocate to the nucleus, nor did it bind with high affinity to target DNA sequences.
Interaction of Escherichia coli inorganic pyrophosphatase active sites
Authors: Avaeva Svetlana , Grigorjeva Olga , Mitkevich Vladimir , Sklyankina Vera , Varfolomeyev Sergei
Published: July 2002

Escherichia coli inorganic pyrophosphatase (PPase) is a hexamer of identical subunits. This work shows that trimeric form of PPase exhibits the interaction of the active sites in catalysis. Some trimer subunits demonstrate high substrate binding affinity typical for hexamer whereas the rest of subunits reveal more than 300‐fold substrate affinity decrease. This fact indicates the appearance of negative cooperativity of trimer subunits upon substrate binding. Association of the wild‐type (WT) trimer with catalytically inactive, but still substrate binding mutant trimer into hexameric chimera restores the high activity of the first trimer, characteristic of trimer incorporated in the hexamer of WT PPase. Interaction of PPase active sites suggests that there are pathways for information transmission between the active sites, providing the perfect organization and concerted functioning of the hexameric active sites in catalysis.
Virus‐induced permeability transition in mitochondria
Authors: Zorova Ljubava D. , Krasnikov Boris F. , Kuzminova Alevtina E. , Polyakova Irina A. , Dobrov Eugeny N. , Zorov Dmitry B.
Published: July 2002

Isolated rat liver mitochondria undergo permeability transition after supplementation with a suspension of tobacco mosaic virus. Four mitochondrial parameters proved the opening of the permeability transition pore in the inner mitochondrial membrane: increased oxygen consumption, collapse of the membrane potential, release of calcium ions from mitochondria, and high amplitude mitochondrial swelling. All virus‐induced changes in mitochondria were prevented by cyclosporin A. These effects were not observed if the virus was treated with EGTA or disrupted by heating. Protein component of the virus particle in the form of 20S aggregate A‐protein, or helical polymer, as well as supernatant of the heat‐disrupted virus sample, had no effect on mitochondrial functioning. Electron microscopy revealed the direct interaction of the virus particles with isolated mitochondria. The possible role of the mitochondrial permeability transition pore in virus‐induced apoptosis is discussed.
Characterization of a testicular 17α,20β‐dihydroxy‐4‐pregnen‐3‐one (a spermiation‐inducing steroid in fish) receptor from a teleost, Japanese eel (Anguilla japonica)1
Authors: Todo Takashi , Ikeuchi Toshitaka , Kobayashi Tohru , Kajiura-Kobayashi Hiroko , Suzuki Kunimasa , Yoshikuni Michiyasu , Yamauchi Kohei , Nagahama Yoshitaka
Published: July 2002

A cDNA encoding a nuclear 17α,20β‐dihydroxy‐4‐pregnen‐3‐one (17α,20β‐DP, spermiation‐inducing hormone in fish) receptor (DPR) was, for the first time, isolated from an eel testis cDNA library. The amino acid sequence of DPR shows high homology with those of human and chicken progesterone receptors. The affinity of the bacterial recombinant DPR ligand binding domain protein for 17α,20β‐DP is higher than that of progesterone. In transfection experiments using COS7 cells, the DPR showed progestin‐dependent activation of transcription. 17α,20β‐DP was the most effective activator of transcription. These results indicate that the cDNA encodes a functional eel DPR, and show that 17α,20β‐DP has a nuclear receptor‐mediated action in eel testes.
Forskolin induces circadian gene expression of rPer1, rPer2 and dbp in mammalian rat‐1 fibroblasts
Authors: Yagita Kazuhiro , Okamura Hitoshi
Published: July 2002

Mammalian culture cells have the potential for periodicity, since high concentrations of serum can elicit the circadian expression of clock genes in rat‐1 fibroblasts. However, the mechanism by which serum affects circadian gene expression remains unclear. In the present study, we incubated rat‐1 cells with forskolin and successfully induced the rhythmic expression of Per1, Per2 and dbp. In the initial step of the circadian gene expression, a marked transient induction of Per1 was observed accompanied with CREB phosphorylation. Thus the present study strongly suggests that CREB activation through the cAMP/PKA pathway is involved in the generation of circadian rhythm in rat‐1 cells
The affinity of the GroEL/GroES complex for peptides under conditions of protein folding
Authors: Preuss Monika , Miller Andrew D
Published: July 2002

The affinity of four short peptides for the Escherichia coli molecular chaperone GroEL was studied in the presence of the co‐chaperone GroES and nucleotides. Our data show that binding of GroES to one ring enhances the interaction of the peptides with the opposite GroEL ring, a finding that was related to the structural readjustments in GroEL following GroES binding. We further report that the GroEL/GroES complex has a high affinity for peptides during ATP hydrolysis when protein substrates would undergo repeated cycles of assisted folding. Although we could not determine at which step(s) during the cycle our peptides interacted with GroEL, we propose that successive state changes in GroEL during ATP hydrolysis may create high affinity complexes and ensure maximum efficiency of the chaperone machinery under conditions of protein folding.
Electrostatic attraction at the core of membrane fusion
Authors: Montal M.
Published: July 2002

SNARE proteins appear to be involved in homotypic and heterotypic membrane fusion events [Söllner et al. (1993) Nature 362, 318–324]. The crystal structure of the synaptic SNARE complex exhibits a parallel four‐helical bundle fold with two helices contributed by SNAP‐25, a target SNARE (t‐SNARE), and the other two by a different t‐SNARE, syntaxin, and a donor vesicle SNARE (v‐SNARE), synaptobrevin. The carboxy‐terminal boundary of the complex, predicted to occur at the closest proximity between the apposed membranes, displays a high density of positively charged residues. This feature combined with the enrichment of negatively charged phospholipids in the cytosolic exposed leaflet of the membrane bilayer suggest that electrostatic attraction between oppositely charged interfaces may be sufficient to induce dynamic and discrete micellar discontinuities of the apposed membranes with the transient breakdown at the junction and subsequent reformation. Thus, the positively charged end of the SNARE complex in concert with Ca2+ may be sufficient to generate a transient ‘fusion pore'.
Women and the third and fourth age
Authors: Diczfalusy E. , Benagiano G.
Published: July 2002

In 1900, the world population was less than 1.7 billion people; the United Nations projects that in 2000 it will be 6.2, and in 2020, 7.9 billion. The proportion of the elderly (65 years and over), will increase from 5.1% (1950) to 6.8% by the year 2000 and to 8.8% by 2020, when out of an elderly population of 796 million people, 124 million are projected to be 80 years and over. Due to an increasing gender inequality in life expectation, the majority of the elderly will be women. An aged population is a basically new feature in the history of humanity, the implications of which are — as yet — incompletely understood. It is clear, however, that the last years of life are accompanied by an increase in disability and sickness, with very high demands for health and social services. Hence, the soaring elderly population will raise major social, economic and ethical issues worldwide and may strain to the limit the ability of health, social and economic infrastructures of many countries. It may also result in an increasingly large proportion of humanity (the elderly in general and elderly women, in particular) living in absolute poverty. The demographic, health, socioeconomic and ethical dimensions of the problem are discussed with particular emphasis on the situation of elderly women and a plea is made for greatly increased medical and socioeconomic research.
A new model for collaboration — making emergency contraceptives available in developing countries
Authors: Senanayake P.
Published: July 2002

Private/public‐sector collaboration in contraceptive research and development offers a fresh opportunity to consider a holistic approach to making emergency contraception (EC) available in developing countries. Emergency contraception has been available since the 1970s but has remained under‐utilized. Emergency contraception may be used by women who want to prevent a pregnancy and therefore has a specific use, in a specific situation. This paper highlights the distinct and reciprocal advantages of a collaborative approach between the Consortium for Emergency Contraception (the public sector) and a pharmaceutical company (the private sector), to the introduction of EC in developing countries. The importance of cultivating a public/private‐sector collaborative approach, which serves the interests of both parties concerned, in order to foster progress in this important initiative, is highlighted.
Beyond improved quality: the motivational effects of statistical process control
Authors: Rungtusanatham Manus
Published: July 2002

The deployment of statistical process control (SPC) in manufacturing environments is a prominent global phenomenon. Managers have frequently justified investments in SPC by citing and/or demonstrating the improvements in quality and costs from the effective implementation and practice of SPC. This paper complements this rationalization by presenting conceptual arguments and empirical evidence to further our understanding of the motivational effects that result from the deployment of SPC within production environments. Several hypotheses derived from relating the deployment of SPC to process operators’ jobs and their affective reactions to work are tested using data provided by 100 process operators. The empirical results, generated from applying path analysis, suggest that the effective implementation and practice of SPC, in fact, would create more enriched jobs for process operators that lead to higher levels of work motivation and job satisfaction.
Degradation of the cartilage collagen matrix associated with changes in chondrocytes in osteoarthrosis. Assessment by loss of background fluorescence and immunodetection of matrix components
Authors: Gibson G. J. , Verner J. J. , Nelson F. R. T. , Lin D.‐L.
Published: July 2002

Articular cartilage damage and eventual loss is the primary pathological change seen in osteoarthrosis (OA). In this study we have investigated the link between turnover of the collagen matrix and changes in chondrocytes. The background fluorescence of articular cartilage, as indicated by its emission spectrum and resistance to extraction was generated by the slow non‐enzymic modification of the collagen matrix by advanced glycation end products (AGEs). Assessment of changes in background fluorescence in sections of articular cartilage provided a narrative of collagen degradation. Patients without OA pathology typically had a uniform strong background fluorescence throughout the depth of the cartilage. Cartilage from OA patients showed a range of changes in background fluorescence dependent on depth from the articular surface and proximity to overt lesions. Loss of background fluorescence was centered on chondrocytes, more extensive near the surface and associated with detection of the proteoglycan epitope 7D4. Expression of type X collagen was seen in articular cartilage in the region of the interface of with subchondral bone in most OA patients but was not associated with prominent, pericellular, loss of background fluorescence. These observations are consistent with progressive cartilage damage in OA, whereby collagen turnover and loss of surface integrity is associated with chondrocyte activity similar to that seen in immature articular cartilage. © 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Major symptoms and differential diagnosis of neuroleptic malignant syndrome: three case reports
Authors: Védie C. , Poinso F. , Hemmi F. , Rivet B.
Published: July 2002

The authors describe the cases of three patients presenting a major extrapyramidal symptom with rising CPK, inconstant hyperthermia and autonomic dysfunction. Through a brief review of the literature, the authors question the unity of the malignant syndrome. If hypertonia is quite constant, the rise in the seric CPK is aspecific and hyperthermia is inconstant.
Early neurohormonal effects of trandolapril in patients with left ventricular dysfunction and a recent acute myocardial infarction: a double‐blind, randomized, placebo‐controlled multicentre study
Authors: Sigurdsson A. , Eriksson S.V. , Hall C. , Kahan T. , Swedberg K.
Published: July 2002

Angiotensin‐converting enzyme inhibitors improve long‐term survival in patients with left ventricular dysfunction after a myocardial infarction, but their mechanism of action is not entirely clear. The neurohormonal effects may be important in this respect, as well as an early hemodynamic unloading induced by these drugs. The primary objective was to assess the effect of trandolapril on plasma levels of atrial natriuretic peptide. A secondary objective was to assess the effects of trandolapril on selected neurohormones, vasoactive peptides and enzymes, which may be important in the development of left ventricular remodeling and heart failure following an acute myocardial infarction. A total of 119 patients with an acute myocardial infarction and a wall motion index ≤1.2 (16‐segment echocardiographic model) were randomized to double blind treatment with trandolapril or placebo within 3–7 days after the onset of infarction. Blind treatment was discontinued 21 days after the index infarction. Venous blood samples were collected at rest, before randomization and on the day after treatment was discontinued. At the end of the study, there were no differences in plasma levels of atrial natriuretic peptide between the two treatment groups. Angiotensin‐converting enzyme activity was suppressed and plasma renin activity was higher in the trandolapril group. No differences in plasma levels of N‐terminal pro‐atrial natriuretic peptide, brain natriuretic peptide, aldosterone, noradrenaline, adrenaline, vasopressin, big endothelin‐1 and neuropeptide Y were found between the two treatment groups. There were positive correlations between several markers of neurohormonal activation at baseline and variables expressing left ventricular dysfunction and clinical heart failure. Neurohormonal activation is related to left ventricular dysfunction. The effects of 2–3 weeks of angiotensin‐converting enzyme inhibition on neurohormonal activation does not predict the already established beneficial long‐term effects after myocardial infarction. Thus, early modulation of circulatory neurohormone levels may not be a major mechanism for the efficacy of angiotensin‐converting enzyme inhibitors in these patients. Selected plasma hormone markers may still be used to identify patients who might get the greatest benefit from treatment.
Dopant Diffusion Equilibrium Overcoming Impurity Loss of Doped QDs for Multimode Anti‐Counterfeiting and Encryption
Authors: Bai Bing , Xu Meng , Li Jianzhong , Zhang Shuping , Qiao Chen , Liu Jiajia , Zhang Jiatao
Published: April 2021

High ion diffusivity of Cu+ dopants accelerates outdiffusion in quantum dots (QDs) at high temperatures. This kind of self‐purification gives rise to a sharp decrease in dopant photoluminescence (PL) intensity. Herein, a dopant diffusion equilibrium strategy is developed by introducing extra Cu+ in the epitaxial growth process. By preventing the loss of dopant Cu+, both the decrease of dopant PL and increase of band‐edge PL intensity are successfully suppressed. The coexistence of visible and invisible near‐infrared (NIR) PL bands for Cu‐doped CdSe@CdS QDs demonstrates their novel multimode anti‐counterfeiting/encryption potential. Via printing by combined using of intrinsic and doped QD “inks” with visible and invisible NIR emissions, respectively, the bulk‐sized patterns, texts, and numerals can achieve visible–invisible PL synergetic confidential information multimode anti‐counterfeiting and encryption.
Covalent Assembly of Two‐Dimensional COF‐on‐MXene Heterostructures Enables Fast Charging Lithium Hosts
Authors: Guo Dong , Ming FangWang , Shinde Digambar B. , Cao Li , Huang Gang , Li Chunyang , Li Zhen , Yuan Youyou , Hedhili Mohamed N. , Alshareef Husam N. , Lai Zhiping
Published: April 2021

2D heterostructured materials combining ultrathin nanosheet morphology, defined pore configuration, and stable hybrid compositions, have attracted increasing attention for fast mass transport and charge transfer, which are highly desirable features for efficient energy storage. Here, the chemical space of 2D–2D heterostructures is extended by covalently assembling covalent organic frameworks (COFs) on MXene nanosheets. Unlike most COFs, which are generally produced as solid powders, ultrathin 2D COF‐LZU1 grows in situ on aminated Ti3C2Tx nanosheets with covalent bonding, producing a robust MXene@COF heterostructure with high crystallinity, hierarchical porosity, and conductive frameworks. When used as lithium hosts in Li metal batteries, lithium storage and charge transport are significantly improved. Both spectroelectrochemical and theoretical analyses demonstrate that lithiated COF channels are important as fast Li+ transport layers, by which Li ions can be precisely nucleated. This affords dendrite‐free and fast‐charging anodes, which would be difficult to achieve using individual components.
Bioengineered Dual‐Targeting Protein Nanocage for Stereoscopical Loading of Synergistic Hydrophilic/Hydrophobic Drugs to Enhance Anticancer Efficacy
Authors: Wang Zhuoran , Zhang Shuai , Zhang Ruofei , Chen Xuehui , Sun Guoming , Zhou Meng , Han Qiubai , Zhang Baoli , Zhao Yue , Jiang Bing , Yang Yili , Yan Xiyun , Fan Kelong
Published: April 2021

A biocompatible and modifiable protein nanocarrier is a promising candidate for tumor targeted drug delivery. However, it is challenging to effectively load hydrophobic drugs, not to mention to upload both hydrophilic and hydrophobic drugs on one protein nanocarrier. Here, an amphiphilic multi‐drug loading protein nanocage (Am‐PNCage) is presented which is generated by replacing the fifth helix of human H‐ferritin (HFn) subunit with a functional motif composed of hydrophobic–hydrophilic‐RGD peptides. The Am‐PNCage possesses a dual targeting property resulting from the intrinsic CD71 targeting ability of HFn and the integrin α vβ3 targeting ability of displayed RGD peptides. Through the hydrophilic drug entry channel in the protein nanocage and hydrophobic peptides displayed on the outer surface, amphiphilic epirubicin (132)/camptothecin (50) are stereoscopically loaded into the inner cavity/outer protein shell, respectively, for one Am‐PNCage, exhibiting cascade drug release pattern. The dual‐targeted Am‐PNCage promotes the loaded drugs penetrating various 3D tumor models in vitro, as well as traversing the brain blood barrier and accumulating in brain tumors in vivo. Moreover, the drug loaded Am‐PNCage shows reduced side effects and significantly enhances synergistic efficacy against brain tumor, metastatic liver cancers, and drug resistant breast tumor. Thus, the Am‐PNCage represents a novel promising protein nanocarrier for targeted combination chemotherapy.
Giant Ferroelectric Resistance Switching Controlled by a Modulatory Terminal for Low‐Power Neuromorphic In‐Memory Computing
Authors: Xue Fei , He Xin , Wang Zhenyu , Retamal José Ramón Durán , Chai Zheng , Jing Lingling , Zhang Chenhui , Fang Hui , Chai Yang , Jiang Tao , Zhang Weidong , Alshareef Husam N. , Ji Zhigang , Li Lain‐Jong , He Jr‐Hau , Zhang Xixiang
Published: April 2021

Ferroelectrics have been demonstrated as excellent building blocks for high‐performance nonvolatile memories, including memristors, which play critical roles in the hardware implementation of artificial synapses and in‐memory computing. Here, it is reported that the emerging van der Waals ferroelectric α‐In2Se3 can be used to successfully implement heterosynaptic plasticity (a fundamental but rarely emulated synaptic form) and achieve a resistance‐switching ratio of heterosynaptic memristors above 103, which is two orders of magnitude larger than that in other similar devices. The polarization change of ferroelectric α‐In2Se3 channel is responsible for the resistance switching at various paired terminals. The third terminal of α‐In2Se3 memristors exhibits nonvolatile control over channel current at a picoampere level, endowing the devices with picojoule read‐energy consumption to emulate the associative heterosynaptic learning. The simulation proves that both supervised and unsupervised learning manners can be implemented in α‐In2Se3 neutral networks with high image recognition accuracy. Moreover, these heterosynaptic devices can naturally realize Boolean logic without an additional circuit component. The results suggest that van der Waals ferroelectrics hold great potential for applications in complex, energy‐efficient, brain‐inspired computing systems and logic‐in‐memory computers.
Ultrahigh‐Performance Solar‐Blind Photodetectors Based on High Quality Heteroepitaxial Single Crystalline β‐Ga2O3 Film Grown by Vacuumfree, Low‐Cost Mist Chemical Vapor Deposition
Authors: Xu Yu , Cheng Yaolin , Li Zhe , Chen Dazheng , Xu Shengrui , Feng Qian , Zhu Weidong , Zhang Yachao , Zhang Jincheng , Zhang Chunfu , Hao Yue
Published: April 2021

Due to the suitable bandgap, superior chemical and physical properties, the β‐phase gallium oxide (β‐Ga2O3) has the great potential to fabricate the deep ultraviolet solar‐blind photodetectors (DUV PDs). However, the low material quality, high material growth cost, and insufficient device performance, are urgently required to be solved for practical applications. In this work, by using a vacuumfree, low‐cost mist chemical vapor deposition method, the high quality β‐Ga2O3 single crystal films are successfully heteroepitaxially grown on (0001) sapphire substrates. X‐ray diffraction and transmission electron microscopy measurements identify the heteroepitaxial relationship with (01) β‐Ga2O3‖(0001) sapphire. At the optimal growth temperature of 800 °C, the film shows a high quality pure β‐Ga2O3 phase with the small full width at half maximum of 0.71°. Furthermore, the metal–semiconductor–metal DUV PDs are fabricated based on such single crystal β‐Ga2O3 films, which exhibit excellent photoelectric performance. A very high photoresponsivity 22 000 A W−1 under 254 nm light illumination, which corresponds to a quantum efficiency of 1.07 × 107% and a high detectivity of 1.1 × 1016 Jones, almost the highest ever reported. The low‐cost film heteroepitaxial growth method and the ultrahigh device performance pave an alternative way for the fabrication of high‐performance β‐Ga2O3 solar‐blind DUV PDs.
Manganese Catalyzed Enantioselective Epoxidation of α,β‐Unsaturated Amides with H2O2
Authors: Ottenbacher Roman V. , Kurganskiy Vladimir I. , Talsi Evgenii P. , Bryliakov Konstantin P.
Published: April 2021

Herewith, we report the enantioselective epoxidation of electron‐deficient cis‐ and trans‐α,β‐unsaturated amides with the environmentally benign oxidant H2O2. The catalysts ‐ manganese complexes with bis‐amino‐bis‐pyridine and structurally related ligands ‐ exhibit reasonably high efficiency (up to 100 TON) and excellent chemo‐ and enantioselectivity (up to 100% and 99% ee, respectively). Crucially, the cis‐enamides epoxidation enantioselectivity and yield are dramatically enhanced by the presence of NH‐moiety, which effect can be explained by the hydrogen bonding interaction between the cis‐enamide substrate and the manganese based oxygen transferring species.

magnified image
Enhanced Targeting and Immune Activation of Tumor Microenvironment by Nanomodified Anti‐PD1 in Liver Cancer
Authors: Ou Da‐Liang , Tseng S.‐Ja , Kempson Ivan M. , Hsu Chia‐Lang , Yang Pan‐Chyr , Liao Zi‐Xian
Published: April 2021

Liver cancer is one of the most common cancers worldwide, 75% of which are hepatocellular carcinoma (HCC). Generally, chronic inflammation and an immunosuppressive tumor microenvironment are steadily activated in HCC. Although the US Food and Drug Administration (FDA) has approved immune checkpoint inhibitors (ICIs) for use as a clinically advanced HCC treatment, their efficacy in the clinical setting is not satisfactory. Moreover, only a small fraction of antibody reaches the target via systemic circulation due to neutralization of antibodies and off‐target delivery. To enhance the localized effects of ICIs, iron oxide nanoparticles (≈10 nm) are conjugated with an antiprogrammed death‐1 (anti‐PD1) antibody and introduced the ironized antibodies into orthotopic HCC tumors via the systemic circulation. When mice are sacrificed 13 days after the final treatment, mice treated with ironized anti‐PD1 significantly regulate tumor‐infiltrating leukocytes (TILs), particularly amplifying T‐cell functions and recruiting M1 macrophages. More importantly, biochemical indices indicate that mice treated with ironized anti‐PD1 recover liver function. This work presents iron oxide nanoparticles integrated with an anti‐PD1 antibody that immunomodulates the immunosuppressive tumor microenvironment to generate synergistic effects that achieve tumor inhibition and immune response activation in the context of HCC therapy.
Synergistic Activation of Antitumor Immunity by a Particulate Therapeutic Vaccine
Authors: Mai Junhua , Li Zhaoqi , Xia Xiaojun , Zhang Jingxin , Li Jun , Liu Haoran , Shen Jianliang , Ramirez Maricela , Li Feng , Li Zheng , Yokoi Kenji , Liu Xuewu , Mittendorf Elizabeth A. , Ferrari Mauro , Shen Haifa
Published: April 2021

Success in anticancer immune therapy relies on stimulation of tumor antigen‐specific T lymphocytes and effective infiltration of the T cells into tumor tissue. Here, a therapeutic vaccine that promotes proliferation and tumor infiltration of antigen‐specific T cells in both inflamed and noninflamed tumor types is described. The vaccine consists of STING agonist 2′3′‐cGAMP, TLR9 ligand CpG, and tumor antigen peptides that are loaded into nanoporous microparticles (μGCVax). μGCVax is effective in inhibiting lung metastatic melanoma, primary breast cancer, and subcutaneous colorectal cancer in their respective murine models, including functional cure of HER2‐positive breast cancer. Mechanistically, μGCVax potently stimulates type I interferon expression in dendritic cells, and promotes CD8+ and CD103+ dendritic cell maturation and migration to lymph nodes and other lymphatic tissues. Antitumor responses are dependent on TLR9 and interferon α/β receptor signaling, and to a less extent on STING signaling. These results demonstrate a high potential for μGCVax in mediating antitumor immunity in personalized cancer therapy.
Ultrathin [110]‐Confined Li4Ti5O12 Nanoflakes for High Rate Lithium Storage
Authors: Fu Shuting , Yu Xuefang , Wu Qili , Yang Xianfeng , Liu Zheng , Li Xiaohui , He Shiman , Wang Da , Li Yanchun , Tong Shengfu , Wu Mingmei
Published: April 2021

Improving the high‐rate performance of spinel lithium titanate (Li4Ti5O12, LTO) is one of the critical requirements to promote its practical application in Li‐ion batteries (LIBs). Herein, the possible Li+ ion diffusion routes in LTO are theoretically analyzed and compared by computational investigation. The calculations show that the most feasible diffusion path for Li+ ions is along the [110] direction indicated by the lowest energy barrier. Inspired by this prediction, ultrathin [110]‐confined LTO nanoflakes are rationally prepared through a function‐led targeted synthesis. The [110] orientation of the material sufficiently provides preferable transport channels which can promote the anisotropic diffusion of lithium ions within LTO nanoflakes. Furthermore, the ultrathin 2D nanostructure effectively shortens the diffusion length along the [110] direction, facilitating ion transport across the nanoflakes and thus improving the diffusion kinetics. Owing to these unique features, the LIB composed of optimized [110]‐confined LTO exhibits remarkable high rate capability and long‐term cycling stability, with a capacity of 146 mAh g‐1 at an ultrahigh rate of 100 C and a capacity retention of 88% even after 1500 cycles at 50 C. The as‐prepared [110]‐confined LTO nanoflakes have promising applications and show commercial viability for high‐power facilities.