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In response to the COVID-19 pandemic, governments around the world have implemented public health policies that limit individual freedoms in order to control disease transmission. While such limitations on liberties are sometimes necessary for pandemic control, many of these policies have been overly broad or have neglected to consider the costs for populations already susceptible to human rights violations. Furthermore, the pandemic has exacerbated preexisting inequities based on health care access, poverty, racial injustice, refugee crises, and lack of education. The worsening of such human rights violations increases the need to utilize a human rights approach in the response to COVID-19. This paper provides a global overview of COVID-19 public health policy interventions implemented from January 1 to June 30, 2020, and identifies their impacts on the human rights of marginalized populations. We find that over 70% of these public health policies negatively affect human rights in at least one way or for at least one population. We recommend that policy makers take a human rights approach to COVID-19 pandemic control by designing public health policies focused on the most marginalized groups in society. Doing so would allow for a more equitable, realistic, and sustainable pandemic response that is centered on the needs of those at highest risk of COVID-19 and human rights violations.

Career situation of first and presenting author Student for a master or a PhD. Introduction Prominent features of rheumatoid arthritis (RA) are pain, joint swelling and erosion induced by massive infiltration of immune cells into the inflamed tissue. Among these immune cells, granulocytes and monocytes play a crucial role. Both express sialic acid-binding immunoglobulin-like lectins (Siglecs) −7 and −9 (in mice Siglec-E), trans-membrane proteins generally transmitting inhibitory signals through immunoreceptor tyrosine-based inhibitory motifs in their cytoplasmic tails. So far, there has been only limited research on the effects of Siglecs in RA. Objectives To evaluate the potential role of Siglec 7- and −9 during disease progression in RA by comparing the expression on blood leukocytes with disease activity in RA patients. Additionally we monitored Siglec-E knockout mice in an experimental arthritis model. Methods Blood samples from 45 healthy donors (HD) and 37 RA patients were analyzed by flow cytometry for Siglec-7 and −9 expressions on NK cells (CD14+/CD56+/CD3-), granulocytes (CD16+/CD19-) and monocytes (CD14+/CD16-). Expression was correlated with autoantibody positivity and disease severity. Siglec-E knockout mice and wildtype controls were used in a serum transfer induced arthritis model and disease manifestation was monitored by measurement of paw swelling. Additionally we performed functional ex vivo assays to study Siglec impact on granulocytes and monocytes. Results There was a diminished Siglec-7/9 expression on NK cells from RA patients, especially in highly CCP positive patients (>500 U/ml), while no differences were observed in neutrophils and monocytes compared to healthy controls. Interestingly we observed a correlation between a higher DAS28 score and lower Siglec-9 expression levels on granulocytes in seropositive patients. Siglec-E knockout mice displayed higher disease scores and paw swelling in serum transfer induced arthritis, especially at the peak and the resolution phase. Functional studies unraveled that granulocytes are in a more active state if Siglec-7 and −9 are missing. Conclusions Together our data support that Siglec-7/9 expression negatively correlates with pathogenesis and disease manifestation in RA patients. We showed in vivo and ex vivo, that Siglecs possess an important role concerning granulocyte and monocyte function and are capable of dampening immune response. Due to their inhibitory potential, Siglecs should be considered as potential therapeutic starting point in future studies. Acknowledgements This work was supported by DFG (HA 8163/1–1) and STAEDTLER Stiftung (WW/eh20/17). Disclosure of Interest None declared.

Printed organic sensors on plastic substrates are of great interest due to their flexibility and low-cost fabrication. We here present a fully inkjet-printed flexible Wheatstone bridge used for temperature sensing. A carbon nanoparticle ink and a mixture of poly(3,4-ethylenedioxythophene):poly(4-styrene-sulfonate) (PEDOT:PSS) and dimethyl sulfoxide (DMSO) are used as positive (PTC) and negative (NTC) thermal coefficient materials, respectively. Different carbon inks and DMSO concentrations from 0.5 to 40 wt% are evaluated in order to optimize the temperature coefficient of resistance (TCR) and the reliability of the PTC and NTC materials. The single materials are printed on PEN substrates, and subsequently encapsulated. A climate chamber is used to evaluate their reliability. The Wheatstone bridge sensors show good linearity and little hysteresis within a temperature range of 20 °C to 70 °C and exhibit a sensitivity of ∼4 mV/°C at a bias current of 1 mA. We furthermore investigate the reproducibility of the temperature sensor fabrication in order to analyze the potential of industrial applicability of inkjet-printing.

Aim of the study was to investigate the possible mechanisms leading to stunted growth and osteoporosis in experimental arthritis. Fourty-two female rats of 7-8 weeks of age were randomly assigned to three groups of 14 animals each: (a) controls; (b) adjuvant-inoculated (AA); and (c) adjuvant-inoculated rats receiving 10 mg cyclosporin A (CsA) orally for 30 days. Biological parameters studied were: hindpaw swelling; vertebral length progression expressed as Delta increments between days 1 and 30 as a parameter of skeletal growth, and estimation of total skeletal mineral content by dual energy X-ray absorptiometry (n=10 each group) on day 30. Endocrine parameters measured were pulsatile release of growth hormone (rGH) on day 30 following jugular cannulation and measurement of insulin-like growth factor (IGF-1) in pooled plasma from rGH profiles. Results can be summarized as follows: Untreated AA rats exhibited local signs of inflammation in comparison with controls (hindpaw diameter 8.1-8.9 mm vs. 5.3-5.6 mm in controls). Treatment with CsA normalized this parameter (4.9-5.6 mm). Vertebral growth was significantly retarded in AA rats in comparison with controls (214+/-32 vs. 473+/-33 microm; p

The peripheral actions of growth hormone (STH) are mediated by somatomedins or "insulin-like growth factors" (IGF I and II). In untreated acromegaly (n = 24) IGF I was always found increased, IGF II, however, was unchanged. The mean IGF-I-level (+/- SEM) was 553 +/- 75 (range 319-1066) ng/ml in active acromegaly and 193 +/- 10 (range 120-300) ng/ml in control persons. The corresponding IGF-II-values were 533 +/- 38 (range 187-720) and 647 +/- 21 (range 400-900) ng/ml. After treatment of acromegaly IGF I followed changes of the basal STH level with a delay of 4-8 weeks independent of the mode of treatment. This was in contrast to behaviour of IGF II. When STH was suppressible below 1 ng/ml after oral administration of 100 g glucose IGF I was never increased. STH after glucose of more than 5 ng/ml was always associated with increased IGF I. STH values between 1 and 5 ng/ml after glucose were combined with IGF-I-increases in 3 out of 6 cases. Thus, IGF I represents a valuable diagnostic criterion for assessment of activity of acromegaly, particularly in borderline cases, in contrast to IGF II. The criterion of normal somatotrophic function is suggested to be suppressibility of STH level below 1 ng/ml after oral administration of 100 g glucose.

It was investigated if IGF-1 levels in cats which experience diabetic remission (i.e. transient diabetes mellitus) differ from those in cats with permanent disease. Thirteen of 32 diabetic cats showed remission within 16 weeks after initiating insulin therapy, 19 cats continued to need insulin therapy. IGF-1 concentrations were measured before (t(0)), 1-3 (t(1)) and 4-8 (t(2)) weeks after initiating insulin therapy. No difference in IGF-1 levels was found between cats with transient and permanent diabetes at any point in time. In both groups of cats IGF-1 concentrations were significantly lower compared to those of controls before insulin administration. After starting insulin therapy IGF-1 increased significantly in both groups. In cats with transient diabetes IGF-1 levels were not different from controls already at t(1), whereas in cats with permanent diabetes it took until t(2). Although IGF-1 levels seem to normalize faster in cats with transient diabetes mellitus, measurement is not helpful to predict the course of the disease.

In addition to the redundancy of the receptors for the Fc portion of immunoglobulins, glycans result in potential ligands for a plethora of lectin receptors found in immune effector cells. Here we analysed the exposure of glycans containing fucosyl residues and the fucosylated tri-mannose N-type core by complexed native IgG in longitudinal serum samples of well-characterized patients with systemic lupus erythematosus. Consecutive serum samples of a cohort of 15 patients with systemic lupus erythematosus during periods of increased disease activity and remission were analysed. All patients fulfilled the 1982 American College of Rheumatology classification criteria. Sera of 15 sex- and age-matched normal healthy blood donors served as controls. The levels and type of glycosylation of complexed random IgG was measured with lectin enzyme-immunosorbent assays. After specifically gathering IgG complexes from sera, biotinylated lectins Aleuria aurantia lectin and Lens culinaris agglutinin were employed to detect IgG-associated fucosyl residues and the fucosylated tri-mannose N-glycan core, respectively. In sandwich-ELISAs, IgG-associated IgM, IgA, C1q, C3c and C-reactive protein (CRP) were detected as candidates for IgG immune complex constituents. We studied associations of the glycan of complexed IgG and disease activity according to the physician’s global assessment of disease activity and the systemic lupus erythematosus disease activity index 2000 documented at the moment of blood taking. Our results showed significantly higher levels of Aleuria aurantia lectin and Lens culinaris agglutinin binding sites exposed on IgG complexes of patients with systemic lupus erythematosus than on those of normal healthy blood donors. Disease activity in systemic lupus erythematosus correlated with higher exposure of Aleuria aurantia lectin-reactive fucosyl residues by immobilized IgG complexes. Top levels of Aleuria aurantia lectin-reactivity were found in samples taken during the highest activity of systemic lupus erythematosus. Our results show that native circulating IgG complexes from active systemic lupus erythematosus patients expose fucosyl residues and their glycan core is accessible to soluble lectins. Two putative mechanisms may contribute to the increased exposure of these glycans: (1) the canonical N-glycosylation site of the IgG-CH2 domain; (2) an IgG binding non-IgG molecule, like complement or C-reactive protein. In both cases the complexed IgG may be alternatively targeted to lectin receptors of effector cells, e.g. dendritic cells.

Hydrothermal synthesis has been exploited in the preparation of two new materials of the Ag(I)-organodiimine class of materials. By exploiting variations in ligand geometry and tether length and the structural influence of different oxoanions, the inorganic oxides [Ag(dpe)(NO3)](dpe=1,2-bias(4-pyridyl)ethane) and [Ag2(2,4′-bpy)2(SO4)(H2O)]·5H2O(2·5H2O) were isolated. Compound 1 was prepared in the reaction of Ag(NO3), dpe, and H2O in the mole ratio 1:1:500 at 120°C for 24 h, while compound 2 was prepared from Ag2SO4, 2,4′-bpy, and H2O under similar conditions. The structure of 1 is constructed from {Ag(dpe)}nn+ chains linked through η2, μ2–NO3− groups into a two-dimensional network. The structure of 2·5H2O consists of one-dimensional sinusoidal chains. The Ag(I) sites exhibit two distinct geometries: one is ‘T’-shaped through bonding to two nitrogen donors from two 2,4′-bpy groups and a sulfate oxygen; the second site is also ‘T’-shaped through bonding to two pyridyl nitrogen atoms and an aqua ligand.

The sections in this article are: 1 Indirect Evidence that Insulin-Like Growth Factor I Participates in the Regulation of Somatic Growth 1.1 Clinical: Correlations Between Growth and Insulin-Like Growth Factor I Levels in Serum 1.2 Experimental: Growth Hormone-Dependent Regulation of Insulin-Like Growth Factor I mRNA and Protein Expression in Various Tissues and the Autocrine/Paracrine Versus Endocrine Role of Insulin-Like Growth Factor I 2 Direct Evidence that Insulin-Like Growth Factor I Promotes Growth 2.1 Insulin-Like Growth Factor I as a Growth and Differentiation Factor In Vitro 2.2 Effects of Insulin-Like Growth Factor I Administration on Growth In Vivo 2.3 Transgenic Animals Overexpressing Growth Hormone or Insulin-Like Growth Factor I 2.4 Insulin-Like Growth Factor I and Type 1 Insulin-Like Growth Factor Receptor Knock-Out Animals 2.5 The Somatomedin Hypothesis Revisited

The hydrothermal reaction of MoO3 with 4,4′-dipyridylamine yields [Mo8O26(4,4′-dpa)2][4,4′-dpaH2]2. The structure consists of octamolybdate clusters linked via H-bonding to the (dpaH2)2+ cations into one-dimensional ribbons which are in turn connected through H-bonding into two-dimensional sheets.

The influence of organic components on the microstructure of inorganic solids has been extensively documented in recent years and has been shown to provide an efficacious method for the design of new materials. The synergism between the various chemical constituents at the organic/inorganic interface may result in imprinting of structural information from the organic molecules onto the inorganic framework. In this paper, the structural consequences of introducing organic components into several families of materials, including oxometalphosphates, transition metal oxides and transition metal halides and pseudohalides are briefly reviewed.

To examine whether insulin-like growth factor I (IGF I) or growth hormone (GH) influences leptin in vivo we measured leptin mRNA in epididymal fat pads and serum leptin of normal rats infused subcutaneously for 6 days with recombinant human (rh)IGF I (1 mg/day), rhGH (200 mU/day), or vehicle. In addition, we determined fat pad weight and food consumption as well as IGF I, insulin, glucose, non-esterified fatty acid (NEFA), glycerol, β-hydroxybutyrate and triglyceride (TG) serum concentrations. Food intake was identical during all three treatments. RhIGF I but not rhGH raised IGF I serum concentrations, reduced fat pad weight (60.3 ± 7.4 % of control rats, p = 0.019), and suppressed leptin mRNA (38.8 ± 11.9 % of control rats, p = 0.002), serum leptin (51.6 ± 10.5 % of control rats, p = 0.0028) and serum triglycerides (39.3 ± 8.0 % of control rats, p = 2.6 × 10–6). Both rhIGF I and rhGH reduced non-esterified fatty acids (NEFA) (p = 0.00 001 and 0.0007, respectively), whereas serum glycerol, β-OH butyrate and glucose concentrations remained unchanged. Serum insulin concentrations during rhIGF I were lower than during rhGH infusion and correlated with leptin mRNA (r = 0.589, p = 0.016) and fat pad weight (r = 0.643, p = 0.007). Reduction of adipose tissue mass and suppression of leptin by IGF I appear to be due to reduced circulating insulin leading to enhanced fat mobilization and NEFA oxidation as well as to increased gluconeogenesis from glycerol. In contrast, decreased NEFA concentrations during rhGH in the presence of unchanged fat pad weight, serum glycerol and triglycerides might result from more efficient re-esterification of released fatty acids within the triglyceride-fatty acid cycle. The results also show that exogenously infused IGF I and GH act on lipid metabolism by different mechanisms and suggest an IGF-independent, probably direct, metabolic effect of GH. Finally, in agreement with previous studies in GH-infused hypophysectomized rats, it appears unlikely that GH regulates leptin in the rat. [Diabetologia (1999) 42: 160–166]

Two new vanadium oxide compounds, which contain interlamellar transition metal complexes bound to vanadium oxide sheets, were synthesized hydrothermally. The crystal structure of each reveals unusual coordination geometries and interlayer bonding. [Ni(2,2′-bipyridine)]2[V12O32] (1) was prepared from the reaction of V2O5, NiO, H2O and 2,2′-bipyridyl in the molar ratio 4:8:3312:0.5. The isomorphous compounds [M(2,2′-bipy)]2[V12O32] (where M is Co (1a) and Cu (1b)) were prepared in a similar fashion. The Ni coordination compound 1 crystallizes as amber needles, and the structure was solved in the space group C2/m (#12) with unit cell parameters a =24.344(3) A , b =6.897(3) A , c =12.028(2) A , β=93.60(2)° (R(Rw)=0.039(0.038)). This compound is composed of vanadium(V) oxide layers with nickel atoms coordinated within a single layer via four Ni–O–V linkages. Bidentate bipyridine (bpy) ligands complete the coordination sphere of the nickel atoms and interdigitate via π–π stacking with bpy ligands from the adjacent layer. Cu(en)2[V6O14] (2) crystallizes as black plates in the space group P21/n (#14) with unit cell parameters a =8.934(2) A , b =6.558(1) A , c =15.694(2) A , β=99.93(2)° (R(Rw)=0.039(0.035)), from the reaction of CuCl2·2H2O, V2O5, H2O and ethylenediamine in the ratio 1:1:447:4. This structure consists of mixed-valent vanadium(IV,V) oxide sheets forming weak O–Cu bonds to intercalated copper bis(ethylenediamine) complexes.

The hydrothermal reaction of MoO3 and 4,4‘ -bipyridylamine yields [Mo4O13(Hbpa)2], a two-dimensional material constructed from molybdenum oxide chains linked through hydrogen bonding of the protonated, pendant arms of the Hbpa+ ligand.

Non-islet cell tumour hypoglycaemia (NICTH) is characterised by severe and recurrent fasting hypoglycaemia, and is usually caused by secretion of insulin-like growth factor-II (IGF-II) by the tumour. This induces secondary changes in the circulating levels of insulin, growth hormone (GH), and the IGF-binding proteins (IGFBPs), resulting in an increased insulin-like hypoglycaemic activity of IGF-II. A participating role of IGF-I is not established. We measured serum levels of free IGF-I and free IGF-II, total IGF-I, total IGF-II, big IGF-II and IGFBP-1, IGFBP-2 and IGFBP-3 in patients with NICTH before (n = 14) and after surgical removal of the tumour (n = 3). A control group (n = 20) was included for comparison. In NICTH patients, free IGF-II was 20-fold increased (26.8 ± 8.1 [mean ± SEM] vs. 1.3 ± 0.1 μg/l), and free IGF-I was four fold increased (2.8 ± 0.4 vs. 0.7 ± 0.1 μg/l), as compared to control subjects (p < 0.0001). In accordance with earlier observations levels of total IGF-I, total IGF-II, and IGFBP-3 were decreased, whereas IGFBP-1 and IGFBP-2 were increased in NICTH (all p-values < 0.05). The highly elevated levels of free IGF-I and free IGF-II most likely imply a considerable hypoglycaemic insulin-like activity, and may, by negative feedback explain the marked suppression of the GH/IGF-I axis observed in NICTH. Finally, free IGF-II seems to be a powerful biochemical marker in the diagnosis of NICTH. [Diabetologia (1998) 41: 589–594]

The hydrothermal reactions of molybdenum oxide starting materials with iron(II) and iron(III) halides in the presence of 2,2‘-bipyridine have afforded the three related one-dimensional solid materials [MoO4{Fe(III)Cl(2,2‘-bpy)}] (1), [Mo3O12{Fe(III)(2,2‘-bpy)}2]·0.25H2O (2), and [Mo4O15{Fe(III)(2,2‘-bpy)}2] (3). The structures of these three materials are based on a common one-dimensional ribbon exhibited by 1. The ribbon is constructed from four-polyhedra rings consisting of two {MoO4} tetrahedra and two {FeXN2O3} (X = Cl for 1, O for 2 and 3) octahedra. These polyhedra corner share such that each molybdenum center serves to bridge the two iron octahedra in the ring. Attachment to the next such four-ring is through the third corner sharing interaction of each molybdenum tetrahedron. Replacement of the pendant chloride substituents on adjacent iron centers in 1 with an {MoO4} unit leads to compound 2, while an {Mo2O7} linkage between adjacent iron centers affords 3.

Leptin is thought to exert its actions on energy homeostasis through the long form of the leptin receptor (OB-Rb), which is present in the hypothalamus and in certain peripheral organs, including adipose tissue. In this study, we examined whether leptin has direct effects on the function of brown and white adipose tissue (BAT and WAT, respectively) at the metabolic and molecular levels. The chronic peripheral intravenous administration of leptin in vivo for 4 d resulted in a 1.6-fold increase in the in vivo glucose utilization index of BAT, whereas no significant change was found after intracerebroventricular administration compared with pair-fed control rats, compatible with a direct effect of leptin on BAT. The effect of leptin on WAT fat pads from lean Zucker Fa/ fa rats was assessed ex vivo, where a 9- and 16-fold increase in the rate of lipolysis was observed after 2 h of exposure to 0.1 and 10 nM leptin, respectively. In contrast, no increase in lipolysis was observed in the fat pads from obese fa/fa rats, which harbor an inactivating mutation in the OB-Rb. At the level of gene expression, leptin treatment for 24 h increased malic enzyme and lipoprotein lipase RNA 1.8+/-0.17 and 1.9+/-0.14-fold, respectively, while aP2 mRNA levels were unaltered in primary cultures of brown adipocytes from lean Fa/fa rats. Importantly, however, no significant effect of leptin was observed on these genes in brown adipocytes from obese fa/fa animals. The presence of OB-Rb receptors in adipose tissue was substantiated by the detection of its transcripts by RT-PCR, and leptin treatment in vivo and in vitro activated the specific STATs implicated in the signaling pathway of the OB-Rb. Taken together, our data strongly suggest that leptin has direct effects on BAT and WAT, resulting in the activation of the Jak/STAT pathway and the increased expression of certain target genes, which may partially account for the observed increase in glucose utilization and lipolysis in leptin-treated adipose tissue.

Spo0F is a secondary messenger in the "two-component" system controlling the sporulation of Bacillus subtilis. Spo0F, like the chemotaxis protein CheY, is a single-domain protein homologous to the N-terminal activator domain of the response regulators. We recently reported the crystal structure of a phosphatase-resistant mutant Y13S of Spo0F with Ca2+ bound in the active site. The crystal structure of wild-type Spo0F in the absence of a metal ion is presented here. A comparison of the two structures reveals that the cation induces significant changes in the active site. In the present wild-type structure, the carboxylate of Asp11 points away from the center of the active site, whereas when coordinated to the Ca2+, as in the earlier structure, it points toward the active site. In addition, Asp54, the site of phosphorylation, is blocked by a salt bridge interaction of an Arg side chain from a neighboring molecule. From fluorescence quenching studies with Spo0F Y13W, we found that only the amino acid Arg binds to Spo0F in a saturable manner (Kd = 15 mM). This observation suggests that a small molecule with a shape complementary to the active site and having a guanidinium group might inhibit phosphotransfer between response regulators and their cognate histidine kinases.

Three one-dimensional molybdenum oxide/2,2‘-bipyridine species have been prepared by hydrothermal methods and structurally characterized. The reaction of MoO3, 2,2‘-bipyridine, and H2O in the mole ratio 1:0.68:680 at 160 °C for 120 h in a 23 mL Teflon-lined Parr acid digestion bomb produces colorless rods of [MoO3(2,2‘-bipy)] (1) mixed with colorless octahedra of [Mo3O9(2,2‘-bipy)2] (3). The structure of 1 consists of one-dimensional chains of corner-sharing distorted {MoO4N2} octahedra. [Mo2O6(2,2‘-bipy)] (2) was prepared from a mixture of Na2MoO4·2H2O, MoO3, 2,2‘-bipyridine, MnCl2·4H2O, and H2O in the mole ratio 1:1:2:1.9:263 and was isolated as colorless plates. In contrast to the structure of 1, compound 2 consists of a chain of alternating corner-sharing {MoO4N2} octahedra and {MoO4} tetrahedra. Compound 3 was isolated as colorless octahedra. The structure of 3 consists of a chain of corner-sharing {MoO4N2} octahedra and {MoO4} tetrahedra that alternate such that each {MoO4N2} octahedron corner-share...

The title compound, Sn(O3PCH2CH3), (1), was synthesized from a mixture of SnF2, CH3CH2PO3H2, and H2O in the mole ratio 1:0.85:1741 at 25°C for 1 h. Phosphonate (1) crystallizes in the orthorhombic space groupPbcawitha=7.785(2),b=7.450(1),c=20.026(4) A,V=1161.5(6) A3,Z=8, andR=0.0797. The two-dimensional structure of (1) is composed of corner sharing {SnO3} pyramids and {O3PC} tetrahedra that alternate to form four- and eight-member polyhedral rings within the layers. The ethyl groups of the phosphonate tetrahedra are directed outward from both faces of the layer, effectively forming inorganic layers alternating with organic bilayers.

NMR has been employed for structural and dynamic studies of the bacterial response regulator, Spo0F. This 124-residue protein is an essential component of the sporulation phosphorelay signal transduction pathway in Bacillus subtilis. Three-dimensional 1H, 15N, and 13C experiments have been used to obtain full side chain assignments and the 1511 distance, 121 dihedral angle, and 80 hydrogen bonding restraints required for generating a family of structures (14 restraints per residue). The structures give a well-defined (alpha/beta)5 fold for residues 4-120 with average rms deviations of 0.59 A for backbone heavy atoms and 1.02 A for all heavy atoms. Analyses of backbone 15N relaxation measurements demonstrate relative rigidity in most regions of regular secondary structure with a generalized order parameter (S2) of 0.9 +/- 0.05 and a rotational correlation time (taum) of 7.0 +/- 0.5 ns. Loop regions near the site of phosphorylation have higher than average rms deviation values and T1/T2 ratios suggesting significant internal motion or chemical exchange at these sites. Additionally, multiple conformers are observed for the beta4-alpha4 loop and beta-strand 5 region. These conformers may be related to structural changes associated with phosphorylation and also indicative of the propensity this recognition surface has for differential protein interactions. Comparison of Spo0F structural features to those of other response regulators reveals subtle differences in the orientations of secondary structure in the putative recognition surfaces and the relative charge distribution of residues surrounding the site of phosphorylation. These may be important in providing specificity for protein-protein interactions and for determining the lifetimes of the phosphorylated state.

The hydrothermal reactions of vanadium oxide and molybdenum oxide starting materials with divalent first-row transition metal cations in the presence of nitrogen donor chelating ligands yield the heterometallic hexanuclear clusters [{Zn(bipy)(2)}(2)V(4)O(12)] (2), [{Zn(phen)(2)}(2)V(4)O(12)].H(2)O (3.H(2)O), and [{Ni(bipy)(2)}(2)Mo(4)O(14)] (4). A similar reaction in the presence of excess 2,2'-bipyridine yields [Zn(bipy)(3)](2)[V(4)O(12)].11H(2)O (1.11H(2)O), a species with an isolated {V(4)O(12)}(4)(-) cluster. The structure of 2 consists of a {V(4)O(12)}(4)(-) ring covalently attached to each of two {Zn(bipy)(2)}(2+) moieties through the terminal oxo groups of alternate vanadium sites. In contrast, the structure of 3 exhibits a {V(4)O(12)}(4)(-) ring linked through oxo groups of adjacent vanadium sites to two {Zn(phen)(2)}(2+) moieties. The structure of 4 is constructed from two {Mo(2)O(7)}(2)(-) units linked through two {Ni(bipy)(2)}(2+) groups to form a cyclic 12-membered {Mo(4)Ni(2)O(6)} core. Crystal data: [Zn(bipy)(3)](2)[V(4)O(12)].11H(2)O (1.11H(2)O), a = 21.910(4) A, b = 14.044(2) A, c = 23.815(4) A, beta = 106.15(1) degrees, monoclinic, C2/c, Z = 4; [{Zn(bipy)(2)}(2)V(4)O(12)] (2), a = 12.017(2) A, c = 15.120(2) A, tetragonal P4(2)/n, Z = 2. [{Zn(o-phen)(2)}(2)V(4)O(12)].H(2)O (3.H(2)O), a = 18.182(2) A, b = 11.3668(9) A, c = 23.455(2) A, beta = 97.815(7) degrees, monoclinic P2(1)/c, Z = 4; [{Ni(bipy)(2){(2)Mo(4)O(14)] (4), a = 12.323(2) A, c = 14.897(4) A, tetragonal P4(2)2(1)2, Z = 2.

One-dimensional and two-dimensional solids consisting of polyoxoanions bridged by (M(LL)2)2+ groups have been synthesized by hydrothermal methods and structurally characterized by X-ray crystallography.

The first Sn(II)–organophosphonate solid phases have been prepared and structurally characterized by single crystal X-ray diffraction. The one-dimensional species [Sn(HO3PCH2PO3H)] ·H2O (1) was prepared conventionally from a mixture of SnCl2, CH2(PO3H2)2, and H2O in the mole ratio 1:2.9:8.17 kept at 4°C for 12 h. The three-dimensional phase [Sn2{O3PC(OH)(CH3)PO3}] (2) was prepared hydrothermally from a mixture of SnCl2, CH3C(OH)(PO3H)2, 1,4 diaminopropane · HCl, and H2O in the mole ratio 1:3.87:1.9:2215 with pH adjusted to 3.5 by addition of (CH3)4NOH, heated at 150°C for 135.5 h. Compound 1 consists of linear chains of {SnO3} pyramids bridged by (HO3PCH2PO3H)2−groups. The structure of 2 is a three-dimensional open framework. Crystal data: 1, triclinic P1a= 4.8777(1) A,b= 8.786(2) A,c= 9.446(2) A, α = 84.52(3)°, β = 78.78(3)°, γ = 74.39(3)°,V= 382.0(2) A3,Z= 2,Dcalc= 2.701 g cm−3, structure solution and refinement based on 1059 reflections converged atR= 0.060; 2, monoclinic P21/c,a= 10.889(2) A,b= 8.556(2) A,c= 9.460(2) A, β = 96.92(2)°,V= 874.9(4) A3,Dcalc= 3.336 g cm−3, structure solution and refinement based on 1121 reflections, converged atR= 0.055.

This chapter provides an overview of the state-of-the-art in the area of multifunctional, ultra-lightweight, ultra-thin and bendable organic and large-area electronic (OLAE) systems. This chapter introduces three possible applications, all based on a fully printed, textile compatible, sound module: textile integrated audio module including broadcast radio and solar supply; active receiver tag for wireless streaming of acoustic data and advertizing; and security tag system with acoustic alarm, motion and/or temperature sensors. There are reviews of the OLAE components and systems required for these applications. For the realization of these components and systems, the advantages of several flexible OLAE technologies need to be combined, while keeping cost at a minimum. Interface and packaging issues are discussed for full system integration on a common flexible foil enabling bending radii down to 1 cm. By combining these components, a variety of novel multifunctional OLAE systems can be enabled: the resulting market potential is discussed at the end of the chapter.

Osteopenia and retarded skeletal growth are consistent features of juvenile polyarthritis. Although the former has also been described in the experimental animal, the consequences of induced joint inflammation on skeletal growth have not yet been documented. In order to investigate the effect of experimental arthritis on these parameters, we studied female rats with adjuvant arthritis (AA) subjected to chronic treatment with cyclosporin A (CsA, Sandimmun ® ). This compound has been found to prevent the development of articular swelling and also repair joint and skeletal lesions in AA rats. Five groups of 8 animals each received oral CsA, 2.5, 5, 10, 20, or 30 mg/kg daily for 30 days. Eight normal and eight diseased, untreated rats served as placebo controls. The parameters studied were (a) measurement of hindpaw swelling, (b) radiometric assessment of vertebral growth, (c) vertebral trabecular density, (d) weight control and nutritional status. At the end of the investigational period, AA-rats on no therapy had severe osteopenia and growth retardation. Treatment with CsA, 2.5 mg/kg, was ineffective, but doses between 5 and 20 mg/kg prevented the development of articular and osseous lesions and normalized growth. A catch-up phenomenon was also observed. The 20 mg/kg dose showed no better effect than 10 mg/kg, and 30 mg/kg produced a significant reduction in bone density and skeletal growth, an effect thought to be toxic in nature. Body weight paralleled growth profiles, and average food consumption was stable in all groups with the exception of somewhat low records in the animals receiving 30 mg/kg. A comparison with classical features of human juvenile arthritis indicated that the clinical and radiological profiles concerning joint swelling, osteopenia, skeletal growth, and response to treatment, occur in a similar fashion, although it cannot be inferred that the operating mechanisms are common to both situations. It is concluded that skeletal growth measurements may represent a sensitive additional parameter in the evaluation of experimental arthritis and its response to potential therapeutic agents.

Adult rat cardiomyocytes in long-term culture express type 1 insulin-like growth factor (IGF) receptors. In contrast to insulin receptors, type 1 IGF receptors are up-regulated during culturing. IGF-I added to the cells at plating increased granular density and pseudopodia number per cell after 7 days. After 16 days, IGF-I-treated cells showed, as compared with controls, a dramatic increase of the number of newly built sarcomeres and were packed with myofibrils. At the same time, IGF-I suppressed the accumulation of smooth muscle alpha-actin (sm-alpha-actin) in a dose-dependent manner. Under the conditions of this in vitro system, growth hormone had no effect on cell morphology or sm-alpha-actin. sm-alpha-Actin, a nonsarcomeric isoform of actin expressed in early fetal cardiac development, reappears both during long-term culture of adult rat cardiomyocytes and during heart hypertrophy. This study shows that type 1 IGF receptors are up-regulated in adult rat cardiomyocytes in long-term culture and that IGF-I enhances myofibril development and concomitantly down-regulates sm-alpha-actin. This protein forms stress-fiber-like structures and may temporarily serve as a scaffold for the formation of new sarcomeres until myofibrils have developed throughout the cell and the scaffold is no longer needed. Our findings thus allow us to propose another hypothesis for the mechanism leading to overload heart hypertrophy.

Day 1 human colostrum contains 5 times more IGF I than IGF II. By day 3 postpartum, IGF I drops by 80% to constant levels whereas IGF II increases 3-fold up to day 7. Colostrum contains mainly IGFBP-2, little IGFBP-3 and no detectable IGFBP-1 or IGFBP-4. IGFBP-2 rises 20-fold up to day 6 of lactation. The major IGFBPs of newborn serum are IGFBP-2, -3 and -4. Early maternal serum contains only small amounts of IGFBP-2 and -3 and no detectable IGFBP-4. The pronounced differences between the IGFBP patterns of colostrum and early maternal serum suggest that IGFBP-2 does not pass from maternal blood into colostrum but is produced and secreted by mammary tissue itself. On the other hand, most of the IGF I, but not IGF II, in day 1 colostrum appears to stem from the maternal circulation.

Our results show that an insulin-like growth factor binding protein, IGFBP-3, purified from rat serum, is an inhibitor of chick embryo fibroblast (CEF) growth. It abolished DNA synthesis in CEF stimulated by IGF-I as well as by human serum. Rat IGFBP-3 and IDF45 (an inhibitory diffusible factor secreted by mouse cells) had the same activities, confirming that they have an intrinsic capacity to inhibit serum stimulation and may be considered as growth inhibitors. Our data show that inhibition by IGFBP-3 of serum stimulation was not simply the result of its inhibition of IGF present in the serum: 1) While anti-IGF-I IgG was able to completely inhibit stimulation induced by added IGF-I, it did not decrease stimulation induced by 1% human serum. Anti-IGF-II IgG inhibited the stimulation induced by added IGF-II, but only 25% decreased the stimulation induced by 0.7% serum. The percent inhibition was not significantly increased when the concentration of serum was decreased to 0.2%, which induced 140% stimulation of DNA synthesis; 2) stimulation by 0.2% serum was much more inhibited by IGFBP-3 than by IgG anti IGF-II; 3) after separation of IGF-I and IGF-II from serum by chromatography of acidified serum proteins on BioGel P150, the remaining serum proteins (with a molecular mass greater than 45 kDa) which were depleted in IGF-I and -II (verified by RIA determination) still stimulated DNA synthesis, and this stimulation was 80% inhibited by IGFBP-3.

Isolated cells produce insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Two distinct cell types were studied with regard to IGFBP-2 expression: (i) rat hepatocytes, which produce IGF I at a high rate and thus regulate its plasma concentration; and (ii) rat osteoblasts, which are targets of IGF I action. IGFBP-2 expression is low in hepatocytes prepared from normal adult rats and high in calvaria cells from newborn rats. Retinoic acid stimulates IGFBP-2 production by liver cells. Insulin suppresses both basal and retinoic acid-induced IGFBP-2 mRNA expression in hepatocytes and has no such effect on osteoblasts. Retinoic acid and insulin regulate IGFBP-2 expression in a tissue-specific manner.

Tumor necrosis factor alpha (TNF-alpha), a major mediator of inflammation, also possesses a wide pleiotropism of actions, suggesting its involvement in physiological conditions. TNF-alpha mRNA is present in mouse embryonic tissues and also in fetal thymus and spleen. Repeated injections of a monospecific polyclonal rabbit anti-mouse TNF-alpha antibody in mice, starting either during pregnancy or at birth, led to a severe but transient growth retardation, already present at birth, reaching a 35% decrease in body weight at 3 wk, with complete recovery at 8 wk. The insulin growth factor I (IGF-I) blood levels were decreased to about 50%; growth hormone release and other endocrine functions were unaltered. A marked atrophy of the thymus, spleen, and lymph nodes was also observed, with lymphopenia and impaired development of T and B cell peripheral lymphoid structures. The pathways involving TNF-alpha in IGF-I release and early body growth are probably distinct from those by which TNF-alpha participates in early development of lymphoid tissues, where its low physiological release may contribute to enhance lymphoid cell expansion.

Three insulin-like growth factor binding proteins (IGFBP) with apparent molecular masses of 24, 28-30, and 30 kDa, nonreduced, have been isolated from human serum. The 15 NH2-terminal amino acids of the 24-kDa binding protein are identical with those of the 30-kDa BP. The apparent molecular mass of the latter is reduced to 24 kDa by N-glycanase, suggesting that the 30-kDa BP is the glycosylated form of the isolated 24-kDa BP. The complete amino acid sequences derived from the cloned cDNAs represent two new IGFBPs. They are tentatively termed IGFBP-4 and -5. The prepeptide sequences of BP-4 and -5 contain 27 and 21, the mature proteins 213 and 237 amino acids, respectively (Mr = 22,610 and 25,980). The NH2- and COOH-terminal thirds of BP-4 and -5 display pronounced homology to the other three human BPs. 16 of the 16-20 cysteines and 37 of the 213-289 amino acids (12.8-17.1%) are conserved in all five mature BPs. 10 amino acid positions located in the NH2-terminal region and shared by BP-1, -2, -3, and -5 are different in BP-4. These differences may account for the preferential affinity of BP-4 for IGF II. A most intriguing homology exists between the COOH-terminal quarter of the five IGFBPs, 10 repetitive domains of human thyroglobulin, a gastrointestinal tumor-associated antigen, and the invariant chain of the class II histocompatibility antigen. The cDNAs of five human IGFBPs are now available. They will allow their expression and production in sufficient quantities for in vivo studies to unravel their role in growth and metabolism.

The mechanism of tumor-associated hypoglycemia was investigated in 10 (six hypoglycemic and four normoglycemic) southern African blacks with hepatocellular carcinoma. The mean basal blood glucose concentration was significantly lower (2.4 +/- 0.1 v 3.6 +/- 0.2 mmol/L; P less than .01) and steady-state exogenous glucose requirements were increased fourfold (3.6 +/- 0.6 v 0.97 +/- 0.2 mg/kg/min; P less than .01) in the hypoglycemic compared with the normoglycemic patients. Plasma insulin and C-peptide levels were suppressed to the lower limit of sensitivity of each of the assays in both groups of patients. The concentrations of insulin-like growth factors (IGF) I and II were lower (19 +/- 1.6 v 25 +/- 4.6 insulin-like growth factors (IGF) I and II were lower (19 +/- 1.6 v 25 +/- 4.6 ng/L) and higher (230 +/- 42 v 173 +/- 40 ng/L), respectively, in the hypoglycemic patients, although the differences were not statistically significant. Of the counterregulatory hormones measured, only the growth hormone (GH) concentration was significantly lower in the hypoglycemic patients (0.9 +/- 0.2 v 18.6 +/- 5.6 micrograms/L; P less than .01). Correction of the plasma GH level into the high-normal physiological range in two hypoglycemic patients failed to reduce steady-state exogenous glucose requirements. However, the glucose requirements were reduced from 2.6 to 1.1 mg/kg/min in the same two patients when "acromegalic" plasma concentrations of GH were achieved. We conclude that steady-state glucose requirements are increased in black patients with hypoglycemia complicating hepatocellular carcinoma, and that short-term correction of the associated hyposomatotropism fails to reduce the enhanced requirements.

Insulin-like growth factors (IGF) I and II produce acute insulin-like effects or promote growth indices in hypophysectomized rats, depending on their mode of administration. Intravenous bolus injections of IGF I and II, like insulin, lower the blood sugar level and lead to a pronounced stimulation of glycogen synthesis in skeletal muscle. The two factors are equipotent in this respect. Continuous subcutaneous infusions of IGF I or II over six days have no hypoglycaemic effect. They mimic the effects of growth hormone, increasing the width of the tibial epiphysis and stimulating the thymidine-incorporating activity of costal cartilage in the absence of growth hormone. IGF I (identical to somatomedin C) is more potent than IGF II and causes a dose-dependent increase in body weight at concentrations where IGF II is still ineffective. The absence of acute insulin-like effects in long-term experiments is explained by the presence in serum of highly specific carrier proteins that interfere with the insulin-like properties of IGF I and II and restrict their capillary permeability. Growth hormone induces the formation of both IGF and the major IGF carrier protein in the liver. Thus, while IGFs mediate the actions of growth hormone on growth, growth hormone appears to modulate these actions via IGF carrier proteins.

The goal of this study was to find out whether GH or insulin regulate the mRNA expression of the fetal binding protein of insulin-like growth factor (IGFBP-2). Primary hepatocytes from adult rats were used as a test system. IGFBP-2 mRNA was abundant in cells cultured in the absence of hormones and markedly reduced in cultures containing insulin. Addition of GH had no effect on IGFBP-2 mRNA levels although the cells are responsive to GH as demonstrated by a GH mediated elevation of IGF l mRNA levels. Half-maximal down-regulation of IGFBP-2 mRNA levels occurred at an insulin concentration of 1 to 2 x 10(-10) M. The finding that insulin is a potent negative regulator of hepatic IGFBP-2 mRNA levels suggests a physiologically important regulatory link between the two hormones insulin and IGF l.

Serum concentrations of insulin-like growth factor 1 (IGF-1) and growth hormone were measured in 25 cats with untreated diabetes mellitus (11 of which were used for follow-up measurements, one to three, four to eight, nine to 12 and 13 to 16 weeks after their treatment with insulin began), 14 diabetic cats that had previously been treated with insulin, and seven diabetic cats that also had hypersomatotropism, two of which had not previously been treated with insulin; 18 healthy cats were used as controls. In the untreated diabetic cats the concentration of IGF-1 ranged from 13.0 to 433.0 ng/ml (median 170.5 ng/ml), which was significantly lower than the concentrations in the control cats (196.0 to 791.0 ng/ml, median 452.0 ng/ml). Their IGF-1 concentrations increased significantly when they were treated with insulin and after four to eight weeks were not different from those in the control cats. In the diabetic cats that had previously been treated with insulin the IGF-1 concentrations were 33.0 to 476.0 ng/ml (median 316.0 ng/ml), which was significantly lower than the concentrations in the control cats, but significantly higher than in the untreated diabetic cats. The IGF-1 concentrations in the two previously untreated diabetic cats with hypersomatotropism were low and low-normal but increased markedly after treatment with insulin. In the five previously treated cats with hypersomatotropism the concentration of IGF-1 was above the normal range. The concentrations of growth hormone in the treated and untreated diabetic cats without hypersomatotropisms were not significantly different and there was an overlap in its concentrations in the diabetic cats with and without hypersomatotropism.

Wafer level packaging (WLP) technologies are cost effective packaging solutions which are used increasingly. Second level reliability, i.e. mainly the thermo-mechanical reliability during thermal cycling, is a major concern of WLP. To avoid excessive solder straining, solder balls have been replaced by resilient interconnects, which can adopt the main part of the thermal mismatch deformation. One solution combining an increased reliability on module level with advantages in processing and the capability of full wafer level test and burn-in is ELASTecreg (ELASTec hArr Elastic-bump on Silicon Technology), particularly developed for memory products. The new failure risks are mainly related to fatigue of the metallic redistribution layer (RDL). Parametric studies using finite element analyses (FEA) were performed to avoid excessive straining of the metal lines. A balance of metal straining and solder straining had to be achieved. Comparisons were made for different soft bump layouts and RDL patterns. Optimal solutions figured out by FEA were also investigated experimentally by thermal cycle tests. However, the thermo-mechanical characteristics like stress-strain behaviour and fatigue resistance of the metallic films are the most important parameters for reliability predictions. In particular, the elastic-plastic properties of thin metallic Cu and Ni films are shown to depend on features like film thickness, grain size and orientation, resulting in a thin film strength exceeding the bulk strength of the same metal by several hundred percent

A wafer level packaging technology ELASTecreg has been developed; which uses a resilient bump contact system. The advantages are twofold; because on the one hand the elastic contact system simplifies wafer probing and on the other hand the elastic interconnects allow an increase in board level reliability. Excessive solder bump straining caused by the mismatch of thermal expansion coefficients (CTE) between silicon and organic board materials can be avoided because of the compliance of the contact system, which can take over the main part of the mismatch deformation. Since the electrical connection is made by an electrodeposited copper/nickel redistribution layer (RDL), placed on top of the bump surface, other failures risks than solder fatigue emerge which were avoided by parametric studies using finite element analyses (FEA). The thermo-mechanical characteristics like stress-strain behavior and fatigue resistance of the RDL metallic films are the most important parameters for reliability predictions by FEA, discussed in some detail. The FEA based prediction that the fatigue performance of a spiral RDL layout is superior is proven experimentally and other reliability test data is provided

A powerfully instrumented, reliable, low -cost, and 3 -axis stabilized nanosatellite is being developed as part of the Air Force University Nanosatellite -3 Program. The Thunderstorm Effects in Space: Technology (TEST) nanosatellite imple ments a new, highly modular satellite bus structure and common electrical interface that is conducive to satellite modeling, development, testing, and integration flow. TEST is a low -cost ($0.2 M) nanosatellite (30kg) in final development by Taylor Univer sity and the University of Illinois. TEST implements a variety of plasma, energetic particle, and remote sensing instrumentation with the objective of understanding how lightning and thunderstorms influence the upper atmosphere and the near -space environme nt. The TEST modular design and instrumentation challenges portions of satellite systems (such as future DOD DMSP and NASA LWS Geospace Missions), while complementing large multi -probe and remote sensing programs. TEST includes a variety of proven instrume ntation: two 1m Electric Field (EP) probes, a thermal plasma density Langmuir Probe (LP), a 5 to 100 kHz Very Low Frequency (VLF) Receiver, two large geometric factor cooled ( -60 ° C) Solid State Detector (SSD) spectrometers for energetic electrons and ions (10 keV< E

The formation of voids in small solder volumes, e.g. flip-chip-soldered electronic components, is of vital interest to determine their reliability. The aim of the study was to understand the physical and chemical reasons for void formation in small solder volumes, the determination of void diameters depending on soldering temperature and flux content. A further investigation was made to define the strength of the solder balls depending on void diameter and void distribution. The diameter and the location of the voids was measured by X-ray-detection. The results show an increase of voids with increasing soldering time at constant temperature and a rapid decrease of void diameter at a soldering time nearby 60 sec followed by a slower increase of voids. The distribution of void diameter shows a great amount of small voids and only some big voids. The distribution of the void diameter is a skew distribution. The shear strength of the soldered joints shows only a little influence on the voids amount. These results give hints for the optimized time-temperature-curves for the best soldering profile. Further investigations are necessary to determine the influence of the voids to thermomechanical stresses and vibration behavior.

Tamoxifen is the endocrine treatment of choice for all stages of estrogen receptor (ER)-positive breast cancer, and it is the first drug approved to reduce the incidence of breast cancer in high-risk women. Unfortunately, tamoxifen also possesses some estrogen-like effects in the uterus that cause a modest increase in the risk of endometrial cancer. GW5638 is a tamoxifen derivative with a novel carboxylic acid side chain with no uterotropic activity in the rat (Willson et al., J Med Chem, 1994, 37:1550-1552). We have compared and contrasted the actions of 4-hydroxytamoxifen (4-OHT, the active metabolite of tamoxifen) with GW7604 [the presumed metabolite of GW5638 in breast (MCF-7) and endometrial (ECC-1) cell lines in vitro]. GW7604 did not cause the growth of ECC-1 cells at any concentration (10(-11)-10(-6) M), but 4-OHT was weakly estrogen-like at low concentrations (10(-11)-10(-10) M). Compounds (10(-7) M) blocked the growth promoting action of estradiol (10(-10) M) in both ECC-1 and MCF-7 cells. Western blotting was used to show that GW7604 and raloxifene did not affect ER levels significantly, compared with controls, in MCF-7 cells; whereas the pure antiestrogen ICI182,780 decreased ER levels (P0.05). An assay system was used that can classify compounds into tamoxifen-like, raloxifene-like, or pure antiestrogens. The assay depends on the activation of the transforming growth factor alpha (TGFalpha) gene in situ by wild-type or D351Y mutant ER stably transfected into MDA-MB-231 cells (MacGregor-Schafer et al., Cancer Res, 1999, 59:4308-4313). GW7604 inhibited both estradiol (10(-9) M) and 4-OHT (10(-8), 10(-7) M) induction of TGFalpha in a concentration related manner (10(-9)-10(-6) M). GW7604 and raloxifene stimulated TGFalpha with the D351Y ER. In contrast, ICI 182,780 (10(-6) M) did not initiate TGFalpha and blocked the induction of TGFalpha with GW7604, raloxifene, and 4-OHT in D351Y-transfected cells. Using computer-assisted molecular models of ER complexes, we found that the antiestrogenic side chain of 4-OHT weakly interacted with the surface amino acid 351 (aspartate), but the carboxylic acid of GW7604 caused a strong repulsion of aspartate 351. We propose that GW7604 is less estrogen-like than 4-OHT, because it disrupts the surface charge around aa351 required for coactivator docking in the 4-OHT:ER complex. This charge is restored in the D351Y ER, thus converting GW7604 from an antiestrogen to an estrogen-like molecule.

The so-called somatomedin hypothesis (1) states that growth hormone (GH) acts on skeletal tissues indirectly by inducing the production of a growth factor, somatomedin, circulating in blood and mediating the effects of GH on growth. After the isolation and amino sequencing of insulin-like growth factor I (IGF I) and its biological characterization it became evident that this polypeptide was the postulated somatomedin. IGF I consists of 70 amino acids and has a molecular weight of 7649 (2). It is mainly produced and secreted by the liver. However, many other tissues synthesize IGF I which acts locally on these tissues. The significance of endocrine versus auto-/paracrine actions of IGF I is still under debate. Two recent publications provide evidence that in mice liver-derived circulating IGF I is not required for growth (3, a). IGF I tissue expression is under the control of GH (5), but other factors, like insulin or nutrition, also influence IGF I production. Both endogenous and administered IGF I mimic trophic effects of pituitary GH. In contrast, some effects of administered IGF I on intermediary metabolism are opposite to those of GH (6, 7). Moreover, the two hormones act by different mechanisms, which implies that endogenous IGF I induced by GH does in general not mediate the effects of GH on intermediary metabolism. Cardiac effects of IGF were first investigated by Meuli and Froesch in 1975 in the perfused rat heart (8). IGF, like insulin, stimulated glucose transport and lactate production. The biological potency ratio between IGF and insulin in this model was higher than in adipose tissue. Based on this finding and on competitive binding studies, it was concluded that insulin and IGF act on the heart separately via the insulin and the type 1 IGF receptor, respectively (9). In 1986 Borner and Froesch showed that IGF I stimulated the contractility of the isolated perfused rat heart (Figure 1). Since the availability of pure IGF I was limited at that time the positive inotropic effects of IGF I could not be extensively tested, and the data remained unpublished.

Conflicting data exist as to whether insulin-like growth factor I (IGF-I) messenger RNA (mRNA) and peptide are expressed within chondrocytes. This question is pertinent to the mode of GH action on longitudinal bone growth. We have, therefore, investigated this issue in normal rats and in hypophysectomized rats treated for 24 h with GH or IGF-I using in situ hybridization and immunohistochemistry. Serum IGF-I, body weight, and tibial growth plate, but not articular cartilage, height increased with both treatments. Both IGF-I mRNA and IGF-I immunoreactivity occurred in all chondrocyte layers of growth plate and articular cartilage. The percentage of cells with IGF-I mRNA correlated well with IGF-I immunoreactivity under all experimental conditions. In normal rats, IGF-I expression was highest in the upper hypertrophic zone in growth plate (68-71%) and articular cartilage (32-34%). Hypophysectomy, GH, or IGF-I did not significantly affect this percentage. In the stem cell and proliferative and lower hypertrophic zones of growth plate, hypophysectomy dramatically reduced the percentage of labeled chondrocytes, and GH restored it. IGF-I increased IGF-I mRNA and immunoreactivity only in the proliferative zone. In articular cartilage, both remained unchanged under all experimental conditions. Together with our previous finding that GH infusion of hypophysectomized rats enhances chondrocyte maturation at all differentiation stages, the present results are compatible with the idea that IGF-I produced by all chondrocyte layers under the influence of GH mediates chondrocyte maturation and thus longitudinal bone growth in an autocrine/paracrine manner.

We recently showed that insulin-like growth factor-binding protein-4 (IGFBP-4) proteolytic degradation in ovine preovulatory ovarian follicles is IGF-dependent and regulated by the heparin-binding domain (HBD) from IGFBP-3 and from connective tissue growth factor (CTGF), heparan/heparin-interacting protein (HIP), and vitronectin. The present study investigated regulation of IGFBP-4 proteolytic degradation in porcine, bovine, and equine ovarian preovulatory follicles. Follicular fluid from such preovulatory follicles contains proteolytic activity, degrading exogenous IGFBP-4. An excess of IGF-I enhanced IGFBP-4 degradation. In contrast, IGFBP-2 or -3 or monoclonal antibodies against IGF-I or -II dose-dependently inhibited IGFBP-4 degradation, and IGF-I or -II reversed this inhibition in a dose-dependent manner. Heparin-binding peptides derived from the C-terminal domain of IGFBP-3 or -5 inhibited IGFBP-4 degradation. Other heparin-binding peptides derived from CTGF, HIP, and vitronectin also inhibited IGFBP-4 degradation, except in porcine follicles. Finally, IGFBP-3 that was mutated in its HBD was less effective at inhibiting IGFBP-4 degradation. Thus, in bovine, porcine, and equine preovulatory follicles, IGFBP-4 proteolytic degradation both depends on IGFs and is inhibited by peptides containing HBD. Overall, these results suggest that during terminal development of follicles to the preovulatory stage in domestic animal species, the increase in IGF bioavailability might enhance IGFBP-4 degradation. In contrast, in atretic follicles, the decrease in IGF bioavailability, resulting partly from the increase in IGFBP-2 (sow, heifer, mare) and IGFBP-5 (heifer) expression would participate in the decrease of IGFBP-4 degradation. In bovine atretic follicles, IGFBP-5 would also strengthen the inhibition of IGFBP-4 degradation by direct interaction of its HBD with the protease. The involvement of other HBD-containing proteins in the modulation of intrafollicular proteases degrading IGFBP-4 remains to be investigated.

The insulin-like growth factors (IGF) I and II mediate endocrine and auto-/paracrine effects of growth hormone (GH) on cell growth, cell differentiation and tissue repair. Despite their insulin-like actions in vitro, they do not play a significant role in the acute regulation of substrate metabolism, as compared to insulin and growth hormone. In contrast, administration of IGF I in vivo causes a broad spectrum of effects: it increases insulin sensitivity, improves the lipid profile, supports protein anabolism, enhances kidney function and bone turnover, and exerts beneficial effects on the cardiovascular system. Understanding of the mechanisms underlying these effects provides the basis for potential therapeutic use of IGF I.