D2 D4 Research Articles

A “breathing” dendritic molecule—conformational fluctuation induced by external stimuli

A series of PAMAM dendrimers peripherally modified with tetraphenylethylene (TPE), a typical chromophore with emission enhancement in aggregate, were synthesized (D0–D4). The dendrimers are molecularly dissolved in toluene, a selective solvent. The intramolecular rotation of TPE is depressed by the restrained conformation caused by the congested packing periphery in higher generation dendrimers (D2–D4), which results in a remarkable emission enhancement. The fluorescence quantum yield increases more than 10-fold in D3 and D4 dendrimers compared with a model compound. Furthermore, the emission intensity of dendrimers can be tuned by changing the temperature or solvent conditions, which alters the conformational confinement. Unimolecular spheres with multiple chromophores and conformation-controlled emission are reminiscent of proteins with modulated sizes and photofunctions. Developing these dendritic systems will promote the research of multi-functionalized chromophores and lead to their potential applications in biomimics and sensors.

The Importance of the Hook Region of the Cochlea for Bone-Conduction Hearing

For the most part, the coiled shape of the cochlea has been shown to have only minor importance for air-conducted hearing. It is hypothesized, however, that this coiled shape may play a more significant role for the bone-conducted (BC) route of hearing, through inertial forces exerted by the middle ear and cochlear fluid, and that this can be tested by comparing the results of applying BC stimuli in a variety of different directions. A three-dimensional finite element model of a human middle ear coupled to the inner ear was formulated. BC excitations were simulated by applying rigid-body vibrations normal to the surface of the basilar membrane (BM) at 0.8 (d1), 5.8 (d2), 15.6 (d3), and 33.1 (d4) mm from the base of the cochlea, such that relative motions of the fluid within the cochlea produced excitations of the BM. The vibrational direction normal to the BM surface at the base of the cochlea (d1) produced the highest BM velocity response across all tested frequencies—higher than an excitation direction normal to the BM surface at the nonbasal locations (d2–d4), even when the stimulus frequency matched the best frequency for each location. The basal part of the human cochlea features a well-developed hook region, colocated with the cochlear vestibule, that features the largest difference in fluid volume between the scala vestibuli (SV) and scala tympani (ST) found in the cochlea. The proximity of the hook region to the oval and round windows, combined with it having the biggest fluid-volume difference between the SV and ST, is thought to result in a maximization of the pressure difference between the SV and ST for BC stimuli normal to the BM in this region, and consequently a maximization of the resulting BM velocity.

Cocaine Inhibits Dopamine D2 Receptor Signaling via Sigma-1-D2 Receptor Heteromers

Under normal conditions the brain maintains a delicate balance between inputs of reward seeking controlled by neurons containing the D1-like family of dopamine receptors and inputs of aversion coming from neurons containing the D2-like family of dopamine receptors. Cocaine is able to subvert these balanced inputs by altering the cell signaling of these two pathways such that D1 reward seeking pathway dominates. Here, we provide an explanation at the cellular and biochemical level how cocaine may achieve this. Exploring the effect of cocaine on dopamine D2 receptors function, we present evidence of σ1 receptor molecular and functional interaction with dopamine D2 receptors. Using biophysical, biochemical, and cell biology approaches, we discovered that D2 receptors (the long isoform of the D2 receptor) can complex with σ1 receptors, a result that is specific to D2 receptors, as D3 and D4 receptors did not form heteromers. We demonstrate that the σ1-D2 receptor heteromers consist of higher order oligomers, are found in mouse striatum and that cocaine, by binding to σ1 -D2 receptor heteromers, inhibits downstream signaling in both cultured cells and in mouse striatum. In contrast, in striatum from σ1 knockout animals these complexes are not found and this inhibition is not seen. Taken together, these data illuminate the mechanism by which the initial exposure to cocaine can inhibit signaling via D2 receptor containing neurons, destabilizing the delicate signaling balance influencing drug seeking that emanates from the D1 and D2 receptor containing neurons in the brain.

Dopaminergic modulation of tonic but not phasic GABAA-receptor-mediated current in the ventrobasal thalamus of Wistar and GAERS rats

Activation of GABAA receptors by GABA causes phasic and tonic conductances in different brain areas. In the ventrobasal (VB) thalamus, tonic inhibition originates from GABA acting on extrasynaptic receptors. Here we show that dopamine (DA), the D2-like agonist quinpirole and the selective D4R agonist PD-168,077 decrease the magnitude of the tonic GABAA current while D1-like agonist SKF39383 lacks any significant effects in VB neurons of Wistar rats. On the other hand, DA and D1/D2 receptor activation does not alter phasic GABAA conductance. As we previously reported that an increased tonic GABAA current in VB neurons is critical for absence seizure generation, we also investigated whether D2–D4 receptor activation is capable of normalizing this aberrant conductance in genetic absence epilepsy rats from Strasbourg (GAERS). Quinpirole and PD-168,077 selectively reduces tonic GABAA current as in normal rats. Therefore, it is conceivable that some DA anti-absence effects occur via modulation of tonic GABAA current in the VB.

Mushrooms not only Produce Vitamin D2 but can also Produce Vitamin D3 and Vitamin D4

It has been previously reported that mushrooms have the ability to produce both vitamin D2 and vitamin D4. Using high performance liquid chromatography with a photodiode ultraviolet (UV) absorbance detector we detected several vitamin Ds and provitamin Ds in mushroom samples. UV irradiated mushroom powder (Monterey Mushroom) extracted with methanol was run on a Zorbax C18 column along with standards for vitamin D2 (D2)and vitamin D3 (D3). The resulting chromatograms revealed 3 separate peaks with retention times of 11.2, 12.9 and 13.9 minutes that were similar to retention times for standards of D2, D3 and vitamin D4 (D4), respectively. Additionally, isolated pro‐vitamin D from a shitake mushroom sample was run on a Zorbax ODS column along with standards for pro‐vitamin D2 (pro‐D2; ergosterol) and provitamin D3 (pro‐D3; 7‐dehydrocholesterol). The resulting chromotograms revealed three separate peaks with retention times of 7.4, 8.2 and 8.8 minutes which were consistent with retention times for standards of pro‐D2, pro‐D3 and pro‐D4, respectively. The UV absorption spectra for D2, D3, D4, pro‐D2, pro‐D3 and pro‐D4 in the mushroom samples matched the UV absorption spectra of a 5,6‐cis triene of vitamin D and a 5,7‐diene of pro‐vitamin D standards. These results demonstrate that in addition to vitamin D2, mushrooms can also produce vitamin D3 and vitamin D4.

Structural and thermochronometric evidence for multi-stage exhumation of southern Syros, Cycladic islands, Greece

The Attic–Cycladic metamorphic-core complex province was formed during Miocene to recent regional back-arc extension in response to slab-rollback and gravitational collapse. The development of several metamorphic-core complexes along extensional low-angle detachment faults resulted in the exhumation of lower-plate rocks and the tectonic denudation of the upper plate that is only sparsely exposed throughout the Aegean Sea. One of these areas is in southern Syros where the tectonic configuration includes three tectonometamorphic units separated by two detachment faults. The lower-plate Cycladic Blueschist Unit underwent late Cretaceous–Eocene HP/LT metamorphism and subsequent greenschist-facies overprint during Oligo-Miocene times. The tectonically overlying greenschist-facies Upper Unit is a tectonic sliver between the Cycladic Blueschist Unit and the structurally highest unit, the Vari Unit, which is dominated by quartzofeldspathic gneisses that are affected by four distinct deformation events (D1–D4). The late Cretaceous upper greenschist-facies D1 episode is related to late Cretaceous–Eocene subduction while D2–D4 fabrics were formed in response to late Cenozoic extension and exhumation. Field relations and structural data suggest that the late Miocene brittle Vari Detachment juxtaposes both Vari Unit and Upper Unit against the Cycladic Blueschist Unit. Mylonitic rocks observed at the base of Vari Unit along the contact with Upper Unit and zircon and apatite (U–Th)/He thermochronometry corroborate this scenario with lower-plate Cycladic Blueschist Unit rocks recording rapid cooling at ~8–10Ma. In contrast, cooling ages from the Vari Unit cluster at ~13–15Ma, indicating rapid exhumation coeval with activity along the Livadi Detachment on the neighboring island of Tinos. These data document new evidence that Vari Unit was affected by a major middle Miocene phase of exhumation and an older semi-brittle episode, both unrelated to late Miocene detachment faulting, revealing that crustal extension occurred in multiple stages and in a protracted episodic fashion similar to other parts of the Cyclades.

Effects of pyrolysis temperature on changes in fuel characteristics of biomass char

The fuel characteristics, the combustion profile, and the kinetic study of char that had been pyrolyzed at 300−500 °C were investigated for RH (rice husks), WC (wood chips), and WP (wood pellets). When a higher pyrolysis temperature was used, the calorific value became proportional to the fuel ratio and inversely proportional to that of the volatile matter. The pyrolysis temperature increased, the coal-band migrated toward that of coal. The number of DTG (differential thermogravimetric) peaks decreased from two to one with an increase in pyrolysis temperature. When WP was blended with coal, the unprocessed samples (WP Raw) showed two DTG peaks for all co-combustion ratios, but WP 400 (pyrolyzed at 400 °C) showed one DTG peak and a lower activation energy for all co-combustion ratios. It was observed that the combustion reaction mechanism of the WP Raw/coal-blended samples was similar to the third-order reaction model (O3) in the primary reaction (devolatilization stage), and to the diffusion model (D2–D4) in the secondary reaction (char combustion stage). On the other hand, it was thought that the secondary reaction of the WP 400/coal-blended samples had a reaction mechanism most similar to a first-order reaction (O1) at all co-combustion ratios.

Dietary values of astaxanthin and canthaxanthin in Penaeus monodon in the presence and absence of cholesterol supplementation: effect on growth, nutrient digestibility and tissue carotenoid composition

Penaeus monodon (mean initial wet weight 1·19 (SE 0·01) g) were fed seven diets in triplicate: a control diet (D1) without carotenoids; three diets formulated to supply 0·1 % astaxanthin alone (D2), 0·2 % astaxanthin alone (D3), and a combination of 0·1 % astaxanthin and 1 % cholesterol (D4); three diets with 0·07 % canthaxanthin alone (D5), 0·13 % canthaxanthin alone (D6), and a combination of 0·07 % canthaxanthin and 1 % cholesterol (D7). Weight gain (WG, %), specific growth rate (SGR, %/d) and survival were chosen as parameters of shrimp growth performance. Total antioxidant status (TAS), superoxide dismutase (SOD), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were chosen as indices of shrimp plasma antioxidant capacity. Meanwhile, digestibility, retention efficiency and tissue carotenoids were also investigated to determine the additive effect of cholesterol on the efficiency of astaxanthin and canthaxanthin. After 74 d rearing, WG and SGR of shrimp fed D2-D4 and D7 were higher than those of shrimp fed D1 (P < 0·05). Shrimp fed D4 had the highest survival. The apparent digestibility coefficients (ADC) of astaxanthin in D2-D4 were higher than those of canthaxanthin in D5-D7 (P < 0·05). Although ADC of astaxanthin were quite high (>98 %) in D2-D4 and no differences were found among them (P>0·05), the carotenoid retention efficiencies in the whole body, muscle and shell (D2-D3 treatments) were considerably low; however, cholesterol supplementation significantly improved the carotenoid retention efficiencies in the whole body, muscle and shell (D4 treatment). Accordingly, the addition of cholesterol also significantly enhanced the carotenoid contents of tissues. Shrimp fed supplemented carotenoid diets (D2-D7) had higher TAS and lower SOD, ALT and AST than shrimp fed D1 (P < 0·05). A low dissolved oxygen stress test was conducted for 7 d after the rearing trial and shrimp survival was also compared among the treatments. The survival of shrimp fed the diets supplemented with astaxanthin or canthaxanthin was higher than that of shrimp fed D1 during the stress test (P < 0·05). In conclusion, all data suggested that astaxanthin was better than canthaxanthin as the dietary carotenoid source in the commercial diet of P. monodon, and the supplement of cholesterol could positively enhance the efficiency of astaxanthin and canthaxanthin.

Dopamine polymorphisms and depressive symptoms predict foods intake. Results from a nationally representative sample

Depression and variation in dopamine related genes have both independently been associated with food consumption. Depressive symptoms could synergistically interact with genetic variation to influence food intake. We examined the interaction between high depressive symptoms and functional polymorphisms of dopamine transporter (SLC6A3), monoamine oxidase A (MAOA), dopamine receptor D2 (DRD2) and dopamine receptor D4 (DRD4) on intake of high-calorie sweet, high-calorie non-sweet, and low-calorie foods in the National Longitudinal Study of Adolescent Health (Add Health). Multivariate linear regression analyses were used to examine main effects of gene and depression symptoms and their interaction (genotype-by-high depression symptoms) on food categories. Applying a false discovery rate criterion for multiple comparisons indicated a statistically significant interaction for females with high depressive symptoms and the SLC6A3 gene, such that those with the SLC6A3 10/10 allele reported greater intake of high-calorie sweet foods than their counterparts high in depressive symptoms with the SLC6A3 any 9 allele (LS mean 10/10 allele = 2.5, SE = .13; LS mean any 9 allele = 1.8, SE = .13, p < .05). These findings highlight that the relationship between depression and food intake may vary as a function of genetic polymorphism. Further research is needed to confirm these findings.

Fucoxanthin exerts differing effects on 3T3-L1 cells according to differentiation stage and inhibits glucose uptake in mature adipocytes

Progression of 3T3-L1 preadipocyte differentiation is divided into early (days 0–2, D0–D2), intermediate (days 2–4, D2–D4), and late stages (day 4 onwards, D4-). In this study, we investigated the effects of fucoxanthin, isolated from the edible brown seaweed Petalonia binghamiae, on adipogenesis during the three differentiation stages of 3T3-L1 preadipocytes. When fucoxanthin was applied during the early stage of differentiation (D0–D2), it promoted 3T3-L1 adipocyte differentiation, as evidenced by increased triglyceride accumulation. At the molecular level, fucoxanthin increased protein expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), sterol regulatory element-binding protein 1c (SREBP1c), and aP2, and adiponectin mRNA expression, in a dose-dependent manner. However, it reduced the expression of PPARγ, C/EBPα, and SREBP1c during the intermediate (D2–D4) and late stages (D4–D7) of differentiation. It also inhibited the uptake of glucose in mature 3T3-L1 adipocytes by reducing the phosphorylation of insulin receptor substrate 1 (IRS-1). These results suggest that fucoxanthin exerts differing effects on 3T3-L1 cells of different differentiation stages and inhibits glucose uptake in mature adipocytes.

Structural and Functional Characterization of the Streptococcus pneumoniae RrgB Pilus Backbone D1 Domain

Streptococcus pneumoniae expresses on its surface adhesive pili, involved in bacterial attachment to epithelial cells and virulence. The pneumococcal pilus is composed of three proteins, RrgA, RrgB, and RrgC, each stabilized by intramolecular isopeptide bonds and covalently polymerized by means of intermolecular isopeptide bonds to form an extended fiber. RrgB is the pilus scaffold subunit and is protective in vivo in mouse models of sepsis and pneumonia, thus representing a potential vaccine candidate. The crystal structure of a major RrgB C-terminal portion featured an organization into three independently folded protein domains (D2-D4), whereas the N-terminal D1 domain (D1) remained unsolved. We have tested the four single recombinant RrgB domains in active and passive immunization studies and show that D1 is the most effective, providing a level of protection comparable with that of the full-length protein. To elucidate the structural features of D1, we solved the solution structure of the recombinant domain by NMR spectroscopy. The spectra analysis revealed that D1 has many flexible regions, does not contain any intramolecular isopeptide bond, and shares with the other domains an Ig-like fold. In addition, we demonstrated, by site-directed mutagenesis and complementation in S. pneumoniae, that the D1 domain contains the Lys residue (Lys-183) involved in the formation of the intermolecular isopeptide bonds and pilus polymerization. Finally, we present a model of the RrgB protein architecture along with the mapping of two surface-exposed linear epitopes recognized by protective antisera.

Open M2-branes with flux and the modified Basu–Harvey equation

The supersymmetric actions of closed multiple M2 branes with flux for the Bagger–Lambert (BL) and ABJM theories have been constructed recently by Lambert and Richmond (2009 J. High Energy Phys. JHEP10(2009)084). In this paper, we extend the construction to the case of open M2-branes with flux and derive the boundary conditions. This allows us to derive the modified Basu–Harvey equation in the presence of flux. As an example, we consider the Lorentzian BL model. A new feature of the fuzzy funnel solution describing a D2–D4 intersection is obtained as a result of the flux.

D2 and D4 dopamine receptor mRNA distribution in pyramidal neurons and GABAergic subpopulations in monkey prefrontal cortex: implications for schizophrenia treatment

D2 and D4 dopamine receptors play an important role in cognitive functions in the prefrontal cortex and they are involved in the pathophysiology of neuropsychiatric disorders such as schizophrenia. The eventual effect of dopamine upon pyramidal neurons in the prefrontal cortex depends on which receptors are expressed in the different neuronal populations. Parvalbumin and calbindin mark two subpopulations of cortical GABAergic interneurons that differently innervate pyramidal cells. Recent hypotheses about schizophrenia hold that the root of the illness is a dysfunction of parvalbumin chandelier cells that produces disinhibition of pyramidal cells. In the present work we report double in situ hybridization histochemistry experiments to determine the prevalence of D2 receptor mRNA and D4 receptor mRNA in glutamatergic neurons, GABAergic interneurons and both parvalbumin and calbindin GABAergic subpopulations in monkey prefrontal cortex layer V. We found that around 54% of glutamatergic neurons express D2 mRNA and 75% express D4 mRNA, while GAD-positive interneurons express around 34% and 47% respectively. Parvalbumin cells mainly expressed D4 mRNA (65%) and less D2 mRNA (15–20%). Finally, calbindin cells expressed both receptors in similar proportions (37%). We hypothesized that D4 receptor could be a complementary target in designing new antipsychotics, mainly because of its predominance in parvalbumin interneurons.

Roles of Fragile X Mental Retardation Protein in Dopaminergic Stimulation-induced Synapse-associated Protein Synthesis and Subsequent α-Amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) Receptor Internalization

Fragile X syndrome, the most common form of inherited mental retardation, is caused by the absence of the RNA-binding protein fragile X mental retardation protein (FMRP). FMRP regulates local protein synthesis in dendritic spines. Dopamine (DA) is involved in the modulation of synaptic plasticity. Activation of DA receptors can regulate higher brain functions in a protein synthesis-dependent manner. Our recent study has shown that FMRP acts as a key messenger for DA modulation in forebrain neurons. Here, we demonstrate that FMRP is critical for DA D1 receptor-mediated synthesis of synapse-associated protein 90/PSD-95-associated protein 3 (SAPAP3) in the prefrontal cortex (PFC). DA D1 receptor stimulation induced dynamic changes of FMRP phosphorylation. The changes in FMRP phosphorylation temporally correspond with the expression of SAPAP3 after D1 receptor stimulation. Protein phosphatase 2A, ribosomal protein S6 kinase, and mammalian target of rapamycin are the key signaling molecules for FMRP linking DA D1 receptors to SAPAP3. Knockdown of SAPAP3 did not affect surface expression of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) GluR1 receptors induced by D1 receptor activation but impaired their subsequent internalization in cultured PFC neurons; the subsequent internalization of GluR1 was also impaired in Fmr1 knock-out PFC neurons, suggesting that FMRP may be involved in subsequent internalization of GluR1 through regulating the abundance of SAPAP3 after DA D1 receptor stimulation. Our study thus provides further insights into FMRP involvement in DA modulation and may help to reveal the molecular mechanisms underlying impaired learning and memory in fragile X syndrome.

Démarche d’assurance qualité en chirurgie ambulatoire de la main

Objective To determine the level of satisfaction in terms of pain relief and comfort among patients receiving different postoperative analgesia protocols after hand surgery under regional anaesthesia in a day care unit. Methods Cohort study among patients after hand surgery under regional anaesthesia during two consecutive three months time periods, with patient stratification according to the expected pain level with different balanced analgesia protocols (group A: carpal tunnel, group B: other surgery without bone involvement, group C: bone surgery). A telephone survey, scoring analgesia and comfort, each with a numerical (0–10) scale was conducted on days 1 and 7. During the first period analgesia for groups A and B was the same (acetaminophen-dextropropoxyphene or acetaminophen-codein) and group C patients were treated with acetaminophen-ketoprofen-tramadol. In the second period analgesia was reduced for group A (acetaminophen alone) and increased for group B (acetaminophen-ketoprofen-tramadol) and group C (duration increased from 3 to 7 days). Results For carpal tunnel surgery, analgesia with acetaminophen alone was efficient, (Pain scale [PS] d0 = 2[0–10], PS d1 = 1 [0–10] and PS d2–d4 = 0,5 [0–10]). This surgery does not elicit important pain, there is no benefit in adding other analgesics. For group B, a significant improvement in postoperative pain was observed (postoperative d1 p < 0.03) with a major increase in side effects (2/57 vs 17/48 p < 0.001). For group C, therapeutic changes were ineffective (PS d0 = 2 vs 3.5 et PS d1 = 3 vs 5 [NS]) and we noticed an increase in side effects ( p < 0.05). One third of all patients are totally satisfied on day 7, logistic regression showing the role of unefficient analgesia in late postoperative period (PS > 2 between d2–d4). Between day 1 and day 7, 20% of the patients change their point of view, those who feel less satisfied on day 7 complained of a more severe postoperative pain between day 2 and 4 ( p < 0.001) and between day 5–7 ( p < 0.01). Conclusion For hand surgery on day case, quality of late postoperative analgesia (day 2-day 7) is strongly related to patient's satisfaction on day 7.

The effects of dietary fatty acids on liver fatty acid composition and Δ 6-desaturase expression differ with ambient salinities in Siganus canaliculatus

Δ 6-Desaturase (linoleoyl-CoA desaturase, EC 1.14.19.3) is the rate-limiting enzyme in the biosynthetic pathway of highly unsaturated fatty acid (HUFA). In this report, a Δ6 desaturase-like cDNA was cloned, and the relation of HUFA biosynthetic activity in liver with ambient salinity as well as dietary fatty acids was investigated in the euryhaline teleost Siganus canaliculatus. After the juveniles were fed four formulated diets (D1–D4) with different essential fatty acid composition (D1 with 23.49% HUFA, D2–D4 were HUFA-free, linoleic and α-linolenic acids account for 21.1% and 0.38%, 13.99% and 11.64%, 18.31% and 5.82% of the total fatty acids, respectively) for nine weeks, the growth performance showed no difference among groups in brackish water (10 ppt) or seawater (32 ppt) ( P > 0.05). Comparing liver fatty acids with fish fed D1, the content of arachidonic acid in fish fed D2 or D4 was significantly higher in 10 ppt ( P < 0.05), but showed no difference in 32 ppt; the contents of eicosapentaenoic (EPA), docosapentaenoic (DPA) and docosahexaenoic (DHA) acids in 10 ppt, as well as EPA in 32 ppt in fish fed D3 showed no difference, whereas those of DPA and DHA were significantly lower in 32 ppt ( P < 0.05). These data suggest that S. canaliculatus may convert linoleic and α-linolenic acids into HUFA and such a capacity was stronger in low salinity than that in high salinity. Consistent with this, the liver levels of Δ6 desaturase mRNA in fish fed D2–D4 were generally higher than in fish fed D1 in both salinities, and the total expression level in 10 ppt was about 1.56 times of that in 32 ppt, suggesting that transcriptional control of Δ6 desaturase is involved in such a HUFA biosynthesis. To our knowledge, this is the first report showing the relation of HUFA biosynthetic activity with ambient salinity in a euryhaline fish.

Thrusting and multiple folding in the Neoproterozoic Pan-African basement of Wadi Hodein area, south Eastern Desert, Egypt

Detailed field mapping and structural studies of the area around the mouth of Wadi Hodein, some 20 km west of Shalatein at the Red Sea coast in the south Eastern Desert of Egypt, revealed four phases of structural deformation (D1–D4) affecting the Neoproterozoic Pan-African basement rocks. D1 is related to arc–arc collision and is represented by ENE–WSW oriented megascopic upright open folds associated with low angle thrusts and mesoscopic tight, overturned and recumbent F1 folds. Kinematic indicators indicate thrusting towards the SSE. D2 is represented by NNW–SSE oriented megascopic and mesoscopic folds, which are tight, verge towards the WSW and display a left-stepping en echelon pattern. D3 includes major NNW–SSE trending sinistral shear zones that show subordinate reverse fault components and dip steeply towards the ENE. These sinistral shear zones are comparable with the Najd Fault System, as they display a similar sense of movement and relationships to earlier structures. Therefore, they are interpreted to be the continuation of the Najd Shear System in southern Egypt. D2 and D3 are related to accretion of east and west Gondwana. D4 is represented by E–W oriented dextral faults with left-stepping segments. The first three deformation events are in agreement with the general evolutionary model for the East African Orogen in the Arabian–Nubian Shield that begins with NNW–SSE shortening, followed by ENE–WSW compression and subsequent deformation by the NNW–SSE striking Najd Fault System. The E–W dextral faults may be the conjugate shear fractures to the D3 NNW–SSE oriented sinistral wrench faults or are related to a subsequent event, D4. NW–SE oriented gold-bearing quartz veins originated during D1 and were subsequently deformed by D2–D4 events.

Novel Inhibitors for Murine and Human Leukemia Inhibitory Factor Based on Fused Soluble Receptors

Fusion proteins of the extracellular parts of cytokine receptors, also known as cytokine traps, turned out to be promising cytokine inhibitors useful in anti-cytokine therapies. Here we present newly designed cytokine traps for murine and human leukemia inhibitory factor (LIF) as prototypes for inhibitors targeting cytokines that signal through a heterodimer of two signaling receptors of the glycoprotein 130 (gp130) family. LIF signals through a receptor heterodimer of LIF receptor (LIFR) and gp130 and induces the tyrosine phosphorylation of STAT3 leading to target gene expression. The analysis of various receptor fusion and deletion constructs revealed that a truncated form of the murine LIF receptor consisting of the first five extracellular domains was a potent inhibitor for human LIF. For the efficient inhibition of murine LIF, the cytokine-binding module of murine gp130 had to be fused to the first five domains of murine LIFR generating mLIF-RFP (murine LIFR fusion protein). The tyrosine phosphorylation of STAT3 and subsequent gene induction induced by human or murine LIF are completely blocked by the respective inhibitor. Furthermore, both inhibitors are specific and do not alter the bioactivities of the closely related cytokines interleukin (IL)-6 and oncostatin M. The gained knowledge on the construction of LIF inhibitors can be transferred to the design of inhibitors for related cytokines such as IL-31, IL-27, and oncostatin M for the treatment of inflammatory and malignant diseases.

Vickers Hardness Investigation of Work-Hardening in Used NiTi Rotary Instruments

A contributing mechanism for clinical failure of NiTi rotary instruments might be excessive work hardening. Vickers hardness was measured with 300 gm load near the flutes in three regions (D2–D4, D6–D10, and D14 towards the shank) for nine representative clinically used ProFile GT instruments that had been axially sectioned (10 measurements in each region). Consistent values could not be obtained at D1. Minimum hardness occurred at D2 to D4, with means from 313 to 324 (SD from 7 to 16). Maximum hardness with means ranging widely from 330 to 481 was found beyond D14. Mean hardness at D2 to D4 was 320 for an as-received ProFile instrument. Because a mean Vickers hardness of 326 has been reported for a shape-memory NiTi orthodontic wire product, it can be concluded that the NiTi instruments did not experience substantial work hardening at D 2 to D4 during clinical use, in agreement with previous differential scanning calorimetric analyses.

Ten- and eleven-dimensional perspectives on N = 2 black holes

We give an 11- and 10-dimensional supergravity description of M5-branes wrapping 4-cylces in a Calabi–Yau manifold and carrying momentum along a transverse S1. These wrapped branes descend to a class of N = 2 black holes in 4 dimensions. Our description gives the conditions on the geometry interpolating between the asymptotic and near-horizon regions. We employ the ideas of geometric transitions to show that the near-horizon geometry in 10 dimensions is AdS2 × S2 × CY3 while in 11 dimensions it is AdS3 × S2 × CY3. We also show how to obtain the complete N = 2 black hole supergravity solution in 4 dimensions for this class of black holes starting with our 11-dimensional description. Finally, we generalize our results on the 10- and 11-dimensional near-horizon supergravity solution to the case of black holes carrying arbitrary charges (D0–D2–D4–D6 in type IIA description). We argue that the near-horizon geometry corresponding to wrapped D6 and D2 branes in 11 dimensions is AdS2 × S3 × CY3.