Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural dominance analysis and theory building in system dynamics

We provide a review of different approaches to linking model structure to observed behaviour with a particular view towards using models for theory building. We argue that theory building cannot be based upon pure simulation and model building alone: the inference from system dynamics models invariably uses concepts and analogies from simple feedback systems and models. Strengthening the analytical foundation for this inference will therefore have a direct impact on the strength of system dynamics as a theory-building tool. We identify four approaches to establish this link (traditional, pathway participation, eigenvalue and eigenvector), assess the strengths and weaknesses of each approach, and point to challenges and tasks ahead. We find that the eigenvalue and eigenvector approaches carry significant potential but that a more solid theoretical foundation of the method is required. However, since a ‘grand unified theory’ will never be possible, all tools will be based on approximations and it is only in their practical use that we can discover their real value. Copyright # 2008 John Wiley & Sons, Ltd.
Geometry and electronic structure of [0001]/(1 230) Σ = 7 symmetric tilt boundary in ZnO

Abstract The [0001]/(1 230) ∑ = 7 symmetric tilt boundary in ZnO has been investigated by a combination of static lattice and first-principles molecular orbital calculations. Four types of stable boundary geometries with energies of approximately 1.5Jm−2 were obtained by the static lattice calculations. The electronic structures of the derived geometries are discussed comparatively with those of ZnO bulk and the (1010) surface. In the configuration with the lowest energy, there are small open channels at the boundary core but all the ions have preserved the fourfold coordination. The electronic structure resembles that of the bulk, regardless of the presence of the small open channels, and no remarkable interfacial electronic states are observed. The configurations with higher energy have relatively large open channels and some of the ions adjacent to the channels have been reduced to threefold coordination. Local electronic states at the ions are similar to the surface states in the valence and the conduction bands. However, no deep interfacial states are found, either.
Pathophysiological and Clinical Importance of Insulin-Like Growth Factor-I with Respect to Bone Metabolism

The modern concept of causality of diseases emphasizes the study of natural defense functions of the organism and possibilities of influencing them, which will lead to effective prevention of these diseases. A great deal of information has been obtained on the system growth hormone (GH)/insulin-like growth factor (IGF)-I, which is of quite fundamental importance for the integrity of the organism. A dysbalance of the system may be the cause of diseases of the neonatal period, as well as diseases associated with aging. In old age, the synthesis of the crucial peptide system, IGF-I, declines as well as the sensitivity of tissues to this hormone. At the same time the changes in the expression of IGF-binding proteins (IGFBP) occur. Systemic growth factors are present in measurable concentrations in the circulation, they are, however, taken up or synthesized by some tissues, where they act as local cellular regulators. IGFI is produced by many tissues, including bones under the control of estrogens, growth hormone and the parathyroid hormone. A decline of bone IGF-I in the cortical portion of bones is one of the many mechanisms leading to the development of involutional osteoporosis. Correlation studies, which have provided evidence of a relationship between the IGF system and the building of peak bone mass and its subsequent loss contributed to the understanding of the pathogenesis of this disease. It may be foreseen that the results of intervention studies focused on the effects of the recombinant IGF-I will also influence therapeutic and preventive approaches. Modern antiresorption pharmacotherapy stabilizes or enhances bone density and reduces the risk of fractures. The addition of effective anabolics might increase the effectiveness of treatment by shifting the remodeling equilibrium in favor of formative processes. Because both recombinant GH and IGF-I have certain therapeutic limitations, it is considered to utilize substances which either stimulate endogenous IGF-I production directly in the bone or modulate synthesis and distribution of binding proteins for the peptide. Further new findings related to physiology and pathophysiology of this peptide will contribute to designing new strategies in the prevention of osteoporosis and other serious diseases of old age, such as diabetes, neoplasias or cardiovascular diseases.
Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP‐binding cassette transporter g5/g8 in mice

Scavenger receptor class B type I (SR‐BI) mediates selective uptake of cholesterol from high‐density lipoprotein (HDL) particles by the liver and influences biliary cholesterol secretion. However, it is not clear, if this effect is direct or indirect. The aim of this study was to determine the impact of SR‐BI on biliary cholesterol secretion, especially in a functional context with ATP‐binding cassette transporter g5 (Abcg5)/Abcg8 and Abcb4. SR‐BI was overexpressed by means of adenovirus (AdSR‐BI) in livers of wild‐type, liver X receptor–null (Lxr−/−), Abcg5−/−, and Abcb4−/− mice. Consistent with previous reports, AdSR‐BI decreased plasma HDL cholesterol levels in all models (P < 0.001). Hepatic cholesterol content increased (at least P < 0.05), whereas expression of sterol regulatory element binding protein 2 target genes was decreased (at least P < 0.05,) and established Lxr target genes were unaltered. Biliary cholesterol secretion was increased by AdSR‐BI in wild‐type as well as in Lxr−/− and Abcg5−/− mice, and considerably less in Abcb4−/− mice (each P < 0.001), independent of bile acid and phospholipid secretion. Immunogold electron microscopy and western blot showed a substantial increase of SR‐BI protein localized to basolateral and canalicular membranes in response to SR‐BI overexpression. Subcellular fractionation revealed a significantly higher cholesterol content of canalicular membranes (P < 0.001) upon SR‐BI overexpression. Inhibition of microtubule function did not affect SR‐BI–mediated biliary cholesterol secretion, indicating that transcytosis pathways are not involved. Conclusion: Our data indicate that SR‐BI mediates biliary cholesterol secretion independent of Abcg5, yet largely depends on Abcb4‐mediated phospholipid secretion and mixed micelles as acceptors in bile. SR‐BI–mediated biliary cholesterol secretion has a high capacity, can compensate for the absence of Abcg5, and does not require transcytosis pathways. (HEPATOLOGY 2009.)
Regional Difference in Sex Steroid Action on Formation of Morphological Sex Differences in the Anteroventral Periventricular Nucleus and Principal Nucleus of the Bed Nucleus of the Stria Terminalis

Sex steroid action is critical to form sexually dimorphic nuclei, although it is not fully understood. We previously reported that masculinization of the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), which is larger and has more neurons in males than in females, involves aromatized testosterone that acts via estrogen receptor-α (ERα), but not estrogen receptor-β (ERβ). Here, we examined sex steroid action on the formation of the anteroventral periventricular nucleus (AVPV) that is larger and has more neurons in females. Morphometrical analysis of transgenic mice lacking aromatase, ERα, or ERβ genes revealed that the volume and neuron number of the male AVPV were significantly increased by deletion of aromatase and ERα genes, but not the ERβ gene. We further examined the AVPV and BNSTp of androgen receptor knockout (ARKO) mice. The volume and neuron number of the male BNSTp were smaller in ARKO mice than those in wild-type mice, while no significant effect of ARKO was found on the AVPV and female BNSTp. We also examined aromatase, ERα, and AR mRNA levels in the AVPV and BNSTp of wild-type and ARKO mice on embryonic day (ED) 18 and postnatal day (PD) 4. AR mRNA in the BNSTp and AVPV of wild-type mice was not expressed on ED18 and emerged on PD4. In the AVPV, the aromatase mRNA level was higher on ED18, although the ERα mRNA level was higher on PD4 without any effect of AR gene deletion. Aromatase and ERα mRNA levels in the male BNSTp were significantly increased on PD4 by AR gene deletion. These results suggest that estradiol signaling via ERα during the perinatal period and testosterone signaling via AR during the postnatal period are required for masculinization of the BNSTp, whereas the former is sufficient to defeminize the AVPV.
The co-evolution of multiply-informed dispersal: information transfer across landscapes from neighbors and immigrants

Dispersal plays a key role in natural systems by shaping spatial population and evolutionary dynamics. Dispersal has been largely treated as a population process with little attention to individual decisions and the influence of information use on the fitness benefits of dispersal despite clear empirical evidence that dispersal behavior varies among individuals. While information on local density is common, more controversial is the notion that indirect information use can easily evolve. We used an individual-based model to ask under what conditions indirect information use in dispersal will evolve. We modeled indirect information provided by immigrant arrival into a population which should be linked to overall metapopulation density. We also modeled direct information use of density which directly impacts fitness. We show that immigrant-dependent dispersal evolves and does so even when density dependent information is available. Use of two sources of information also provides benefits at the metapopulation level by reducing extinction risk and prolonging the persistence of populations. Our results suggest that use of indirect information in dispersal can evolve under conservative conditions and thus could be widespread.
Banning Fisheries Discards Abruptly Has a Negative Impact on the Population Dynamics of Charismatic Marine Megafauna

Food subsidies have the potential to modify ecosystems and affect the provision of goods and services. Predictable Anthropogenic Food Subsidies (PAFS) modify ecosystems by altering ecological processes and food webs. The global concern over the effects of PAFS in ecosystems has led to development of environmental policies aimed at curbing the production or ultimately banning of PAFS. However, the effects of reducing or banning PAFS are not known. We explore the consequences of PAFS removal in a marine ecosystem under two scenarios: 1) gradual reduction, or 2) an abrupt ban, using a mass balance model to test these hypotheses–The reduction or loss of PAFS will: i) modify trophic levels and food webs through effects on foraging by opportunistic species, ii) increase the resilience of opportunistic species to food shortages, and iii) modify predator–prey interactions through shifts in prey consumption. We found that PAFS lower the trophic levels of opportunistic scavengers and increase their food pathways. Scavengers are able to switch prey when PAFS are reduced gradually but they decline when PAFS are abruptly banned. PAFS reduction to a certain minimal level causes a drop in the ecosystem’s stability. We recommend gradual reduction of PAFS to a minimal level that would maintain the ecosystem’s stability and allow species exploiting PAFS to habituate to the food subsidy reduction.
Autism: a novel form of mercury poisoning.

Autism is a syndrome characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recent epidemiological studies suggest that autism may affect 1 in 150 US children. Exposure to mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism, and the similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Thimerosal, a preservative added to many vaccines, has become a major source of mercury in children who, within their first two years, may have received a quantity of mercury that exceeds safety guidelines. A review of medical literature and US government data suggests that: (i) many cases of idiopathic autism are induced by early mercury exposure from thimerosal; (ii) this type of autism represents an unrecognized mercurial syndrome; and (iii) genetic and non-genetic factors establish a predisposition whereby thimerosal's adverse effects occur only in some children.
Synthesis, characterization, and evaluation of paclitaxel loaded in six-arm star-shaped poly(lactic-co-glycolic acid)

Background Star-shaped polymers provide more terminal groups, and are promising for application in drug-delivery systems. Methods A new series of six-arm star-shaped poly(lactic-co-glycolic acid) (6-s-PLGA) was synthesized by ring-opening polymerization. The structure and properties of the 6-s-PLGA were characterized by carbon-13 nuclear magnetic resonance spectroscopy, infrared spectroscopy, gel permeation chromatography, and differential scanning calorimetry. Then, paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles (6-s-PLGA-PTX-NPs) were prepared under the conditions optimized by the orthogonal testing. High-performance liquid chromatography was used to analyze the nanoparticles’ encapsulation efficiency and drug-loading capacity, dynamic light scattering was used to determine their size and size distribution, and transmission electron microscopy was used to evaluate their morphology. The release performance of the 6-s-PLGA-PTX-NPs in vitro and the cytostatic effect of 6-s-PLGA-PTX-NPs were investigated in comparison with paclitaxel-loaded linear poly(lactic-co-glycolic acid) nanoparticles (L-PLGA-PTX-NPs). Results The results of carbon-13 nuclear magnetic resonance spectroscopy and infrared spectroscopy suggest that the polymerization was successfully initiated by inositol and confirm the structure of 6-s-PLGA. The molecular weights of a series of 6-s-PLGAs had a ratio corresponding to the molar ratio of raw materials to initiator. Differential scanning calorimetry revealed that the 6-s-PLGA had a low glass transition temperature of 40°C–50°C. The 6-s-PLGA-PTX-NPs were monodispersed with an average diameter of 240.4±6.9 nm in water, which was further confirmed by transmission electron microscopy. The encapsulation efficiency of the 6-s-PLGA-PTX-NPs was higher than that of the L-PLGA-PTX-NPs. In terms of the in vitro release of nanoparticles, paclitaxel (PTX) was released more slowly and more steadily from 6-s-PLGA than from linear poly(lactic-co-glycolic acid). In the cytostatic study, the 6-s-PLGA-PTX-NPs and L-PLGA-PTX-NPs were found to have a similar antiproliferative effect, which indicates durable efficacy due to the slower release of the PTX when loaded in 6-s-PLGA. Conclusion The results suggest that 6-s-PLGA may be promising for application in PTX delivery to enhance sustained antiproliferative therapy.
Nanoindentation Study of Al356-Al2O3 Nanocomposite Prepared by Ball Milling

In this study ball milling of Al356 and Al2O3 powder mixture was carried out in order to produce Al356-Al2O3 nano-composite containing 20 vol.% Al2O3. The structural evolution and morphological changes of powder particles during ball milling were studied by X-ray diffractometery and scanning electron microscopy analysis. As a result of ball milling Al2O3 particles were uniformly dispersed in Al356 matrix. Furthermore the crystallite size of the Al356 decreased to 25 nm after ball milling for 10 h. Morphological studies of powder particles indicated that the powder particle size continuously decreases with increasing milling time. Hardness and elastic modulus values of powder particles were measured by nanoindentation method. It was found that the hardness and elastic modulus of Al356-20 vol.% Al2O3 nanocomposite were about 216 Hv and 86 GPa, respectively which is higher than 75 Hv and 74 GPa for as-received Al356.
Role of Postnatal Expression of Fgfr1 and Fgfr2 in Testicular Germ Cells on Spermatogenesis and Fertility in Mice

Background Fibroblast growth factor (FGF) signaling is thought to play diverse roles in the male reproductive system. However, its role in testicular cells for spermatogenesis and fertility remains unclear. Methods In this study, the expression and localization of Fgfr 1 (FGF Receptor) and Fgfr 2 in the postnatal mouse testes were examined by RT-PCR, Western blotting and immunohistochemistry. The in vivo function of each receptor in testicular germ cells was determined using germ cell-specific Fgfr mutant animals, Tex101-iCre;Fgfr flox/flox and Tex101-iCre;Fgfr flox/flox mice. The results were analyzed by Kruskal-Wallis test and Dunn's Post-test. Results Both Fgfr1 and Fgfr2 were expressed in the testis throughout the entire postnatal development. Prominent immunostaining of these FGFRs was observed in interstitial and peritubular cells with little or no changes in all phases during postnatal development. Positive staining of these receptors was also detected in germ cells including elongated spermatids and spermatozoa. Germ cell-specific Fgfr1 or Fgfr2 mutant mice were viable with no developmental abnormalities in the testes and accessory sex organs. Fertility studies showed that the fecundity of both mutant mouse lines did not significantly differ from wild-type siblings (n=4, p>0.05). Further analysis indicated the presence of other Fgfrs in testicular germ cells including Fgfr 3, 4 and 5. Conclusion The results demonstrated that Fgfr1 and 2 are expressed in all testicular cell types and that neither Fgfr1 nor Fgfr2 in testicular germ cells is essential for spermatogenesis and fertility. Future studies are needed to investigate the potential functional redundancy among five Fgfrs in male germ cells for spermatogenesis and fertility.
Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3-dose schedules in girls aged 9–14 years: Results to month 12 from a randomized trial

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9–14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV-6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49–1.91] for anti-HPV-16 and 4.52 [3.97–5.13] for anti-HPV-18; HPV-16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54–1.93] for anti-HPV-16 and 3.22 [2.82–3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non-inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8-fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9–14 years).
Immune Responses in Mice after Immunization with Antigens from Different Stages of the Parasite Schistosoma mansoni

Mice responses to immunization with Schistosoma mansoni antigens were investigated. Priming with cercarial antigen preparation (CAP) induced significant (P < 0.05) IgM, IgG, IgG2a, IgG2b, and IgA increases, while booster caused a significant IgG1 increase. A soluble worm antigen preparation (SWAP) caused significant IgG elevation. Priming with soluble egg antigen (SEA) caused significant IgM and IgG2a increases, while booster induced significant IgM, IgG and IgA increases. CAP-immunized mice sera (IMS) recognized CAP peptides ranging from 23 - 78 kDa. SWAP-IMS recognized SWAP peptides ranging from 40 - 75 kDa. SEA-IMS recognized SEA peptides ranging from 33 - 101 kDa. The cross-reactive peptides among the 3 antigens were identified. CAP caused significant increases in mesenteric lymph nodes (MLNs) CD4,8+, B lymphocytes, CD8+ thymocytes, CD4+ T and B splenocytes. SWAP priming caused significant increases in MLNs CD4,8+ thymocytes and B splenocytes. SWAP booster caused significant increases in MLNs CD8+ T and B lymphocytes, CD4,8+ thymocytes and CD4+ T and B splenocytes. SEA caused significant increase in CD4+ T cells.
Synthesis of some quinoline-2(1H)-one and 1, 2, 4 - triazolo [ 4 , 3 -a ] quinoline derivatives as potent anticonvulsants.

PURPOSE A new series of substituted quinoline-2(1H)-one and 1,2,4-triazolo[4,3-a]-quinoline derivatives were designed and synthesized to meet the structural requirements essential for anticonvulsant properties. METHODS 4-substituted-phenyl-3,4-dihydro-2(1H)-quinolines, 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3a]quinolines and 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo-[4,3-a]quinoline-1-(2H)-ones derivatives were synthesized using 3-substituted-phenyl-N-phenyl-acrylamide as a starting material. Their anticonvulsant activity were evaluated by maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxic effects were determined by the rotarod neurotoxicity test. RESULTS The compounds 4-substitued-phenyl-3,4-dihydro-2(1H)-quinolines (2a-f) had increased anticonvulsant effects compared to the parental compounds. The compounds 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3-a]quinolines (3a-f) had significantly increased anticonvulsant activity compared to 2a-f. However, the compounds 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoline-1(2H)-ones(4a-f), exhibited no anticonvulsant effects even under a high dose of 300 mg/kg. CONCLUSIONS The triazole, but not the triazolone, modified series showed stronger anticonvulsant effects than the parent compounds. Among them, compound (3f), 5-(p-fluorophenyl)-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoline, showed the strongest anticonvulsant effect with ED50 of 27.4mg/kg and 22.0mg/kg in the anti-MES and anti-PTZ test, respectively.