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YBCP step-edge junction direct current superconducting quantum interference devices (SQUIDs) are fabricated LaAlO3 substrates using the Inverted Cylindrical Magnetron Sputtering method. The SQUIDs are then studied for their Josephson current versus magnetic field and current versus voltage characteristics. Results show that the SQUIDs are capable of operating up to 77 degrees Kelvin without any degradation in their electrical performance.

The purpose of these studies is to determine the colonic myoelectrical and contractile response after eating a 1000 calorie meal in patients with active ulcerative colitis. During fasting, slow waves are identifiable significantly more in patients with ulcerative colitis than in normal subjects (p < 0 . 01). The predominant slow wave frequency is 6 . 1 +/- 0 . 2 cycles/min, which is similar to the normal subjects. The slow waves are not altered by eating in either group. Minimal spike or contractile activity occurs during the fasting period both in patients with ulcerative colitis and in normal subjects. In patients with ulcerative colitis, spike activity increases rapidly after eating the 1000 calorie meal (P < 0 . 01), but the maximal response is decreased and shorter in duration than in normal subjects. There is no simultaneous increase in colonic contractility above fasting levels after the meal in patients with ulcerative colitis. This is strikingly different from the simultaneous increase in contractile and spike activity (P < 0 . 01) that occurs after eating in normal subjects. These studies suggest that in ulcerative colitis (1) the colonic smooth muscle slow wave activity is intact; and (2) a disturbance in the normal colonic contractile response to eating is present despite an adequate spike response. This lack of colonic contractility may contribute to the increase in diarrhoea that occurs in these patients after eating. [ABSTRACT FROM PUBLISHER]

The current status of the electronic applications of high- T Josephson junctions is briefly reviewed. Recent results obtained by the authors on devices employing step-edge junctions are reported. In particular the design of a microwave oscillator based on a parallel array of junctions is discussed and preliminary experimental results are presented. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effect of different feeding systems on milk fat quality of Murrah buffaloes. Forty Murrah buffaloes from 5 different Brazilian farms (n=8 animals/farm) were used. Milk samples were collected monthly throughout a single lactation, and fatty acid profile was determined by gas chromatography. Milk fatty acid profile was used to calculate the nutritional quality of milk fat according to the following indices: atherogenicity index (AI); thrombogenicity index (TI); omega 6/omega 3 (n6/n3) ratio and desirable fatty acids (DFA). Statistical analyses were performed using PROC Univariete from 7. The smallest AI (1.49±0.43) was observed in milk fat from Buffaloes raised in the Farm 3. No differences among farms were observed for TI and n6/n3 ratio. However, DFA differed among farms, with milk fat of Buffaloes from Farm 3 showing the highest values (47.17%). Our results showed that nutritional quality of milk fat from Murrah Buffaloes is influenced by different feeding systems. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effects of somatic cell count (SCC) on buffalo milk. Samples were collected monthly from 156 Murrah buffaloes during lactation, in 4 production systems (tropical pasture with supplementation), in Brazil. The SCC was determined by flow cytometry, using the Somacount 300. The fat, crude protein and lactose were determined by infrared light reading absorption, using the Bentley 2000 (Bentley Instruments). The SCC range in milk was (x 1.000 cells): Group 1 - until 250; Group 2 - more 250 to 450; Group 3 - more 450 to 750; Group 4 - more 750 to 1.000; Group 5 - more 1.000. The larger frequency of samples was observed in the Group 1 (89.7%). In the Group 2 was observed 4.6% of samples. In turn, in the Group 3 was 1.8%, in the Group 4 was 0.7%, and in the Group 5 was observed 3.2% of milk samples. Milk components such as fat, protein and lactose were not affected in spite of a decrease in their concentration. Perhaps, this result is due to the small number of samples in 3, 4 and 5 Groups. However, significant effect of SCC on the solids was observed. Most total solids concentration was observed in the Group 1 (17.1±1.71%) did not differ from Group 2 (16.5±1.45%) and Group 3 (16.8±2.09%), however was observed statistical effect from intervals 4 (15.8±2.43%) and 5 (14.5±2.39%). In the 2, 3 and 4 Groups was not find statistical difference, however, they differ in the range 5. The SCC did not affect the composition of buffalo's milk. [ABSTRACT FROM AUTHOR]

Abstract Background Current cognitive neuroscience models predict a right-hemispheric dominance for face processing in humans. However, neuroimaging and electromagnetic data in the literature provide conflicting evidence of a right-sided brain asymmetry for decoding the structural properties of faces. The purpose of this study was to investigate whether this inconsistency might be due to gender differences in hemispheric asymmetry. Results In this study, event-related brain potentials (ERPs) were recorded in 40 healthy, strictly right-handed individuals (20 women and 20 men) while they observed infants' faces expressing a variety of emotions. Early face-sensitive P1 and N1 responses to neutral vs. affective expressions were measured over the occipital/temporal cortices, and the responses were analyzed according to viewer gender. Along with a strong right hemispheric dominance for men, the results showed a lack of asymmetry for face processing in the amplitude of the occipito-temporal N1 response in women to both neutral and affective faces. Conclusion Men showed an asymmetric functioning of visual cortex while decoding faces and expressions, whereas women showed a more bilateral functioning. These results indicate the importance of gender effects in the lateralization of the occipito-temporal response during the processing of face identity, structure, familiarity, or affective content.

Inhibition of FGF/FGFR signaling is a promising strategy for the treatment of malignances dependent from FGF stimulation, including multiple myeloma (MM). The steroidal derivative NSC12 (compound 1) is a pan-FGF trap endowed with antitumor activity in vivo. Chemical modifications of compound 1 were explored to investigate structure-activity relationships, focusing on the role of the bis(trifluoromethyl)1,3-propanediol chain, the stereochemistry at C20 and functionalization of C3 position. Our studies unveiled compound 25b, the pregnane 3-keto 20R derivative of compound 1 as an effective agent, blocking the proliferation of MM cells in vitro by inhibiting FGF-dependent receptor activation and slowing MM growth in vivo. Importantly, the absence of the hydroxyl group at C3 prevents binding to estrogen receptors, which might concur to the antitumor activity observed for compound 1, leading to a specific FGF/FGFR system inhibitor, and further supporting the role of FGFR in anticancer therapy in MM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers.

Multiple myeloma, the second most common hematologic malignancy, frequently relapses because of chemotherapeutic resistance. Fibroblast growth factors (FGF) act as proangiogenic and mitogenic cytokines in multiple myeloma. Here, we demonstrate that the autocrine FGF/FGFR axis is essential for multiple myeloma cell survival and progression by protecting multiple myeloma cells from oxidative stress-induced apoptosis. In keeping with the hypothesis that the intracellular redox status can be a target for cancer therapy, FGF/FGFR blockade by FGF trapping or tyrosine kinase inhibitor impaired the growth and dissemination of multiple myeloma cells by inducing mitochondrial oxidative stress, DNA damage, and apoptotic cell death that were prevented by the antioxidant vitamin E or mitochondrial catalase overexpression. In addition, mitochondrial oxidative stress occurred as a consequence of proteasomal degradation of the c-Myc oncoprotein that led to glutathione depletion. Accordingly, expression of a proteasome-nondegradable c-Myc protein mutant was sufficient to avoid glutathione depletion and rescue the proapoptotic effects due to FGF blockade. These findings were confirmed on bortezomib-resistant multiple myeloma cells as well as on bone marrow-derived primary multiple myeloma cells from newly diagnosed and relapsed/refractory patients, including plasma cells bearing the t(4;14) translocation obtained from patients with high-risk multiple myeloma. Altogether, these findings dissect the mechanism by which the FGF/FGFR system plays a nonredundant role in multiple myeloma cell survival and disease progression, and indicate that FGF targeting may represent a therapeutic approach for patients with multiple myeloma with poor prognosis and advanced disease stage. SIGNIFICANCE: This study provides new insights into the mechanisms by which FGF antagonists promote multiple myeloma cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2340/F1.large.jpg., (©2020 American Association for Cancer Research.)

Bladder tumors are a diffuse type of cancer. Long pentraxin-3 (PTX3) is a component of the innate immunity with pleiotropic functions in the regulation of immune response, tissue remodeling, and cancer progression. PTX3 may act as an oncosuppressor in different contexts, functioning as an antagonist of the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system, rewiring the immune microenvironment, or acting through mechanisms not yet fully clarified. In this study we used biopsies and data mining to assess that PTX3 is differentially expressed during the different stages of bladder cancer (BC) progression. BC cell lines, representative of different tumor grades, and transgenic/carcinogen-induced models were used to demonstrate in vitro and in vivo that PTX3 production by tumor cells decreases along the progression from low-grade to high-grade advanced muscle invasive forms (MIBC). In vitro and in vivo data revealed for the first time that PTX3 modulation and the consequent impairment of FGF/FGR systems in BC cells have a significant impact on different biological features of BC growth, including cell proliferation, motility, metabolism, stemness, and drug resistance. PTX3 exerts an oncosuppressive effect on BC progression and may represent a potential functional biomarker in BC evolution. Moreover, FGF/FGFR blockade has an impact on drug resistance and stemness features in BC.

Fibrosarcomas are soft tissue mesenchymal tumors originating from transformed fibroblasts. Fibroblast growth factor-2 (FGF2) and its tyrosine-kinase receptors (FGFRs) play pivotal roles in fibrosarcoma onset and progression, FGF2 being actively produced by fibroblasts in all stages along their malignant transformation to the fibrosarcoma stage. The soluble pattern recognition receptor long pentraxin-3 (PTX3) is an extrinsic oncosuppressor whose expression is reduced in different tumor types, including soft tissue sarcomas, via hypermethylation of its gene promoter. PTX3 interacts with FGF2 and other FGF family members, thus acting as a multi-FGF antagonist able to inhibit FGF-dependent neovascularization and tumor growth. Here, PTX3 overexpression significantly reduced the proliferative and tumorigenic potential of fibrosarcoma cells in vitro and in vivo . In addition, systemic delivery of human PTX3 driven by the Tie2 promoter inhibited the growth of fibrosarcoma grafts in transgenic mice. In a translational perspective, the PTX3-derived small molecule FGF trap NSC12 prevented activation of the FGF/FGFR system in fibrosarcoma cells and reduced their tumorigenic activity in vivo . In conclusion, impairment of the FGF/FGFR system by FGF trap molecules may represent a novel therapeutic approach for the treatment of fibrosarcoma.

NSC12 is an orally available pan-FGF trap able to inhibit FGF2/FGFR interaction and endowed with promising antitumor activity. It was identified by virtual screening from a NCI small molecule library, but no data were available about its synthesis, stereochemistry, and physicochemical properties. We report here a synthetic route that allowed us to characterize and unambiguously identify the structure of the active compound by a combination of NMR spectroscopy and in silico conformational analysis. The synthetic protocol allowed us to sustain experiments aimed at assessing its therapeutic potential for the treatment of FGF-dependent lung cancers. A crucial step in the synthesis generated a couple of diastereoisomers, with only one able to act as a FGF trap molecule and to inhibit FGF-dependent receptor activation, cell proliferation, and tumor growth when tested in vitro and in vivo on murine and human lung cancer cells.

Fibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments. The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies. Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop "two-compartment" targeting agents endowed with both antiangiogenic and antitumor activities remains promising. Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The fibroblast growth factor (FGF)/FGF receptor (FGFR) system plays a crucial role in cancer by affecting tumor growth, angiogenesis, drug resistance, and escape from anti-angiogenic anti-vascular endothelial growth factor therapy. The soluble pattern recognition receptor long-pentraxin 3 (PTX3) acts as a multi-FGF antagonist. Here we demonstrate that human PTX3 overexpression in transgenic mice driven by the Tie2 promoter inhibits tumor growth, angiogenesis, and metastasis in heterotopic, orthotopic, and autochthonous FGF-dependent tumor models. Using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2, we identified a small-molecule chemical (NSC12) that acts as an extracellular FGF trap with significant implications in cancer therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Fibroblast growth factor-8b (FGF8b) affects the epithelial/stromal compartments of steroid hormone-regulated tumors by exerting an autocrine activity on cancer cells and a paracrine pro-angiogenic function, thus contributing to tumor progression. The FGF8b/FGF receptor (FGFR) system may therefore represent a target for the treatment of steroid hormone-regulated tumors. The soluble pattern recognition receptor long pentraxin-3 (PTX3) binds various FGFs, including FGF2 and FGF8b, thus inhibiting the angiogenic and tumorigenic activity of androgen-regulated tumor cells. Nevertheless, the complex/proteinaceous structure of PTX3 hampers its pharmacological exploitation. In this context, the acetylated pentapeptide Ac-ARPCA-NH2 (ARPCA), corresponding to the N-terminal amino acid sequence PTX3(100-104), was identified as a minimal FGF2-binding peptide able to antagonize the biological activity of FGF2. Here, we demonstrate that ARPCA binds FGF8b and inhibits its capacity to form FGFR1-mediated ternary complexes with heparan sulphate proteoglycans. As a FGF8b antagonist, ARPCA inhibits FGFR1 activation and signalling in endothelial cells, hampering the angiogenic activity exerted in vitro and in vivo by FGF8b. Also, ARPCA suppresses the angiogenic and tumorigenic potential of prototypic androgen/FGF8b-dependent Shionogi 115 mammary carcinoma cells and of androgen/FGF8b/FGF2-dependent TRAMP-C2 prostate cancer cells. In conclusion, ARPCA represents a novel FGF8b antagonist with translational implications for the therapy of steroid hormone-regulated tumors.

Statins are largely used in clinics in the treatment of patients with cardiovascular diseases for their effect on lowering circulating cholesterol. Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for ox-LDL, plays a central role in the pathogenesis of atherosclerosis and cardiovascular disorders. We have recently shown that chronic exposure of cells to lovastatin disrupts LOX-1 receptor cluster distribution in plasma membranes, leading to a marked loss of LOX-1 function. Here we investigated the molecular mechanism of statin-mediated LOX-1 inhibition and we demonstrate that all tested statins are able to displace the binding of fluorescent ox-LDL to LOX-1 by a direct interaction with LOX-1 receptors in a cell-based binding assay. Molecular docking simulations confirm the interaction and indicate that statins completely fill the hydrophobic tunnel that crosses the C-type lectin-like (CTLD) recognition domain of LOX-1. Classical molecular dynamics simulation technique applied to the LOX-1 CTLD, considered in the entire receptor structure with or without a statin ligand inside the tunnel, indicates that the presence of a ligand largely increases the dimer stability. Electrophoretic separation and western blot confirm that different statins binding stabilize the dimer assembly of LOX-1 receptors in vivo. The simulative and experimental results allow us to propose a CTLD clamp motion, which enables the receptor-substrate coupling. These findings reveal a novel and significant functional effect of statins.

During melanoma progression, malignant melanocytes are reprogrammed into mesenchymal-like cells through to an epithelial-mesenchymal transition (EMT) process associated with the acquisition of an invasive, prometastatic phenotype. The fibroblast growth factor-2 (FGF2)/FGF receptor (FGFR) system plays a pivotal role in melanoma, leading to autocrine/paracrine induction of tumor cell proliferation and angiogenesis. Long pentraxin-3 (PTX3) interacts with FGF2, and other FGF family members, inhibiting FGF-dependent neovascularization and tumor growth. Here, PTX3 protein and the PTX3-derived acetylated pentapeptide Ac-ARPCA-NH2 inhibit FGF2-driven proliferation and downstream FGFR signaling in murine melanoma B16-F10 cells. Moreover, human PTX3-overexpressing hPTX&#95;B16-F10 cells are characterized by the reversed transition from a mesenchymal to an epithelial-like appearance, inhibition of cell proliferation, loss of clonogenic potential, reduced motility and invasive capacity, downregulation of various mesenchymal markers, and upregulation of the epithelial marker E-cadherin. Accordingly, PTX3 affects cell proliferation and EMT transition in human A375 and A2058 melanoma cells. Also, hPTX&#95;B16-F10 cells showed a reduced tumorigenic and metastatic activity in syngeneic C57BL/6 mice. In conclusion, PTX3 inhibits FGF/FGFR-driven EMT in melanoma cells, hampering their tumorigenic and metastatic potential. These data represent the first experimental evidence about a nonredundant role of the FGF/FGFR system in the modulation of the EMT process in melanoma and indicate that PTX3 or its derivatives may represent the basis for the design of novel therapeutic approaches in FGF/FGFR-dependent tumors, including melanoma., (©2013 AACR.)

Differences in how the hands of gorillas and chimpanzees contact the ground while knuckle walking have been noted but generally not quantified. It is widely believed that gorillas maintain a pronated arm and contact the ground with digits 2-5 consistently, while chimpanzees have variable arm position and digit contact. To further test these generalizations, distribution of pressure across the manus, peak digital pressures, and hand position were quantified using a pressure mat in eight captive chimpanzees (Pan troglodytes) and seven gorillas (Gorilla gorilla). Chimpanzees and gorillas make initial ground contact with the ulnar aspect of the hand and pressure moves radially. They differ in which digit usually makes final contact and receives maximum pressure, and hand position during contact. Gorillas regularly use a palm-back hand position and touch-off with digit 2. They show less variation in pressure application across the digits. Chimpanzees are more variable in hand position and pressure application. In both, hand position plays a key role in determining which digit acts as the final touch-off element., (Copyright © 2013 Wiley Periodicals, Inc.)

Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells, is up-regulated in atherosclerotic lesions. Statins are the principal therapeutic agents for cardiovascular diseases and are known to down-regulate LOX-1 expression. Whether the effect on the LOX-1 receptor is related to statin-mediated cholesterol-lowering activity is unknown. We investigate the requirement of cholesterol for LOX-1-mediated lipid particle internalization, trafficking, and processing and the role of statins as inhibitors of LOX-1 function. Disruption of cholesterol-rich membrane microdomains by acute exposure of cells to methyl-β-cyclodextrin or chronic exposure to different statins (lovastatin and atorvastatin) led to a spatial disorganization of LOX-1 in plasma membranes and a marked loss of specific LOX-1 function in terms of ox-LDL binding and internalization. Subcellular fractionation and immunochemical studies indicate that LOX-1 is naturally present in caveolae-enriched lipid rafts and, by cholesterol reduction, the amount of LOX-1 in this fraction is highly decreased (≥60%). In contrast, isoprenylation inhibition had no effect on the distribution and function of LOX-1 receptors. Furthermore, in primary cultures from atherosclerotic human aorta lesions, we confirm the presence of LOX-1 in caveolae-enriched lipid rafts and demonstrate that lovastatin treatment led to down-regulation of LOX-1 in lipid rafts and rescue of the ox-LDL-induced apoptotic phenotype. Taken together, our data reveal a previously unrecognized essential role of membrane cholesterol for LOX-1 receptor activity and suggest that statins protect vascular endothelium against the adverse effect of ox-LDL by disruption of membrane rafts and impairment of LOX-1 receptor function.

This article examines the curvature of the manual proximal and middle phalanges of species belonging to Pan, Gorilla, Ateles, Macaca, Pongo, Hylobates, and Cebus to determine whether middle phalangeal curvature, when considered in conjunction with proximal phalangeal curvature, yields a locomotor signal. Prior studies have demonstrated the discriminatory power of proximal phalanges for separating suspensory species (including knuckle walkers) from pronograde quadrupedal species, but less emphasis has been placed on the distinguishing phalangeal characteristics of taxa within the suspensory category. This study demonstrates, first, that middle phalanges discriminate suspensory from nonsuspensory species, although not as cleanly as proximal phalanges. Finer discrimination of locomotor signals, including subtle differences among animals employing different modes of suspension, is possible through a comparison of the curvatures of the proximal phalanges and corresponding middle phalanges. Their relative curvature differs in quadrupeds, brachiators, and knuckle walkers. Knuckle walkers (Pan and Gorilla) have relatively little curvature of the middle phalanges coupled with marked curvature of the proximal phalanges, whereas brachiators (Ateles and Hylobates) display marked curvature of both proximal and middle phalanges, and pronograde quadrupeds (Cebus and Macaca) have relatively straight proximal and moderately curved middle phalanges. Quadrumanous climbers (Pongo) have a unique combination of traits, whereby curvature is high in both proximal and middle phalanges, but less so in the latter than the former. These differences, predictable on the basis of the biomechanical forces to which digits are subjected, may open a new venue for future research on the locomotor repertoire of prebipedal ancestors of hominins., ((c) 2007 Wiley-Liss, Inc.)

Several studies have provided evidence of a women's better accuracy in interpreting emotional states. Despite this difference is generally ascribed to the primary role of female gender in the affective relation with the offspring, to date, little information is available regarding gender differences in the ability to interpret infant facial expressions. In the present study, we examined the roles of gender and expertise in interpreting infant expression in 34 men and women who differed in their experience with infants. Women showed a significantly higher level of decoding accuracy compared to men. Expertise positively affected facial expressions decoding among women only. Our results suggest that in judging emotional facial expressions of infants, there is an interaction of biological (i.e., gender) and cultural factors that is independent of a woman's socioeconomic status.