A mutation in the ZNF687 gene that is responsible for the severe form of Paget's disease of bone causes severely altered bone remodeling and promotes hepatocellular carcinoma onset in a knock-in mouse model

Paget’s disease(PDB)is a late-onset bone remodeling disorder with a broad spectrum of symptoms and complications.One of the most aggressive forms is caused by the P937R mutation in the ZNF687 gene.Although the genetic involvement of ZNF687 in PDB has been extensively studied,the molecular mechanisms underlying this association remain unclear.Here,we describe the first Zfp687 knock-in mouse model and demonstrate that the mutation recapitulates the PDB phenotype,resulting in severely altered bone remodeling.Through microcomputed tomography analysis,we observed that 8-month-old mutant mice showed a mainly osteolytic phase,with a significant decrease in the trabecular bone volume affecting the femurs and the vertebrae.Conversely,osteoblast activity was deregulated,producing disorganized bone.Notably,this phenotype became pervasive in 16-month-old mice,where osteoblast function overtook bone resorption,as highlighted by the presence of woven bone in histological analyses,consistent with the PDB phenotype.Furthermore,we detected osteophytes and intervertebral disc degeneration,outlining for the first time the link between osteoarthritis and PDB in a PDB mouse model.RNA sequencing of wild-type and Zfp687 knockout RAW264.7 cells identified a set of genes involved in osteoclastogenesis potentially regulated by Zfp687,e.g.,Tspan7,Cpe,Vegfc,and Ggt1,confirming its role in this process.Strikingly,in this mouse model,the mutation was also associated with a high penetrance of hepatocellular carcinomas.Thus,this study established an essential role of Zfp687 in the regulation of bone remodeling,offering the potential to therapeutically treat PDB,and underlines the oncogenic potential of ZNF687.

Anisotropic thermal expansion in high-entropy multicomponent AlB_(2)-type diboride solid solutions

High-entropy(HE)ultra-high temperature ceramics have the chance to pave the way for future applications propelling technology advantages in the fields of energy conversion and extreme environmental shielding.Among others,HE diborides stand out owing to their intrinsic anisotropic layered structure and ability to withstand ultra-high temperatures.Herein,we employed in-situ high-resolution synchrotron diffraction over a plethora of multicomponent compositions,with four to seven transition metals,with the intent of understanding the thermal lattice expansion following different composition or synthesis process.As a result,we were able to control the average thermal expansion(TE)from 1.3×10^(−6)to 6.9×10^(−6)K^(−1)depending on the combination of metals,with a variation of in-plane to out-of-plane TE ratio ranging from 1.5 to 2.8.

Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.

Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis

The nonalcoholic fatty liver disease(NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-alcoholic steatohepatitis(NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes(Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a na?ve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies.

Significance of hepatitis virus infection in the oncogenicinitiation of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common causes of cancer-related death worldwide. Chronic infection of hepatitis B virus(HBV) and/or hepatitis C virus(HCV) is a major risk factor in the development of the HCC, independently from excessive alcohol abuse and metabolic disease. Since the biology of HBV and HCV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with cellular inflammation, oxidative stress, DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally HCC. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of HBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of HBV and HCV in the early initiation of HCC.

Proteomic analysis of gastric cancer and immunoblot validation of potential biomarkers

AIM： To search for and validate differentially expressed proteins in patients with gastric adenocarcinoma.METHODS： We used two-dimensional gel electrophoresis and mass spectrometry to search for differentially expressed proteins in patients with gastric adenocarcinoma. A set of proteins was validated with immunoblotting.RESULTS： We identified 30 different proteins involved in various biological processes： metabolism, development, death, response to stress, cell cycle, cell communication, transport, and cell motility. Eight proteinswere chosen for further validation by immunoblotting. Our results show that gastrokine-1, 39S ribosomal protein L12 （mitochondrial precursor）, plasma cell-induced resident endoplasmic reticulum protein, and glutathione S-transferase mu 3 were significantly underexpressed in gastric adenocarcinoma relative to adjacent non-tumor tissue samples. On the other hand, sep- tin-2, ubiquitin-conjugating enzyme E2 N, and transaldolase were significantly overexpressed. Translationally controlled tumor protein was shown to be differentially expressed only in patients with cancer of the gastric cardia/esophageal border.CONCLUSION： This work presents a set of possible diagnostic biomarkers, validated for the first time. It might contribute to the efforts of understanding gastric cancer carcinogenesis,

Genetic biomarkers for hepatocellular cancer risk in a caucasian population

AIM To uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma(HCC)susceptibility in Caucasians. METHODS The present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two,independent,HCC-free,age/sex-matched control groups.The HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver transplantation.The first control group comprised167 patients that were matched to the HCC cohort for the percentage of hepatitis B(HBV)and/or hepatitis C(HCV)infections.A second control group included192 virus-free,healthy individuals that were used to evaluate the generalizability of the identified predictive markers.All cases and controls were Caucasian.The three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related pathways.The study end-point was to assess the association between genetic variants and HCC onset. RESULTS Five genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/HCV.According to a dominant model,reduced HCC risk was associated with three polymorphisms:ERCC1rs3212986(OR=0.46,95%CI:0.30-0.71,P=0.0005),GST-P1 rs1138272(OR=0.41,95%CI:0.21-0.81,P=0.0097),and CYP17A1 rs743572(OR=0.50,95%CI:0.31-0.79,P=0.0032).Conversely,according to a recessive model,increased HCC risk was associated with two polymorphisms:XRCC3 rs1799794(OR=3.70,95%CI:1.02-13.39,P=0.0461)and ABCB1 rs1128503(OR=2.06,95%CI:1.18-3.61,P=0.0111).These associations remained significant in a subgroup analysis,where patients were stratified according to viral status(HBV-or HCV-positive serology).Two variants exhibited a serology-specific effect:ABCB1 rs1128503(OR=4.18,95%CI:1.55-11.29,P=0.0048)showed an effect in the HBV-positive subgroup;and ERCC1 rs3212986(OR=0.33,95%CI:0.18-0.60,P=0.0003)showed an effect in the HCV-positive subgroup.Among the five markers identified,ERCC1 rs3212986(OR=0.43,P<0.0001)and CYP17A1 rs743572(OR=0.73,P=0.0310)had a different distribution in patients with HCC compared to healthy individuals.With a recursive partitioning approach,we also demonstrated that significant gene-gene interactions between ERCC1rs3212986,CYP17A1 rs743572,GST-P1 rs1138272,and the previously described UGT1A7*3 predictive marker,played a role in the complex trait of HCC susceptibility.CONCLUSION We identified five polymorphisms and interactions that contributed crucially to predicting HCC risk.These findings represented an important step towards improving HCC diagnosis and management.

Surface modified solid lipid microparticles based on homolipids and Softisan 142:preliminary characterization

ObjectiveTo preliminarily investigate three different lipid matrices consisting of two natural homolipids from Capra hircus (goat fat) and Bovine Spp. (tallow fat) and one semi-synthetic lipid (Softisan? 142) separately structured with Phospholipon? 90G (P90G) as potential delivery systems for poorly water soluble drugs.MethodsThe structured lipid matrices were characterized by differential scanning calorimetry (DSC) and employed to prepare solid lipid microparticles (SLMs) by the melt homogenization method using gradient concentrations of polysorbate 80 and at different emulsification times of 2, 5 and 10 min using a Silverson mixer. The SLMs were analyzed for morphology and particle size, thermal properties, stability studies and determination of injectability.ResultsThe results showed that SLM production was optimum at 5 % of lipid matrices, 1.5 % of polysorbate 80 and emulsification time of 5 min. Increase in polysorbate 80 concentrations decreased the particle size of the SLMs. The SLMs were well formed, spherical, smooth and non-porous with particle sizes in the ranges of (13.90 ± 2.10) μm - (0.09 ± 0.01) μm for SLMs produced from the structured - tallow fat; (13.40 ± 1.30) μm - (0.10 ± 0.01) μm for the structured - goat fat and (13.40±2.00) μm - (2.10± 1.00)μm for the structured Softisan? 142 lipid matrices. DSC traces showed that Softisan? 142 was the most crystalline of all three bulk matrices due to its high enthalpy (?7.962 mW/mg) while tallow fat was the least (?5.067 mW/mg) but addition of P90G to the matrices lowered their enthalpies mostly in the structured goat fat matrices. The SLMs when stored at 4-6 ° were most stable and syringeable with 27 G needle.ConclusionsThis suggests that structured goat fat matrices with the enthalpy of ?2.813 mW/mg will mostly favour drug loading of some poorly soluble drugs more than tallow fat (?4.892 mW/mg) and Softisan? 142 (?5.501 mW/mg).

A Web Based Decision Support System for Intermodal Port and Dry Port Facilities

This paper presents a Web-based Decision Support System (Web-DSS) that was designed and developed to support and provide suggestions on the procedures taking place between a port and a dry port, which have to collaborate, work concurrently and optimize their joint operation. The system operates at the highest hierarchical level supervising a number of different components dealing with three different time scale horizons so as to provide assistance at operational, tactical and strategic level. The Web-based DSS coordinates and integrates the subsystems operating at lower levels and it interfaces with all the involved actors: customers, suppliers, relevant authorities so as to receive all the necessary information to come up with “optimal” suggestions and decisions. In this paper, the overall architecture is presented and the individual modules are described.

Inelastic UV Scattering in a Floating Water Bridge

When high voltage is applied to distilled water filled into two beakers close to each other, a watery connection forms spontaneously, giving the impression of a floating water bridge [1-8]. In this work we present the first inelastic ultraviolet scattering data of such an electrohydrodynamic bridge revealing radial gradients of Stokes- and Anti-Stokes shifts and their intensity profiles. Interpretations including density and temperature changes within the bridge are discussed. The obtained data can be satisfactorily explained by the introduction of a second phase consisting of nano bubbles. Results and interpretation are discussed in relation to similar phenomena.

Digital liver biopsy:Bio-imaging of fatty liver for translational and clinical research

The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a "digital biopsy" for in vivo study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines(Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver.

Stratigraphy of the Alveolina elliptica group from the Middle Eocene of Iran:Calibration with calcareous nannofossils biozones and description of Alveolina ozcani n. sp.

Precise taxonomy and the chronostratigraphic calibration of the Middle Eocene Alveolina from Central Iran is here undertaken from the Chah-Talkh section of the southern Sabzevar region(Central Iran). We have identified Alveolina kieli, Alveolina stercusmuris and Alveolina nuttalli along with the new species Alveolina ozcani n. sp. that we include into the Alveolina elliptica group. We have also found Nummulites uroniensis, Nummulites obesus and Nummulites cf. verneuili and associated calcareous nannofossils that look reliable to make thoughtful correlations with the Shallow Benthic Zones(SBZ). The foraminiferal biostratigraphy suggests an assignment to the upper part of the lower Lutetian-lower part of the middle Lutetian,SBZ13(Middle Eocene), further strengthened through the identification of the calcareous nannofossil NP14b-NP15b or CNE8-CNE10 biozones, providing a solid correlation with the global stratigraphic standards.

A DNA origami plasmonic sensor with environment-independent read-out

DNA origami is a promising technology for its reproducibility,flexibility,scalability and biocompatibility.Among the several potential applications,DNA origami has been proposed as a tool for drug delivery and as a contrast agent,since a conformational change upon specific target interaction may be used to release a drug or produce a physical signal,respectively.However,its conformation should be robust with respect to the properties of the medium in which either the recognition or the read-out take place,such as pressure,viscosity and any other unspecific interaction other than the desired target recognition.Here we report on the read-out robustness of a tetragonal DNA-origami/gold-nanoparticle hybrid structure able to change its configuration,which is transduced in a change of its plasmonic properties,upon interaction with a specific DNA target.We investigated its response when analyzed in three different media:aqueous solution,solid support and viscous gel.We show that,once a conformational variation is produced,it remains unaffected by the subsequent physical interactions with the environment.

Contactless Monitoring of the Diameter-Dependent Conductivity of GaAs Nanowires

Contactless monitoring with photoelectron microspectroscopy of the surface potential along individual nano-structures,created by the X-ray nanoprobe,opens exciting possibilities to examine quantitatively size-and surface-chemistry-effects on the electrical transport of semiconductor nanowires(NWs).Implementing this novel approach-which combines surface chemical microanalysis with conductivity measurements-we explored the dependence of the electrical properties of undoped GaAs NWs on the NW width,temperature and surface chemistry.By following the evolution of the Ga 3d and As 3d core level spectra,we measured the position-dependent surface potential along the GaAs NWs as a function of NW diameter,decreasing from 120 to~20 nm,and correlated the observed decrease of the conductivity with the monotonic reduction in the NW diameter from 120 to~20 nm.Exposure of the GaAs NWs to oxygen ambient leads to a decrease in their conductivity by up to a factor of 10,attributed to the significant decrease in the carrier density associated with the formation of an oxide shell.

Structural study of Yb^(3+), Eu^(3+) and Pr^(3+) doped Ca_9Lu(PO_4)_7

The whitlockite-like crystal structure of Ca9Lu（PO4）7 when doped with several ions （Yb3＋, EU3＋ and Pr3＋） at different concentrations （1 tool.%, 5 mol.% and 10 tool.%） was studied, by means of synchrotron X-ray diffraction. In particular for Eu3＋ and Pr3＋, the presence of the dopant ion significantly changed the occupation factors （OFs） of the Ca2＋ and Lu3＋ cations and gave rise to a distortion of the metal-oxygen polyhedra. The observed structural features clearly showed significant impact of the dopant ion on the crystal structure of the host.

Size contrast of Pt nanoparticles formed on neighboring domains within suspended and supported graphene

The relatively small size of thin （one or few layers） graphene flakes makes it extremely difficult to study the behavior of suspended graphene by characterization techniques other than the electron microscopies. Herein, we exploited the capability of spatially resolved photoemission in combination with high resolution transmission electron microscopy to investigate the interaction of thermally evaporated Pt atoms on suspended and supported graphene. Spectroscopic and microscopic analyses reveal that the nucleation of nanometer- sized Pt particles in these two regions exhibit different trends. While only small nanometer-sized islands are present on the supported graphene, relatively larger clusters of islands were also found on the suspended flakes. The X-ray photoemission C ls core levels acquired after the Pt deposition show an increase in the number of vacancies in the graphene sheets.

Weak mismatch epitaxy and structural feedback in graphene growth on copper foil

Graphene growth by low-pressure chemical vapor deposition on low cost copper foils shows great promise for large scale applications. It is known that the local crystallography of the foil influences the graphene growth rate. Here we find an epitaxial relationship between graphene and copper foil. Interfacial restructuring between graphene and copper drives the formation of （nl0） facets on what is otherwise a mostly Cu（100） surface, and the facets in turn influence the graphene orientations from the onset of growth. Angle resolved photoemission shows that the electronic structure of the graphene is decoupled from the copper indicating a weak interaction between them. Despite this, two preferred orientations of graphene are found, ±8° from the Cu[010] direction, creating a non-uniform distribution of graphene grain boundary misorientation angles. Comparison with the model system of graphene growth on single crystal Cu（110） indicates that this orientational alignment is due to mismatch epitaxy. Despite the differences in symmetry the orientation of the graphene is defined by that of the copper. We expect these observations to not only have importance for controlling and understanding the growth process for graphene on copper, but also to have wider implications for the growth of two-dimensional materials on low cost metal substrates.

There is life after coking for Ir nanocatalyst superlattices

Achieving superior performance of nanoparticle systems is one of the biggest challenges in catalysis.Two major phenomena,occurring during the reactions,hinder the development of the full potential of nanoparticle catalysts:sintering and contamination with carbon containing species,sometimes called coking.Here,we demonstrate that Ir nanocrystals,arranged into periodic networks on hexagonal boron nitride(h-BN)supports,can be restored without sintering after contamination by persistent carbon.This restoration yields the complete removal of carbon from the nanocrystals,which keep their crystalline structure,allowing operation without degradation.These findings,together with the possibility of fine tuning the nanocrystals size,confer this nanoparticle system a great potential as a testbed to extract key information about catalysis-mediated oxidation reactions.For the case of the CO oxidation by O2,reaction of interest in environmental science and green energy production,the existence of chemical processes not observed before in other nanoparticle systems is demonstrated.

Inclusion of infrared dielectric screening in the GW method from polaron energies to charge mobilities

We introduce in the many-body GW scheme the modulation of the screened Coulomb interaction W arising from the macroscopic dielectric response in the infrared.We derive expressions for the polaron binding energies,the renormalization of the effective masses and for the electron and hole relaxation times.Electron and hole mobilities are then obtained from the incorporation of appropriate scattering rules.Zinc-blende GaN and orthorhombic MAPbI3 are used as test beds finding fair agreement with results from rigorous electron-phonon coupling approaches.Although limited to polar phonons,our method has a negligible computational cost.