Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1.

Many childhood Wilms tumors are driven by mutations in the microRNA biogenesis machinery, but the mechanism by which these mutations drive tumorigenesis is unknown. Here we show that the transcription factor pleomorphic adenoma gene 1 (PLAG1) is a microRNA target gene that is overexpressed in Wilms tumors with mutations in microRNA processing genes. Wilms tumors can also overexpress PLAG1 through copy number alterations, and PLAG1 expression correlates with prognosis in Wilms tumors. PLAG1 overexpression accelerates growth of Wilms tumor cells in vitro and induces neoplastic growth in the developing mouse kidney in vivo. In both settings, PLAG1 transactivates insulin-like growth factor 2 (IGF2), a key Wilms tumor oncogene, and drives mammalian target of rapamycin complex 1 (mTORC1) signaling. These data link microRNA impairment to the PLAG1-IGF2 pathway, providing new insight into the manner in which common Wilms tumor mutations drive disease pathogenesis.

Ultrafast dynamics of hot carriers in a quasi-two-dimensional electron gas on InSe.

Two-dimensional electron gases (2DEGs) are at the base of current nanoelectronics because of their exceptional mobilities. Often the accumulation layer forms at polar interfaces with longitudinal optical (LO) modes. In most cases, the many-body screening of the quasi-2DEGs dramatically reduces the Fröhlich scattering strength. Despite the effectiveness of such a process, it has been recurrently proposed that a remote coupling with LO phonons persists even at high carrier concentration. We address this issue by perturbing electrons in an accumulation layer via an ultrafast laser pulse and monitoring their relaxation via time- and momentum-resolved spectroscopy. The cooling rate of excited carriers is monitored at doping level spanning from the semiconducting to the metallic limit. We observe that screening of LO phonons is not as efficient as it would be in a strictly 2D system. The large discrepancy is due to the remote coupling of confined states with the bulk. Our data indicate that the effect of such a remote coupling can be mimicked by a 3D Fröhlich interaction with Thomas-Fermi screening. These conclusions are very general and should apply to field effect transistors (FET) with high-κ dielectric gates, van der Waals heterostructures, and metallic interfaces between insulating oxides.

Scaling and Confinement in Ultrathin Chalcogenide Films as Exemplified by GeTe.

Chalcogenides such as GeTe, PbTe, Sb2 Te3 , and Bi2 Se3 are characterized by an unconventional combination of properties enabling a plethora of applications ranging from thermo-electrics to phase change materials, topological insulators, and photonic switches. Chalcogenides possess pronounced optical absorption, relatively low effective masses, reasonably high electron mobilities, soft bonds, large bond polarizabilities, and low thermal conductivities. These remarkable characteristics are linked to an unconventional bonding mechanism characterized by a competition between electron delocalization and electron localization. Confinement, that is, the reduction of the sample dimension as realized in thin films should alter this competition and modify chemical bonds and the resulting properties. Here, pronounced changes of optical and vibrational properties are demonstrated for crystalline films of GeTe, while amorphous films of GeTe show no similar thickness dependence. For crystalline films, this thickness dependence persists up to remarkably large thicknesses above 15 nm. X-ray diffraction and accompanying simulations employing density functional theory relate these changes to thickness dependent structural (Peierls) distortions, due to an increased electron localization between adjacent atoms upon reducing the film thickness. A thickness dependence and hence potential to modify film properties for all chalcogenide films with a similar bonding mechanism is expected.

Functional Monochalcogenides: Raman Evidence Linking Properties, Structure, and Metavalent Bonding.

Pressure- and temperature-dependent Raman scattering in GeSe, SnSe, and GeTe for pressures beyond 50 GPa and for temperatures ranging from 78 to 800 K allow us to identify structural and electronic phase transitions, similarities between GeSe and SnSe, and differences with GeTe. Calculations help to deduce the propensity of GeTe for defect formation and the doping that results from it, which gives rise to strong Raman damping beyond anomalous anharmonicity. These properties are related to the underlying chemical bonding and consistent with a recent classification of bonding in several chalcogenide materials that puts GeTe in a separate class of "incipient" metals.

Pressure-Induced Phase Transitions in Germanium Telluride: Raman Signatures of Anharmonicity and Oxidation.

Pressure-induced phase transitions in GeTe, a prototype phase change material, have been studied to date with diffraction which is not sensitive to anharmonicity-induced dynamical effects. GeTe is also prone to surface oxidation which may compromise surface sensitive measurements. These factors could be responsible for the lack of clarity about the phases and transitions intervening in the phase diagram of GeTe. We have used high-pressure Raman scattering and ab initio pseudopotential density functional calculations to unambiguously establish the high-pressure phase diagram and identify three phases up to 57 GPa, a low-pressure rhombohedral phase, an intermediate pressure cubic phase, and a high-pressure orthorhombic phase. We detect substantial broadening and softening of Raman modes at low pressure and identify the transition regions and possible intermediate phases.

Detecting non-bridging oxygens: non-resonant inelastic X-ray scattering in crystalline lithium borates.

Probing the local environment of low-Z elements, such as oxygen, is of great interest for understanding the atomic-scale behavior in materials, but it requires experimental techniques allowing it to work with versatile sample environments. In this paper, the local environment of lithium borate crystals is investigated using non-resonant inelastic X-ray scattering (NRIXS) at energy losses corresponding to the oxygen K-edge. Large variations of the spectral features are observed close to the edge onset in the 535-540 eV energy range when varying the Li2O content. Calculations allow identification of contributions associated with bridging oxygen (BO) and non-bridging oxygen (NBO) atoms. The main result resides in the observed core-level shift of about 1.7 eV in the spectral signatures of the BO and NBO. The clear signature at 535 eV in the O K-edge NRXIS spectrum is thus an original way to probe the presence of NBOs in borates, with the great advantage of making possible the use of complex environments such as a high-pressure cell or high-temperature device for in situ measurements.

Identification and molecular characterization of a novel splice variant of human 5- lipoxygenase gene.

5-Lipoxygenase (5-LO) is one of the members of Lipoxygenase family. It breaks down arachidonic acid to pro-inflammatory compounds like leukotrienes. Leukotriene plays a major role in the inflammatory process. In this study, while cloning full length 5-LO, a novel splice variant of 5-LO (t5-LO) was found to be expressed in HepG2 cell line. The complete ORF of t5-LO is 420 bp long, expressing 139 amino acid long proteins from N-terminal. The splice variant of 5-LO was cloned, expressed, purified in bacterial system and characterized by MS/MS and western blot experiments. The full length 5-LO is 674 amino acids long encoded by 2,025 bp long ORF. RT-PCR and western blot revealed that t5-LO is extensively expressed in HepG2 cell line.

Association of Systemic Markers of Inflammation with Signs and Symptoms of Dry Eye Disease and Sjogren's Syndrome in the Dry Eye Assessment and Management (DREAM©) Study.

PURPOSE: To evaluate the possible role of systemic inflammation in dry eye disease (DED) via systemic inflammatory marker associations with DED signs and symptoms, and an analysis of a subgroup with Sjogren's Syndrome (SS). METHODS: Participant serums were analyzed using line immunoassays (LIAs) for the presence of antibodies against 34 systemic inflammatory markers. Using the 2012 American College of Rheumatology definition, the 481 participants were categorized into group 1 (SS; n = 52), group 2 (autoimmune disease not including SS; n = 66), or group 3 (control, i.e. no autoimmune disease; n = 363). RESULTS: 3 markers were positive in ≥10% of participants: Ro52 (19.3%), Scl-70 (15.0%), CN-1A (14.2%). 2 markers were positively associated with symptoms: PM-Scl100 (p = 0.02), Sm (p = 0.009). 5 markers were positively associated with signs: U2SnRNP A', Ro52, La, DNA, Ro60. SS participants showed significantly higher positivity for 4 markers compared to participants with no autoimmune disease: PL-7 (p = 0.02), Ro52 (p < 0.0001), La (p < 0.0001), Ro60 (p < 0.0001). SS participants showed significantly higher positivity for 3 markers compared to participants with another autoimmune disease: Ro52 (p < 0.0001), La (p = 0.002), Ro60 (p < 0.0001). CONCLUSIONS: This study did not show evidence of significant systemic inflammation in participants with moderate-to-severe DED, based on the markers tested. PM-Scl100 and Sm may be associated with more severe DED symptoms. U2SnRNP A', Ro52, La, DNA, and Ro60 may be associated with more severe ocular surface disease. Ro52 and PL-7 may be diagnostic markers for SS. Future research evaluating these relationships and their clinical significance is needed.

Anodic bonded 2D semiconductors: from synthesis to device fabrication.

Two-dimensional semiconductors are increasingly relevant for emergent applications and devices, notably for hybrid heterostructures with graphene. We fabricate few-layer, large-area (a few tens of microns across) samples of the III-VI semiconductors GaS, GaSe and InSe using the anodic bonding method and characterize them by simultaneous use of optical microscopy, atomic force microscopy and Raman spectroscopy. Two-terminal devices with a gate are constructed to show the feasibility of applications based on these.

Gate and Temperature Driven Phase Transitions in Few-Layer MoTe2.

MoTe2 has a stable hexagonal semiconducting phase (2H) as well as two semimetallic phases with monoclinic (1T') and orthorhombic (Td) structures. A structural change can thus be accompanied by a significant change in electronic transport properties. The two semimetallic phases are connected by a temperature driven transition and could exhibit topological properties. Here we make extensive Raman measurements as a function of layer thickness, temperature, and electrostatic doping on few layer 2H-MoTe2 and also on 1T'-MoTe2 and Td-WTe2. Recent work in MoTe2 has raised the possibility of a 2H-1T' transition through technology compatible pathways. It has been claimed that such a transition, of promise for device applications, is activated by electrostatic gating. We investigate this claim and find that few-layer tellurides are characterized by high mobility of Te ions, even in ambient conditions and especially through the variation of external parameters like electric field or temperature. These can generate Te clusters, vacancies at crystalline sites, and facilitate structural transitions. We however find that the purported 2H-1T' transition in MoTe2 cannot be obtained by a pure electrostatic field.

Doping by Design: Enhanced Thermoelectric Performance of GeSe Alloys Through Metavalent Bonding.

Doping is usually the first step to tailor thermoelectrics. It enables precise control of the charge-carrier concentration and concomitant transport properties. Doping should also turn GeSe, which features an intrinsically a low carrier concentration, into a competitive thermoelectric. Yet, elemental doping fails to improve the carrier concentration. In contrast, alloying with Ag-V-VI2 compounds causes a remarkable enhancement of thermoelectric performance. This advance is closely related to a transition in the bonding mechanism, as evidenced by sudden changes in the optical dielectric constant ε∞ , the Born effective charge, the maximum of the optical absorption ε2 (ω), and the bond-breaking behavior. These property changes are indicative of the formation of metavalent bonding (MVB), leading to an octahedral-like atomic arrangement. MVB is accompanied by a thermoelectric-favorable band structure featuring anisotropic bands with small effective masses and a large degeneracy. A quantum-mechanical map, which distinguishes different types of chemical bonding, reveals that orthorhombic GeSe employs covalent bonding, while rhombohedral and cubic GeSe utilize MVB. The transition from covalent to MVB goes along with a pronounced improvement in thermoelectric performance. The failure or success of different dopants can be explained by this concept, which redefines doping rules and provides a "treasure map" to tailor p-bonded chalcogenides.

Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

High quality 2D crystals made by anodic bonding: a general technique for layered materials.

Anodic bonding of nanolayers is an easy technique based on a simple apparatus, which has already proven successful in application in the fabrication of high quality graphene. Here we demonstrate its extension to the fabrication of high quality nanolayers from several layered materials. The strengths of this technique are its high throughput rate and ease of application. All fabrication parameters are controllable and need to be determined carefully. We report optimal parameters found for nine layered materials. In general, using optimal parameters results in high quality 2D layers, in most cases much larger than those obtained by 'Scotch tape' microcleavage, with higher yields and which are easily transferable to other substrates. Moreover the samples obtained are clean and the good optical contrast of these layers on the glass substrate makes their identification very easy. This is thus the technique of choice for making nanolayers in the laboratory from any layered material.

Epigenetic regulation of cathepsin L expression in chronic myeloid leukaemia.

The expression and significance of cathepsin L (CTSL) has been extensively studied in solid tumours. However no such information in chronic myeloid leukaemia (CML) was available. We investigated the activity and expression of this protease in peripheral blood mononuclear cells (PBMCs) of 47 adult CML patients. Thirty adults suffering from systemic diseases and 50 healthy volunteers served as controls. The mRNA levels of CTSL, its specific endogenous inhibitor cystatin C and transcriptional up-regulator vascular endothelial growth factor (VEGF) were quantitated by real-time qPCR. CTSL protease activity and its mRNA expression were significantly higher in CML chronic phase (CP) patients compared to CML accelerated phase/blast crisis (AP/BC) patients and controls (P≤ 0.001). VEGF whose expression was most pronounced in CP and declined (P≤ 0.001) in the advanced phases of the malignancy exhibited a strong positive correlation with CTSL expression (r= 0.97; P≤ 0.001). Cystatin C expression was significantly lower (P≤ 0.001) in CML and displayed inverse correlation with CTSL (r=-0.713; P≤ 0.001) activity. CTSL promoter was significantly hypomethylated in CML CP compared to CML AP/BC patients as well as controls. K562, a BC CML cell line displayed CTSL activity, expression and methylation status of CTSL promoter that was comparable to CML AP/BC patients. Treatment of these cells or PBMCs isolated from CML AP/BC patients with 5'-aza-cytidine resulted in a dramatic increase in CSTL activity and/or expression thereby demonstrating the role of promoter methylation in the stage specific expression of CTSL in CML. Differential expression of CTSL in CML at various stages of malignancy may prove useful in identification of the high-risk patients thereby facilitating better management of disease.

Iron under pressure: "Kohn tweezers" and remnant magnetism.

In this work we investigate the magnetic and structural properties of bulk Fe and Fe nanoparticles under pressure with x-ray absorption and emission spectroscopies providing answers to two fundamental questions: (a) the chicken-or-egg problem for the magnetic and structural transitions and (b) magnetism in the high pressure hcp phase. The two transitions, inextricably linked in the bulk, are clearly decoupled in the nanoparticles, with the magnetic collapse preceding the structural transition. Ultrafast x-ray emission spectroscopy detects remnant magnetism, probably antiferromagnetic fluctuations, up to pressures of about 40 GPa in the hcp phase. This could be of direct relevance to the superconductivity in ϵ-Fe [K. Shimizu et al., Nature (London) 412, 316 (2001)] through the existence of a quantum critical point and associated magnetic fluctuations.

Dynamical reconstruction of the exciton in LiF with inelastic x-ray scattering.

The absorption of light by materials proceeds through the formation of excitons, which are states in which an excited electron is bound to the valence hole it vacated. Understanding the structure and dynamics of excitons is important, for example, for developing technologies for light-emitting diodes or solar energy conversion. However, there has never been an experimental means to study the time-dependent structure of excitons directly. Here, we use causality-inverted inelastic x-ray scattering (IXS) to image the charge-transfer exciton in the prototype insulator LiF, with resolutions Delta t = 20.67 as (2.067 x 10(-17) s) in time and Delta x = 0.533 A (5.33 x 10(-11) m) in space. Our results show that the exciton has a modulated internal structure and is coherently delocalized over two unit cells of the LiF crystal (approximately 8 A). This structure changes only modestly during the course of its life, which establishes it unambiguously as a Frenkel exciton and thus amenable to a simplified theoretical description. Our results resolve an old controversy about excitons in the alkali halides and demonstrate the utility of IXS for imaging attosecond electron dynamics in condensed matter.

Advancing the agenda for people-centred accountability of the private healthcare sector.

The thematic track on accountability of the private and corporate healthcare sectors during the COPASAH Global Symposium aimed to analyse the emergence of the global trend of commercialisation of health systems, and the transition of healthcare from being a public good to a marketable commodity, at the cost of publicly funded healthcare in developing countries. It examined the implications of the lack of state regulation and oversight which has enabled the profit driven private healthcare sector to exploit vulnerable people through overcharging, malpractices and violations of patient's rights. Finally, the session addressed challenges in advocacy of patients' rights and showcased effective campaign strategies used by health activists in different countries to promote accountability of the private healthcare sector. Putting together learnings and insights from this track will help in contributing towards a powerful global counter-narrative, while providing activists with the tools to create awareness and engage with this critical issue.

Superconductor-insulator transition in space charge doped one unit cell Bi2.1Sr1.9CaCu2O8+x.

The superconductor-insulator transition in two dimensions is a prototype continuous quantum phase transition at absolute zero, driven by a parameter other than temperature. Here we reveal this transition in one unit-cell Bi2.1Sr1.9CaCu2O8+x by space charge doping, a field effect electrostatic doping technique. We determine the related critical parameters and develop a reliable way to estimate doping in the nonsuperconducting region, a crucial and central problem in these materials. Finite-size scaling analysis yields a critical doping of 0.057 holes/Cu, a critical resistance of ~6.85 kΩ and a scaling exponent product νz ~ 1.57. These results, together with earlier work in other materials, provide a coherent picture of the superconductor-insulator transition and its bosonic nature in the underdoped regime of emerging superconductivity in high critical temperature superconductors.

Wild type p53-dependent transcriptional upregulation of cathepsin L expression is mediated by C/EBPα in human glioblastoma cells.

Mutations in the tumor suppressor gene p53 are frequent in human glioblastomas. Similarly cathepsin L, a lysosomal cysteine protease, is overexpressed and secreted by most human tumors including glioblastomas. However, hitherto there is no information on whether or not the mutation(s) in the p53 gene affect(s) expression of this protease. Using human glioblastoma cell lines harboring wild type and mutant p53, we demonstrate here for the first time that only the wild type but not the mutant p53 upregulates cathepsin L expression. By transfection of promoter reporter constructs, site-directed mutagenesis and chip assays we have established that wild type p53 elevates the levels of cathepsin L in these cells. It does so directly by binding to the cathepsin L promoter and also indirectly by inducing the expression of C/EBPα, which is crucial for the transcription of this protease. In view of its role in tumorigenesis, angiogenesis and tumor cell invasion, increased expression of cathepsin L in glioblastoma cells harboring wild type p53 might confer invasive ability and growth advantage to these cells. Therefore, use of cathepsin L inhibitors could prove useful in the management of these tumors.

Cathepsins B and L in peripheral blood mononuclear cells of pediatric acute myeloid leukemia: potential poor prognostic markers.

The diagnostic and prognostic significance of cathepsin B (CTSB) and L (CTSL) is well documented for solid tumors. However, their significance in acute leukemias is lacking. This study was planned to investigate expression and significance of these proteases in peripheral blood mononuclear cells (PBMCs) of patients with pediatric acute myeloid leukemia (AML). CTSL and CTSB activities were assayed in PBMCs of 24 children with AML and ten healthy controls by spectrofluorimetry. The mRNA levels of these proteases and their specific endogenous inhibitor cystatin C and transcriptional upregulator vascular endothelial growth factor (VEGF) were quantitated by real-time PCR. Correlation analysis of CTSL and CTSB activities/expression with their inhibitor/upregulator and event-free survival (EFS) was done using appropriate statistical tools. CTSL and CTSB protease activity and their mRNA expression were significantly higher in AML patients compared to controls (p ≤ 0.001). A strong positive correlation was observed between VEGF expression and CTSL (r = 0.812; p ≤ 0.001). Similarly, VEGF exhibited a strong positive correlation with CTSB (r = 0.501; p = 0.013). Cystatin expression though significantly high (p ≤ 0.001) in AML was negatively correlated with CTSL (r = -0.920; p ≤ 0.001) and CTSB (r = -0.580, p ≤ 0.001) expression. AML patients with higher CTSL and CTSB activity exhibited an inferior EFS (CTSL: p = 0.045; CTSB: p = 0.002) and overall survival (OS; CTSL: p = 0.05; CTSB: p = 0.004) compared to patients with lower levels of these proteases. This is the first report demonstrating increased expression of CTSL and CTSB in AML, mechanism of their increased expression in relation to VEGF, and their association with poor EFS and OS. These results suggest a potential utility of these proteases as prognostic markers for this malignancy.