A deep learning algorithm to predict risk of pancreatic cancer from disease trajectories.

Pancreatic cancer is an aggressive disease that typically presents late with poor outcomes, indicating a pronounced need for early detection. In this study, we applied artificial intelligence methods to clinical data from 6 million patients (24,000 pancreatic cancer cases) in Denmark (Danish National Patient Registry (DNPR)) and from 3 million patients (3,900 cases) in the United States (US Veterans Affairs (US-VA)). We trained machine learning models on the sequence of disease codes in clinical histories and tested prediction of cancer occurrence within incremental time windows (CancerRiskNet). For cancer occurrence within 36 months, the performance of the best DNPR model has area under the receiver operating characteristic (AUROC) curve = 0.88 and decreases to AUROC (3m) = 0.83 when disease events within 3 months before cancer diagnosis are excluded from training, with an estimated relative risk of 59 for 1,000 highest-risk patients older than age 50 years. Cross-application of the Danish model to US-VA data had lower performance (AUROC = 0.71), and retraining was needed to improve performance (AUROC = 0.78, AUROC (3m) = 0.76). These results improve the ability to design realistic surveillance programs for patients at elevated risk, potentially benefiting lifespan and quality of life by early detection of this aggressive cancer.

The kesterite-stannite structural transition as a way to avoid Cu/Zn disorder in kesterites: the exemplary case of the Cu2(Zn,Mn)SnSe4.

The solid solution series between Cu2ZnSnSe4, crystallizing in the kesterite type structure, and Cu2MnSnSe4, adopting the stannite type structure, i.e. Cu2(Zn1-xMnx)SnSe4, was studied by a combination of neutron and X-ray powder diffraction. Powder samples with 0 ≤ x ≤ 1 were synthesized by the solid state reaction of the pure elements and it was confirmed by wavelength-dispersive X-ray spectroscopy that each contained a homogeneous, off-stoichiometric quaternary phase. The lattice parameters and cation site occupancy factors were determined simultaneously by the Rietveld analysis of the neutron and X-ray powder diffraction data. The refined site occupancy factors were used to determine the average neutron scattering length of the cation sites in the crystal structure of the Cu2(Zn1-xMnx)SnSe4 mixed crystals, from which a cation distribution model was derived. For the end member Cu2ZnSnSe4, the disordered kesterite structure was confirmed and for Cu2MnSnSe4, the stannite structure was confirmed. The cross-over from the kesterite to stannite type structure by Zn2+ ↔ Mn2+ substitution in the Cu2Zn1-xMnxSnSe4 solid solution can be seen as a cation re-distribution process among the positions (0, 0, 0), (0, ½, ») and (0, », ¾), including Cu+, Zn2+ and Mn2+. The Sn4+ cation does not take part in this process and remains on the 2b site. Moreover, the cross-over is also visible in the ratio of the lattice parameters c/(2a), showing a characteristic dependence on the chemical composition. The order parameter Q, the quantitative measure of Cu/BII disorder (BII = Zn and Mn), shows a distinct dependence on the Mn/(Mn + Zn) ratio. In Zn-rich Cu2(Zn1-xMnx)SnSe4 mixed crystals, the order parameter Q ∼ 0.7 and drops to Q ∼ 0 (complete Cu/BII disorder) in the compositional region 0.3 ≥ x ≥ 0.7. In Mn-rich Cu2(Zn1-xMnx)SnSe4 mixed crystals, adopting the stannite type structure, the order parameter reaches almost Q ∼ 1 (order). Thus, it can be concluded that only Mn-rich Cu2(Zn1-xMnx)SnSe4 mixed crystals do not show Cu/BII disorder. A similar trend of the dependence on the chemical composition of both Cu/BII-disorder and the band gap energy Eg in Cu2(Zn1-xMnx)SnSe4 mixed crystals was observed.

Molecular response to PARP1 inhibition in ovarian cancer cells as determined by mass spectrometry based proteomics.

BACKGROUND: Poly (ADP)-ribose polymerase (PARP) inhibitors have entered routine clinical practice for the treatment of high-grade serous ovarian cancer (HGSOC), yet the molecular mechanisms underlying treatment response to PARP1 inhibition (PARP1i) are not fully understood. METHODS: Here, we used unbiased mass spectrometry based proteomics with data-driven protein network analysis to systematically characterize how HGSOC cells respond to PARP1i treatment. RESULTS: We found that PARP1i leads to pronounced proteomic changes in a diverse set of cellular processes in HGSOC cancer cells, consistent with transcript changes in an independent perturbation dataset. We interpret decreases in the levels of the pro-proliferative transcription factors SP1 and ß-catenin and in growth factor signaling as reflecting the anti-proliferative effect of PARP1i; and the strong activation of pro-survival processes NF-κB signaling and lipid metabolism as PARPi-induced adaptive resistance mechanisms. Based on these observations, we nominate several protein targets for therapeutic inhibition in combination with PARP1i. When tested experimentally, the combination of PARPi with an inhibitor of fatty acid synthase (TVB-2640) has a 3-fold synergistic effect and is therefore of particular pre-clinical interest. CONCLUSION: Our study improves the current understanding of PARP1 function, highlights the potential that the anti-tumor efficacy of PARP1i may not only rely on DNA damage repair mechanisms and informs on the rational design of PARP1i combination therapies in ovarian cancer.

High-Yield Human Induced Pluripotent Stem Cell-Derived Monocytes and Macrophages Are Functionally Comparable With Primary Cells.

Macrophages are pivotal effectors of host immunity and regulators of tissue homeostasis. Understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human induced pluripotent stem cell (hiPSC)-derived monocytes and macrophages, as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of macrophage biology and implication in human diseases. In this study, we present a fully optimized differentiation protocol of hiPSC-derived monocytes and granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF). We present characterization of iPSC-derived myeloid lineage cells at phenotypic, functional, and transcriptomic levels, in comparison with corresponding subsets of peripheral blood-derived cells. We also highlight the application of hiPSC-derived monocytes and macrophages as a gene-editing platform for functional validation in research and drug screening, and the study also provides a reference for cell therapies.

HoHO: A Paramagnetic Air-Resistant Ionic Hydride with Ordered Anions.

The substitution of hydrogen for oxygen atoms in metal oxides provides opportunities for influencing the solid-state properties. Such hydride oxides (or oxyhydrides) are potential functional materials and scarce. Here, we present the synthesis and characterization of holmium hydride oxide with the stoichiometric composition HoHO. It was prepared by the reaction of Ho2O3 with either HoH3 or CaH2 as a powder of light-yellow color in sunlight and pink color in artificial light (Alexandrite effect), which is commonly observed for ionic Ho(III) compounds. HoHO crystallizes with an ordered fluorite superstructure (F4̅3m, a = 5.27550(13) Å, half-Heusler LiAlSi type), as evidenced by powder X-ray and neutron powder diffraction on both hydride and deuteride and supported by quantum-mechanical calculations. HoHO is the first representative with considerable ionic bonding for this structure type. The thermal stability and inertness toward air are remarkably high for a hydride because it reacts only above 540 K to form Ho2O3. At 294(1) K and 25(3)% relative humidity, HoHO is stable for at least 3 months. HoHO is paramagnetic with µeff(Ho3+) = 10.41(2) µB without any sign of magnetic ordering down to 2 K.

Siglec-15 recognition of sialoglycans on tumor cell lines can occur independently of sialyl Tn antigen expression.

Siglec-15 is a conserved sialic acid-binding Ig-like lectin expressed on osteoclast progenitors, which plays an important role in osteoclast development and function. It is also expressed by tumor-associated macrophages and by some tumors, where it is thought to contribute to the immunosuppressive microenvironment. It was shown previously that engagement of macrophage-expressed Siglec-15 with tumor cells expressing its ligand, sialyl Tn (sTn), triggered production of TGF-ß. In the present study, we have further investigated the interaction between Siglec-15 and sTn on tumor cells and its functional consequences. Based on binding assays with lung and breast cancer cell lines and glycan-modified cells, we failed to see evidence for recognition of sTn by Siglec-15. However, using a microarray of diverse, structurally defined glycans, we show that Siglec-15 binds with higher avidity to sialylated glycans other than sTn or related antigen sequences. In addition, we were unable to demonstrate enhanced TGF-ß secretion following co-culture of Siglec-15-expressing monocytic cell lines with tumor cells expressing sTn or following Siglec-15 cross-linking with monoclonal antibodies. However, we did observe activation of the SYK/MAPK signaling pathway following antibody cross-linking of Siglec-15 that may modulate the functional activity of macrophages.

Unravelling the crystal structure of Nd5.8WO12-δ and Nd5.7W0.75Mo0.25O12-δ mixed ionic electronic conductors.

Mixed ionic electronic conducting ceramics Nd6-y WO12-δ (δ is the oxygen deficiency) provide excellent stability in harsh environments containing strongly reactive gases such as CO2, CO, H2, H2O or H2S. Due to this chemical stability, they are promising and cost-efficient candidate materials for gas separation, catalytic membrane reactors and protonic ceramic fuel cell technologies. As in La6-y WO12-δ, the ionic/electronic transport mechanism in Nd6-y WO12-δ is expected to be largely controlled by the crystal structure, the conclusive determination of which is still lacking. This work presents a crystallographic study of Nd5.8WO12-δ and molybdenum-substituted Nd5.7W0.75Mo0.25O12-δ prepared by the citrate complexation route. High-resolution synchrotron and neutron powder diffraction data were used in combined Rietveld refinements to unravel the crystal structure of Nd5.8WO12-δ and Nd5.7W0.75Mo0.25O12-δ. Both investigated samples crystallize in a defect fluorite crystal structure with space group Fm 3 m and doubled unit-cell parameter due to cation ordering. Mo replaces W at both Wyckoff sites 4a and 48h and is evenly distributed, in contrast with La6-y WO12-δ. X-ray absorption spectroscopy as a function of partial pressure pO2 in the near-edge regions excludes oxidation state changes of Nd (Nd3+) and W (W6+) in reducing conditions: the enhanced hydrogen permeation, i.e. ambipolar conduction, observed in Mo-substituted Nd6-y WO12-δ is therefore explained by the higher Mo reducibility and the creation of additional - disordered - oxygen vacancies.

The influence of deuteration on the crystal structure of hybrid halide perovskites: a temperature-dependent neutron diffraction study of FAPbBr3.

This paper discusses the full structural solution of the hybrid perovskite formamidinium lead tribromide (FAPbBr3) and its temperature-dependent phase transitions in the range from 3 K to 300 K using neutron powder diffraction and synchrotron X-ray diffraction. Special emphasis is put on the influence of deuteration on formamidinium, its position in the unit cell and disordering in comparison to fully hydrogenated FAPbBr3. The temperature-dependent measurements show that deuteration critically influences the crystal structures, i.e. results in partially-ordered temperature-dependent structural modifications in which two symmetry-independent molecule positions with additional dislocation of the molecular centre atom and molecular angle inclinations are present.

Specific Isotope-Responsive Breathing Transition in Flexible Metal-Organic Frameworks.

An isotope-selective responsive system based on molecular recognition in porous materials has potential for the storage and purification of isotopic mixtures but is considered unachievable because of the almost identical physicochemical properties of the isotopes. Herein, a unique isotope-responsive breathing transition of the flexible metal-organic framework (MOF), MIL-53(Al), which can selectively recognize and respond to only D2 molecules through a secondary breathing transition, is reported. This novel phenomenon is examined using in situ neutron diffraction experiments under the same conditions for H2 and D2 sorption experiments. This work can guide the development of a novel isotope-selective recognition system and provide opportunities to fabricate flexible MOF systems for energy-efficient purification of the isotopic mixture.

Exploiting Dynamic Opening of Apertures in a Partially Fluorinated MOF for Enhancing H2 Desorption Temperature and Isotope Separation.

Deuterium has been recognized as an irreplaceable element in industrial and scientific research. However, hydrogen isotope separation still remains a huge challenge due to the identical physicochemical properties of the isotopes. In this paper, a partially fluorinated metal-organic framework (MOF) with copper, a so-called FMOFCu, was investigated to determine the separation efficiency and capacity of the framework for deuterium extraction from a hydrogen isotope mixture. The unique structure of this porous material consists of a trimodal pore system with large tubular cavities connected through a smaller cavity with bottleneck apertures with a size of 3.6 Å plus a third hidden cavity connected by an even smaller aperture of 2.5 Å. Depending on the temperature, these two apertures show a gate-opening effect and the cavities get successively accessible for hydrogen with increasing temperature. Thermal desorption spectroscopy (TDS) measurements indicate that the locally flexible MOF can separate D2 from anisotope mixture efficiently, with a selectivity of 14 at 25 K and 4 at 77 K.

Towards general network architecture design criteria for negative gas adsorption transitions in ultraporous frameworks.

Switchable metal-organic frameworks (MOFs) have been proposed for various energy-related storage and separation applications, but the mechanistic understanding of adsorption-induced switching transitions is still at an early stage. Here we report critical design criteria for negative gas adsorption (NGA), a counterintuitive feature of pressure amplifying materials, hitherto uniquely observed in a highly porous framework compound (DUT-49). These criteria are derived by analysing the physical effects of micromechanics, pore size, interpenetration, adsorption enthalpies, and the pore filling mechanism using advanced in situ X-ray and neutron diffraction, NMR spectroscopy, and calorimetric techniques parallelised to adsorption for a series of six isoreticular networks. Aided by computational modelling, we identify DUT-50 as a new pressure amplifying material featuring distinct NGA transitions upon methane and argon adsorption. In situ neutron diffraction analysis of the methane (CD4) adsorption sites at 111 K supported by grand canonical Monte Carlo simulations reveals a sudden population of the largest mesopore to be the critical filling step initiating structural contraction and NGA. In contrast, interpenetration leads to framework stiffening and specific pore volume reduction, both factors effectively suppressing NGA transitions.

Negative Thermal Expansion in (Hf,Ti)Fe2 Induced by the Ferromagnetic and Antiferromagnetic Phase Coexistence.

Negative thermal expansion (NTE) is an intriguing physical phenomenon that can be used in the applications of thermal expansion adjustment of materials. In this study, we report a NTE compound of (Hf,Ti)Fe2, while both end members of HfFe2 and TiFe2 show positive thermal expansion. The results reveal that phase coexistence is detected in the whole NTE zone, in which one phase is ferromagnetic (FM), while the other is antiferromagnetic (AFM). With increasing temperature, the FM phase is gradually transformed to the AFM one. The NTE phenomenon occurs in the present (Hf,Ti)Fe2 because of the fact that the unit cell volume of the AFM phase is smaller than that of the FM phase, and the mass fraction of the AFM phase increases with increasing temperature. The construction of phase coexistence can be a method to achieve NTE materials in future studies.

Crystallographic and electronic evolution of lanthanum strontium ferrite (La0.6Sr0.4FeO3-δ) thin film and bulk model systems during iron exsolution.

We study the changes in the crystallographic phases and in the chemical states during the iron exsolution process of lanthanum strontium ferrite (LSF, La0.6Sr0.4FeO3-δ). By using thin films of orthorhombic LSF, grown epitaxially on NaCl(001) and rhombohedral LSF powder, the materials gap is bridged. The orthorhombic material transforms into a fluorite structure after the exsolution has begun, which further hinders this process. For the powder material, by a combination of in situ core level spectroscopy and ex situ neutron diffraction, we could directly highlight differences in the Fe chemical nature between surface and bulk: whereas the bulk contains Fe(iv) in the fully oxidized state, the surface spectra can be described perfectly by the sole presence of Fe(iii). We also present corresponding magnetic and oxygen vacancy concentration data of reduced rhombohedral LSF that did not undergo a phase transformation to the cubic perovskite system based on neutron diffraction data.

The phase diagram of a mixed halide (Br, I) hybrid perovskite obtained by synchrotron X-ray diffraction.

By using synchrotron X-ray powder diffraction, the temperature dependent phase diagram of the hybrid perovskite tri-halide compounds, methyl ammonium lead iodide (MAPbI3, MA+ = CH3NH3 +) and methyl ammonium lead bromide (MAPbBr3), as well as of their solid solutions, has been established. The existence of a large miscibility gap between 0.29 ≤ x ≤ 0.92 (±0.02) for the MAPb(I1-x Br x )3 solid solution has been proven. A systematic study of the lattice parameters for the solid solution series at room temperature revealed distinct deviations from Vegard's law. Furthermore, temperature dependent measurements showed that a strong temperature dependency of lattice parameters from the composition is present for iodine rich compositions. In contrast, the bromine rich compositions show an unusually low dependency of the phase transition temperature from the degree of substitution.

Determination of the miscibility gap in the solid solutions series of methylammonium lead iodide/chloride.

Perovskites are widely known for their enormous possibility of elemental substitution, which leads to a large variety of physical properties. Hybrid perovskites such as CH3NH3PbI3 (MAPbI3) and CH3NH3PbCl3 (MAPbCl3) are perovskites with an A[XII]B[VI]X[II]3-structure, where A is an organic molecule, B is a lead(II) cation and X is a halide anion of iodine or chlorine. Whereas MAPbCl3 crystallizes in the cubic space group Pm{\overline 3}m, MAPbI3 is in the tetragonal space group I4/mcm. The substitution of I by Cl leads to an increased tolerance against humidity but is challenging or even impossible due to their large difference in ionic radii. Here, the influence of an increasing Cl content in the reaction solution on the miscibility of the solid solution members is examined systematically. Powders were synthesized by two different routes depending on the I:Cl ratio. High-resolution synchrotron X-ray data are used to establish values for the limits of the miscibility gap which are 3.1 (1.1) mol% MAPbCl3 in MAPI and 1.0 (1) mol% MAPbI3 in MAPCl. The establishment of relations between average pseudo-cubic lattice parameters for both phases allows a determination of the degree of substitution from the observed lattice parameters.

On the elusive nature of oxygen binding at coordinatively unsaturated 3d transition metal centers in metal-organic frameworks.

Using gas sorption measurements at ambient temperatures and in situ neutron powder diffraction methods, we have studied the interaction strengths and coordination geometries of O2 and N2 near the non-occupied coordination site (open metal site) in the isostructural MOF structures of the CPO-27-M/M-MOF-74 series (with M = Co, Ni, Mn and Cu). Our experimental observations are compared to periodic quantum chemical model calculations. Contrary to recent computational studies, our results, both experimental and theoretical, unequivocally suggest rather weak interactions between the M(ii) coordinatively unsaturated centers and the adsorbate molecules, being mainly dispersive and electrostatic in nature. As a consequence, they exclude significant orbital charge transfer effects that could lead to superoxide/peroxide formation. Calculated binding energies appear in good agreement with the measured isosteric heats of adsorption in the range of 10-20 kJ mol-1. These, relatively weak host-guest interactions, lead to a tilted end-on geometry in all of the investigated M(ii)-guest molecule adducts.

Generation of genome-modified Drosophila cell lines using SwAP.

The ease of generating genetically modified animals and cell lines has been markedly increased by the recent development of the versatile CRISPR/Cas9 tool. However, while the isolation of isogenic cell populations is usually straightforward for mammalian cell lines, the generation of clonal Drosophila cell lines has remained a longstanding challenge, hampered by the difficulty of getting Drosophila cells to grow at low densities. Here, we describe a highly efficient workflow to generate clonal Cas9-engineered Drosophila cell lines using a combination of cell pools, limiting dilution in conditioned medium and PCR with allele-specific primers, enabling the efficient selection of a clonal cell line with a suitable mutation profile. We validate the protocol by documenting the isolation, selection and verification of eight independently Cas9-edited armadillo mutant Drosophila cell lines. Our method provides a powerful and simple workflow that improves the utility of Drosophila cells for genetic studies with CRISPR/Cas9.

Probing the canonicity of the Wnt/Wingless signaling pathway.

The hallmark of canonical Wnt signaling is the transcriptional induction of Wnt target genes by the beta-catenin/TCF complex. Several studies have proposed alternative interaction partners for beta-catenin or TCF, but the relevance of potential bifurcations in the distal Wnt pathway remains unclear. Here we study on a genome-wide scale the requirement for Armadillo (Arm, Drosophila beta-catenin) and Pangolin (Pan, Drosophila TCF) in the Wnt/Wingless(Wg)-induced transcriptional response of Drosophila Kc cells. Using somatic genetics, we demonstrate that both Arm and Pan are absolutely required for mediating activation and repression of target genes. Furthermore, by means of STARR-sequencing we identified Wnt/Wg-responsive enhancer elements and found that all responsive enhancers depend on Pan. Together, our results confirm the dogma of canonical Wnt/Wg signaling and argue against the existence of distal pathway branches in this system.

The bromodomain protein BRD4 regulates splicing during heat shock.

The cellular response to heat stress is an ancient and evolutionarily highly conserved defence mechanism characterised by the transcriptional up-regulation of cyto-protective genes and a partial inhibition of splicing. These features closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response, mainly due to its role in the transcriptional regulation process. In addition, there are also several lines of evidence implicating BRD4 in the splicing process. Using RNA-sequencing we found a significant increase in splicing inhibition, in particular intron retentions (IR), following heat treatment in BRD4-depleted cells. This leads to a decrease of mRNA abundancy of the affected transcripts, most likely due to premature termination codons. Subsequent experiments revealed that BRD4 interacts with the heat shock factor 1 (HSF1) such that under heat stress BRD4 is recruited to nuclear stress bodies and non-coding SatIII RNA transcripts are up-regulated. These findings implicate BRD4 as an important regulator of splicing during heat stress. Our data which links BRD4 to the stress induced splicing process may provide novel mechanisms of BRD4 inhibitors in regard to anti-cancer therapies.

The intron-enriched HERV-K(HML-10) family suppresses apoptosis, an indicator of malignant transformation.

BACKGROUND: Human endogenous retroviruses (HERVs) constitute 8% of the human genome and contribute substantially to the transcriptome. HERVs have been shown to generate RNAs that modulate host gene expression. However, experimental evidence for an impact of these regulatory transcripts on the cellular phenotype has been lacking. RESULTS: We characterized the previously little described HERV-K(HML-10) endogenous retrovirus family on a genome-wide scale. HML-10 invaded the ancestral genome of Old World monkeys about 35 Million years ago and is enriched within introns of human genes when compared to other HERV families. We show that long terminal repeats (LTRs) of HML-10 exhibit variable promoter activity in human cancer cell lines. One identified HML-10 LTR-primed RNA was in opposite orientation to the pro-apoptotic Death-associated protein 3 (DAP3). In HeLa cells, experimental inactivation of HML-10 LTR-primed transcripts induced DAP3 expression levels, which led to apoptosis. CONCLUSIONS: Its enrichment within introns suggests that HML-10 may have been evolutionary co-opted for gene regulation more than other HERV families. We demonstrated such a regulatory activity for an HML-10 RNA that suppressed DAP3-mediated apoptosis in HeLa cells. Since HML-10 RNA appears to be upregulated in various tumor cell lines and primary tumor samples, it may contribute to evasion of apoptosis in malignant cells. However, the overall weak expression of HML-10 transcripts described here raises the question whether our result described for HeLa represent a rare event in cancer. A possible function in other cells or tissues requires further investigation.