Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates

Cerebral amyloid angiopathy (CAA) is an age-related condition and a major cause of intracerebral hemorrhage and cognitive decline that shows close links with Alzheimer's disease (AD). CAA is characterized by the aggregation of amyloid-β (Aβ) peptides and formation of Aβ deposits in the brain vasculature resulting in a disruption of the angioarchitecture. Capillaries are a critical site of Aβ pathology in CAA type 1 and become dysfunctional during disease progression. Here, applying an advanced protocol for the isolation of parenchymal microvessels from post-mortem brain tissue combined with liquid chromatography tandem mass spectrometry (LC-MS/MS), we determined the proteomes of CAA type 1 cases (n = 12) including a patient with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and of AD cases without microvascular amyloid pathology (n = 13) in comparison to neurologically healthy controls (n = 12). ELISA measurements revealed microvascular Aβ1-40 levels to be exclusively enriched in CAA samples (mean: > 3000-fold compared to controls). The proteomic profile of CAA type 1 was characterized by massive enrichment of multiple predominantly secreted proteins and showed significant overlap with the recently reported brain microvascular proteome of patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease (SVD) characterized by the aggregation of the Notch3 extracellular domain. We found this overlap to be largely attributable to the accumulation of high-temperature requirement protein A1 (HTRA1), a serine protease with an established role in the brain vasculature, and several of its substrates. Notably, this signature was not present in AD cases. We further show that HTRA1 co-localizes with Aβ deposits in brain capillaries from CAA type 1 patients indicating a pathologic recruitment process. Together, these findings suggest a central role of HTRA1-dependent protein homeostasis in the CAA microvasculature and a molecular connection between multiple types of brain microvascular disease

From Gapped Excitons to Gapless Triplons in One Dimension

Often, exotic phases appear in the phase diagrams between conventional phases. Their elementary excitations are of particular interest. Here, we consider the example of the ionic Hubbard model in one dimension. This model is a band insulator (BI) for weak interaction and a Mott insulator (MI) for strong interaction. Inbetween, a spontaneously dimerized insulator (SDI) occurs which is governed by energetically low-lying charge and spin degrees of freedom. Applying a systematically controlled version of the continuous unitary transformations (CUTs) we are able to determine the dispersions of the elementary charge and spin excitations and of their most relevant bound states on equal footing. The key idea is to start from an externally dimerized system using the relative weak interdimer coupling as small expansion parameter which finally is set to unity to recover the original model.Comment: 18 pages, 10 figure

Phase locking the spin precession in a storage ring

This letter reports the successful use of feedback from a spin polarization measurement to the revolution frequency of a 0.97 GeV/$c$ bunched and polarized deuteron beam in the Cooler Synchrotron (COSY) storage ring in order to control both the precession rate ($\approx 121$ kHz) and the phase of the horizontal polarization component. Real time synchronization with a radio frequency (rf) solenoid made possible the rotation of the polarization out of the horizontal plane, yielding a demonstration of the feedback method to manipulate the polarization. In particular, the rotation rate shows a sinusoidal function of the horizontal polarization phase (relative to the rf solenoid), which was controlled to within a one standard deviation range of $\sigma = 0.21$ rad. The minimum possible adjustment was 3.7 mHz out of a revolution frequency of 753 kHz, which changes the precession rate by 26 mrad/s. Such a capability meets a requirement for the use of storage rings to look for an intrinsic electric dipole moment of charged particles

The Synovial Sarcoma-Associated SYT-SSX2 Oncogene Antagonizes the Polycomb Complex Protein Bmi1

This study demonstrates deregulation of polycomb activity by the synovial sarcoma-associated SYT-SSX2 oncogene, also known as SS18-SSX2. Synovial sarcoma is a soft tissue cancer associated with a recurrent t(X:18) translocation event that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. The role of the translocation products in this disease is poorly understood. We present evidence that the SYT-SSX2 fusion protein interacts with the polycomb repressive complex and modulates its gene silencing activity. SYT-SSX2 causes destabilization of the polycomb subunit Bmi1, resulting in impairment of polycomb-associated histone H2A ubiquitination and reactivation of polycomb target genes. Silencing by polycomb complexes plays a vital role in numerous physiological processes. In recent years, numerous reports have implicated gain of polycomb silencing function in several cancers. This study provides evidence that, in the appropriate context, expression of the SYT-SSX2 oncogene leads to loss of polycomb function. It challenges the notion that cancer is solely associated with an increase in polycomb function and suggests that any imbalance in polycomb activity could drive the cell toward oncogenesis. These findings provide a mechanism by which the SYT-SSX2 chimera may contribute to synovial sarcoma pathogenesis

Thermal Conductivity of the Martian Soil at the InSight Landing site from HP3 Active Heating Experiments

The heat flow and physical properties package (HP3) of the InSight Mars mission is an instrument package designed to determine the martian planetary heat flow. To this end, the package was designed to emplace sensors into the martian subsurface and measure the thermal conductivity as well as the geothermal gradient in the 0-5 m depth range. After emplacing the probe to a tip depth of 0.37 m, a first reliable measurement of the average soil thermal conductivity in the 0.03 to 0.37 m depth range was performed. Using the HP3 mole as a modified line heat source, we determined a soil thermal conductivity of 0.039 +/- 0.002 W/mK, consistent with the results of orbital and in-situ thermal inertia measurements. This low thermal conductivity implies that 85 to 95% of all particles are smaller than 104-173 micrometer and suggests that any cement contributing to soil cohesion cannot significantly increase grain-to-grain contact areas by forming cementing necks, but could be distributed in the form of grain coatings instead. Soil densities compatible with the measurements are 1211(-113+149) kg/m3, indicating soil porosities of 61

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

Validation of Plasmodium falciparum dUTPase as the target of 5'-tritylated deoxyuridine analogues with anti-malarial activity

BACKGROUND: Malaria remains as a major global problem, being one of the infectious diseases that engender highest mortality across the world. Due to the appearance of resistance and the lack of an effective vaccine, the search of novel anti-malarials is required. Deoxyuridine 5'-triphosphate nucleotido-hydrolase (dUTPase) is responsible for the hydrolysis of dUTP to dUMP within the parasite and has been proposed as an essential step in pyrimidine metabolism by providing dUMP for thymidylate biosynthesis. In this work, efforts to validate dUTPase as a drug target in Plasmodium falciparum are reported. METHODS: To investigate the role of PfdUTPase in cell survival different strategies to generate knockout mutants were used. For validation of PfdUTPase as the intracellular target of four inhibitors of the enzyme, mutants overexpressing PfdUTPase and HsdUTPase were created and the IC50 for each cell line with each compound was determined. The effect of these compounds on dUTP and dTTP levels from P. falciparum was measured using a DNA polymerase assay. Detailed localization studies by indirect immunofluorescence microscopy and live cell imaging were also performed using a cell line overexpressing a Pfdut-GFP fusion protein. RESULTS:Different attempts of disruption of the dut gene of P. falciparum were unsuccessful while a 3' replacement construct could recombine correctly in the locus suggesting that the enzyme is essential. The four 5'-tritylated deoxyuridine analogues described are potent inhibitors of the P. falciparum dUTPase and exhibit antiplasmodial activity. Overexpression of the Plasmodium and human enzymes conferred resistance against selective compounds, providing chemical validation of the target and confirming that indeed dUTPase inhibition is involved in anti-malarial activity. In addition, incubation with these inhibitors was associated with a depletion of the dTTP pool corroborating the central role of dUTPase in dTTP synthesis. PfdUTPase is mainly localized in the cytosol. CONCLUSION: These results strongly confirm the pivotal and essential role of dUTPase in pyrimidine biosynthesis of P. falciparum intraerythrocytic stages

Judicial decision-making within political parties: A political approach

How do German intra-party tribunals manage internal conflicts? More specifically, why do they accept some cases for trial but reject others? Required by law to strictly adhere to implement rule of law standards, German intra-party tribunals are designed to insulate conflict regulation from politics. Meanwhile, research on judicial politics highlights the role of political and strategic considerations in accepting cases for trial. Building on the latter, we develop a theory that emphasizes tribunals’ political concerns such as winning elections. We test our hypotheses with a mixed-effects logit model on a novel data set covering 1088 tribunal decisions in six German parties from 1967 until 2015. Our findings indicate that political factors exert a strong effect on tribunal case acceptance. Tribunals are more likely to accept cases when suffering electoral loss and after losing government office. Moreover, tribunals dismiss cases more easily when their parties display relatively high levels of policy agreement

The InSight HP3 Penetrator (Mole) on Mars: Soil Properties Derived from the Penetration Attempts and Related Activities

The NASA InSight Lander on Mars includes the Heat Flow and Physical Properties Package HP3 to measure the surface heat flow of the planet. The package uses temperature sensors that would have been brought to the target depth of 3–5 m by a small penetrator, nicknamed the mole. The mole requiring friction on its hull to balance remaining recoil from its hammer mechanism did not penetrate to the targeted depth. Instead, by precessing about a point midway along its hull, it carved a 7 cm deep and 5–6 cm wide pit and reached a depth of initially 31 cm. The root cause of the failure – as was determined through an extensive, almost two years long campaign – was a lack of friction in an unexpectedly thick cohesive duricrust. During the campaign – described in detail in this paper – the mole penetrated further aided by friction applied using the scoop at the end of the robotic Instrument Deployment Arm and by direct support by the latter. The mole tip finally reached a depth of about 37 cm, bringing the mole back-end 1–2 cm below the surface. It reversed its downward motion twice during attempts to provide friction through pressure on the regolith instead of directly with the scoop to the mole hull. The penetration record of the mole was used to infer mechanical soil parameters such as the penetration resistance of the duricrust of 0.3–0.7 MPa and a penetration resistance of a deeper layer (> 30 cm depth) of 4.9±0.4 MPa. Using the mole’s thermal sensors, thermal conductivity and diffusivity were measured. Applying cone penetration theory, the resistance of the duricrust was used to estimate a cohesion of the latter of 2–15 kPa depending on the internal friction angle of the duricrust. Pushing the scoop with its blade into the surface and chopping off a piece of duricrust provided another estimate of the cohesion of 5.8 kPa. The hammerings of the mole were recorded by the seismometer SEIS and the signals were used to derive P-wave and S-wave velocities representative of the topmost tens of cm of the regolith. Together with the density provided by a thermal conductivity and diffusivity measurement using the mole’s thermal sensors, the elastic moduli were calculated from the seismic velocities. Using empirical correlations from terrestrial soil studies between the shear modulus and cohesion, the previous cohesion estimates were found to be consistent with the elastic moduli. The combined data were used to derive a model of the regolith that has an about 20 cm thick duricrust underneath a 1 cm thick unconsolidated layer of sand mixed with dust and above another 10 cm of unconsolidated sand. Underneath the latter, a layer more resistant to penetration and possibly containing debris from a small impact crater is inferred. The thermal conductivity increases from 14 mW/m K to 34 mW/m K through the 1 cm sand/dust layer, keeps the latter value in the duricrust and the sand layer underneath and then increases to 64 mW/m K in the sand/gravel layer below