Experimental Study of Brittle Behavior of Clay Shale in Rapid Triaxial Compression

The brittle failure behavior of an over-consolidated clay shale (Opalinus Clay) in undrained rapid triaxial compression was studied. The confining stress levels were chosen to simulate the range of confining stresses relevant for underground excavations at the Mont Terri Underground Research Laboratory, and to investigate the transition from axial splitting failure to macroscopic shear failure. Micro-crack initiation was observed throughout the confining stress range utilized in this study at a differential stress of 2.1MPa on average, which indicates that friction was not mobilized at this stage of brittle failure. The rupture stress was dependent on confinement indicating friction mobilization during the brittle failure process. With increasing confinement net volumetric strain decreased suggesting that dilation was suppressed, which is possibly related to a change in the failure mode. At confining stress levels ≤0.5 MPa specimen rupture was associated with axial splitting. With increasing confinement, transition to a macroscopic shearing mode was observed. Multi-stage triaxial tests consistently showed lower strengths than single-stage tests, demonstrating cumulative damage in the specimens. Both the Mohr-Coulomb and Hoek-Brown failure criteria could not satisfactorily fit the data over the entire confining stress range. A bi-linear or S-shaped failure criterion was found to satisfactorily fit the test data over the entire confinement range studie

Emulator-based global sensitivity analysis for flow-like landslide run-out models

Landslide run-out modeling involves various uncertainties originating from model input data. It is therefore desirable to assess the model's sensitivity. A global sensitivity analysis that is capable of exploring the entire input space and accounts for all interactions, often remains limited due to computational challenges resulting from a large number of necessary model runs. We address this research gap by integrating Gaussian process emulation into landslide run-out modeling and apply it to the open-source simulation tool r.avaflow. The feasibility and efficiency of our approach is illustrated based on the 2017 Bondo landslide event. The sensitivity of aggregated model outputs, such as the apparent friction angle, impact area, as well as spatially resolved maximum flow height and velocity, to the dry-Coulomb friction coefficient, turbulent friction coefficient and the release volume are studied. The results of first-order effects are consistent with previous results of common one-at-a-time sensitivity analyses. In addition to that, our approach allows to rigorously investigate interactions. Strong interactions are detected on the margins of the flow path where the expectation and variation of maximum flow height and velocity are small. The interactions generally become weak with increasing variation of maximum flow height and velocity. Besides, there are stronger interactions between the two friction coefficients than between the release volume and each friction coefficient. In the future, it is promising to extend the approach for other computationally expensive tasks like uncertainty quantification, model calibration, and smart early warning

Effect of acceleration forces during transport through a pneumatic tube system on ROTEM® analysis

Background: ROTEM® is considered a helpful point-of-care device to monitor blood coagulation in emergency situations. Centrally performed analysis is desirable but rapid transport of blood samples is an important prerequisite. The effect of acceleration forces on sample transport through a pneumatic tube system on ROTEM® should be tested at each institution to exclude a pre-analytical influence. The aims of the present work were: (i) to investigate the effect of pneumatic tube transport on ROTEM® parameters; (ii) to compare blood sample transport via pneumatic tube vs. manual transportation; and (iii) to determine the effect of acceleration forces on ROTEM® parameters. Methods: This is a single centre study with 20 healthy volunteers. Five whole blood samples were transferred to the central haematology laboratory by either normal transport or pneumatic delivery with different speed and acceleration forces. EXTEM, INTEM, FIBTEM and APTEM were analysed in parallel with two ROTEM® devices and compared. Acceleration forces were measured during transport with two different instruments. Results: Increment of transport time, speed and distance resulted in an augmentation of acceleration forces and peaks. All results of the ROTEM® analysis after manual transport or pneumatic delivery were within normal range. However, increase in acceleration forces resulted in minimally but statistically significant changes in multiple ROTEM® parameters. The higher the acceleration forces, the more ROTEM® parameters are influenced. Conclusions: Acceleration forces during transport through a pneumatic tube system have an influence on ROTEM® parameters. Prior to transfer blood samples via pneumatic tube system these influences should be tested to exclude clinically relevant blood coagulation activation in vitr

Experimental Study of the Brittle Behavior of Clay shale in Rapid Unconfined Compression

The mechanical behavior of clay shales is of great interest in many branches of geo-engineering, including nuclear waste disposal, underground excavations, and deep well drilling. Observations from test galleries (Mont Terri, Switzerland and Bure, France) in these materials have shown that the rock mass response near the excavation is associated with brittle failure processes combined with bedding parallel shearing. To investigate the brittle failure characteristics of the Opalinus Clay recovered from the Mont Terri Underground Research Laboratory, a series of 19 unconfined uniaxial compression tests were performed utilizing servo-controlled testing procedures. All specimens were tested at their natural water content with loading approximately normal to the bedding. Acoustic emission (AE) measurements were utilized to help quantify stress levels associated with crack initiation and propagation. The unconfined compression strength of the tested specimens averaged 6.9MPa. The crack initiation threshold occurred at approximately 30% of the rupture stress based on analyzing both the acoustic emission measurements and the stress-strain behavior. The crack damage threshold showed large variability and occurred at approximately 70% of the rupture stres

Multi-scale hydraulic characterization of stimulated fractured crystalline rock at Grimsel test site

In-situ Stimulation and Circulation (ISC), Swiss Alps, hydraulic fracturing, hermo-hydro-mechanical (THM) behavior

Crack Initiation and Crack Propagation in Heterogeneous Sulfate-Rich Clay Rocks

Brittle fracture processes were hypothesized by several researches to cause a damage zone around an underground excavation in sulfate-rich clay rock when the stress exceeds the crack initiation threshold, and may promote swelling by crystal growth in newly formed fractures. In this study, laboratory experiments such as unconfined and confined compression tests with acoustic emission monitoring, and microstructural and mineralogical analyses are used to explain brittle fracture processes in sulfate-rich clay rock from the Gipskeuper formation in Switzerland. This rock type typically shows a heterogeneous rock fabric consisting of distinct clayey layers and stiff heterogeneities such as anhydrite layers, veins or nodules. The study showed that at low deviatoric stress, the failure behavior is dominated by the strength of the clayey matrix where microcracks are initiated. With increasing deviatoric stress or strain, growing microcracks eventually are arrested at anhydrite veins, and cracks develop either aligned with the interface between clayey layers and anhydrite veins, or penetrate anhydrite veins. These cracks often link micro-fractured regions in the specimen. This study also suggest that fracture localization in sulfate-rich clay rocks, which typically show a heterogeneous rock fabric, does not take place in the pre-peak range and renders unstable crack propagation less likely. Sulfate-rich clay rocks typically contain anhydrite veins at various scales. At the scale of a tunnel, anhydrite layers or veins may arrest growing fractures and prevent the disintegration of the rock mass. The rock mass may be damaged when the threshold stress for microcrack initiation is exceeded, thus promoting swelling by crystal growth in extension fractures, but the self-supporting capacity of the rock mass may be maintained rendering the possibility for rapidly propagating instability less likely

Osteopontin and Fibronectin Levels Are Decreased in Vitreous of Autoimmune Uveitis and Retinal Expression of Both Proteins Indicates ECM Re-Modeling

Autoimmune uveitis is an intraocular inflammation that arises through autoreactive T-cells attacking the inner eye, eventually leading to blindness. However, the contributing molecular pathomechanisms within the affected tissues remain as yet elusive. The extracellular matrix (ECM) is a highly dynamic structure that varies tremendously and influences the encompassing tissue. In order to assess ECM re-modeling in autoimmune uveitis, we investigated the expression of ECM molecules fibronectin and osteopontin in vitreous and retina samples. This was carried out in the only spontaneous animal model for human autoimmue uveitis, namely equine recurrent uveitis (ERU) that resembles the human disease in clinical as well as in immunopathological aspects. ERU is a naturally occurring autoimmune disease in horses that develops frequently and has already proved its value to study disease-related pathomechanisms. Western blot analysis of fibronectin and osteopontin in healthy and uveitic vitreous revealed significant reduction of both proteins in uveitis. Immunohistochemical expression of fibronectin in healthy retinas was restricted to the inner limiting membrane abutting vimentin positive Müller cell endfeet, while in uveitic sections, a disintegration of the ILM was observed changing the fibronectin expression to a dispersed pattern extending toward the vitreous. Retinal expression of osteopontin in control tissue was found in a characteristic Müller cell pattern illustrated by co-localization with vimentin. In uveitic retinas, the immunoreactivity of osteopontin in gliotic Müller cells was almost absent. The ability of Müller cells to express fibronectin and osteopontin was additionally shown by immunocytochemistry of primary cultured equine Müller cells and the equine Müller cell line eqMC-7. In conclusion, severe ECM re-modeling in autoimmune uveitis reported here, might affect the adhesive function of fibronectin and thus the anchoring of Müller cell endfeet to the ILM. Furthermore, the absence of osteopontin in gliotic Müller cells might represent reduced neuroprotection, an osteopontin attribute that is intensively discussed

Tunnel configurations and seismic isolation optimization in underground gravitational wave detectors

Gravitational wave detectors like the Einstein Telescope will be built a few hundred meters under Earth's surface to reduce both direct seismic and Newtonian noise. Underground facilities must be designed to take full advantage of the shielding properties of the rock mass to maximize the detector's performance. A major issue with the Einstein Telescope design are the corner points, where caverns need to be excavated in stable, low permeability rock to host the sensitive measurement infrastructure. This paper proposes a new topology that moves the top stages of the seismic attenuation chains and Michelson beam re-combination in separate excavations far from the beam-line and equipment induced noise while the test mass mirrors remain in the main tunnels. Distributing the seismic attenuation chain components over multiple tunnel levels allows the use of arbitrarily long seismic attenuation chains that relegate the seismic noise at frequencies completely outside the low-frequency noise budget, thus keeping the door open for future Newtonian noise suppression methods. Separating the input-output and recombination optics of different detectors into separate caverns drastically improves the observatory detection efficiency and allows staged commissioning. The proposed scheme eliminates structural and instrumentation crowding while the reduced sizes of excavations require fewer support measures

PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system

Cancer genomics; OncologyGenómica del cáncer; OncologíaGenòmica del càncer; OncologiaPolybromo-1 (PBRM1) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). PBRM1, a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of PBRM1 mutated (mut) BTCs and to define potential translational aspects. Totally, 1848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of PBRM1 was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. PBRM1 mutations were identified in 8.1% (n = 150) of BTCs and were more prevalent in intrahepatic BTCs (9.9%) compared to gallbladder cancers (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., ARID1A 31% vs. 16%) and DNA damage repair genes (e.g., ATRX 4.4% vs. 0.3%) were detected in PBRM1-mutated (mut) vs. PBRM1-wildtype (wt) BTCs. No difference in real-world overall survival was observed between PBRM1-mut and PBRM1-wt patients (HR 1.043, 95% CI 0.821–1.325, p = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the PBRM1 knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated PBRM1-mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of PBRM1-mut BTCs, which in vitro sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as a rationale for future testing of PARP/ATR inhibitors in PBRM1-mut BTCs

Impact of Phosphorus Restriction and Vitamin D-Substitution on Secondary Hyperparathyroidism in a Proteinuric Mouse Model

Background/Aims: Since the discovery of FGF23, secondary hyperparathyroidism (SHPT) in renal disease has been considered to result primarily from phosphorus retention rather than vitamin D deficiency. However, the impact of phosphorus restriction and vitamin D supplementation on SHPT is still ill defined. Methods: We investigated the development of SHPT in a doxorubicin-induced proteinuric mouse model and tested different treatment strategies including a low phosphorus diet and substitution with native or active vitamin D in 129 S1/SvImJ wild-type mice. Results: Development of SHPT at day 30 was strongly related to the magnitude of induced proteinuria. In mice with a proteinuria 100 mg/mg creatinine) developed marked SHPT (PTH increase 10.1-fold) accompanied by massive increase in FGF23 (27.0-fold increase), hyperphosphatemia (1.8-fold increase), renal failure (7.3-fold urea increase) and depletion of both 25-OH vitamin D and 1,25-OH vitamin D. Substitution with native or active vitamin D was unable to suppress SHPT, whereas a low-phosphorus diet (Pi content 0.013%) completely suppressed SHPT in mice with both mild and heavy proteinuria. Conclusions: The development of SHPT resulted from phosphate retention in this proteinuric model and could completely be suppressed with a low-phosphorus diet