NOTCH3 R545C mutation drives vascular-neuronal dysfunction and cognitive impairment in CADASIL pathogenesis.

Abstract Pulmonary Alveolar Proteinosis (PAP) is rare lung condition characterized by alveolar filling with macrophages due to abnormal accumulation of surfactant in the alveolar space. Classical radiologic findings include ground-glass opacities and interlobular septal thickening. This is a case of a 44-year old gentleman with a 30-pack year smoking history who presented to his local hospital with persistent cough and worsening shortness of breath. He had pulmonary tuberculosis in 2022 but otherwise had an unremarkable medical history. He previously worked as a stone mason for 19 years. CT imaging revealed ground glass opacities and diffuse cysts and he was initially managed as a case of smoking-related ILD with oral and intravenous steroids. A bronchioalveolar (BAL) fluid culture had heavy growth of S pneumoniae and K oxytoca and he was commenced on IV antibiotics and antifungals on suspicion of an atypical chest infection. Autoimmune screen was negative. The patient however continued to deteriorate and was put on high flow nasal oxygen due to increasing oxygen requirements; in parallel, a repeat CT scan showed worsening ground glass change and cystic disease. The patient was referred to our institution and discussed in our ILD multidisciplinary team meeting. A serial review of his scans showed progressive changes suspicious for mucinous adenocarcinoma. A CT-guided biopsy was done and histology showed alveolar spaces filled with granular material which stained strongly for periodic acid-Schiff (PAS). The patient underwent a whole lung lavage with subsequent clinical improvement. Supplemental oxygen requirement decreased to 2 liters/min. Serological testing for Granulocyte-Macrophage Colony Stimulation Factor (GM-CSF) autoantibodies was done and later returned positive. A genetic screen was also done due to the unusual radiological presentation. The patient was discharged on ambulatory oxygen with a clinic follow up for definitive treatment with inhaled GM-CSF. The presence of diffuse ground-glass opacities without the classic crazy-paving pattern, accompanied by cystic changes in histologically-confirmed pulmonary alveolar proteinosis (PAP), is exceedingly rare in literature. This finding emphasizes the need to consider PAP in the differential diagnosis, even when imaging features overlap with other conditions. Anti-GM-CSF antibodies demonstrate 100% sensitivity and specificity for autoimmune PAP in the appropriate clinical context. Although biopsy is typically unnecessary in classic PAP cases, this should be considered when the diagnosis is uncertain. Furthermore, the patient’s marked improvement following therapeutic whole-lung lavage highlights the effectiveness of this treatment, even in atypical presentations of the disease. This abstract is funded by: None

Calcium pyrophosphate deposition (CPPD) disease is an inflammatory arthritis prevalent in elderly individuals. Spinal CPPD is uncommon, and presentation can vary widely with common clinical and radiographic mimics. We identified 9 cases of lumbar and 1 case of thoracic spinal CPPD (age range: 63-85 years; 5 male, 5 female) at our institution over a 10-year period. All presented with pain (90% chronic, 10% acute); 4 had prior instrumentation and 1 had prior trauma. CPPD was not clinically suspected in any case. Preoperative imaging diagnoses include central canal stenosis, neuroforaminal narrowing, septic arthropathy, synovial cyst, degeneration, and epidural mass/abscess. Intraoperatively, a spinal cyst was most often described. All pathologic examinations revealed purple granular calcified material with positively birefringent rhomboid crystals embedded within fibrocartilage. Following a neuropathologic diagnosis, only 2 patients received CPPD treatment. This study aims to highlight that spinal CPPD is underdiagnosed and undertreated. Although clinical presentations are variable, wider recognition of this rare disease among neuropathologists receiving spinal specimens may provide earlier diagnosis. Accurate pathologic diagnosis can improve identification, refine clinical suspicion, and facilitate management. Improved identification, particularly in elderly patients and those with prior trauma/instrumentation, will promote appropriate therapy and management.

Core myopathies are congenital diseases with clinical, pathological and genetic heterogeneity. Main histological features are fiber "cores" showing a focally reduced oxidative enzyme activity. Dusty Core Disease (DuCD) differs from Central Core Myopathy for the presence of irregular areas, without clear borders and round/ovoidal shape, and myofibrillar disorganization characterized by reddish purple granular material depositions. This disorder is defined clinically by severe phenotypes with early onset of disease and molecularly by low level of RyR1 in muscle. Until now DuCD was associated only to biallelic recessive RYR1 mutations. We analyzed the clinical aspects, pathological features and mutational spectrum of four DuCD patients, belonging to our cohort of Congenital Myopathy probands. Molecular analysis detected 5 different RYR1 pathogenic variants, two of them so far unreported. Patients presented a heterogeneous phenotype ranging from severe recessive infantile forms to moderate dominant adult-onset presentations. Histological, immunological and ultrastructural techniques were employed to validate these dominant cases, which expand our knowledge on the inheritance of this subgroup of diseases.

Rock capturing with standard excavator buckets is a challenging task that typically requires skilled human operators. Unlike soil digging, it involves manipulating large, irregular rocks in unstructured environments, where complex contact interactions with granular material make model-based control impractical. Existing autonomous excavation approaches mainly target continuous media or rely on specialized grippers, limiting their applicability in real construction settings. This paper presents a fully data-driven control framework for rock capturing that avoids explicit modeling of rock or soil properties. A model-free reinforcement learning agent is trained in the AGX Dynamics® simulator using Proximal Policy Optimization (PPO) and a guiding reward formulation. The learned policy outputs joint velocity commands directly to the boom, arm, and bucket of a CAT®365 excavator model. Robustness is improved through extensive domain randomization of rock properties and initial configurations. Results show generalization to unseen rocks and soil conditions, achieving high success rates while maintaining machine stability. • Model-free RL controller for rock capture with a standard excavator. • No explicit modeling of rock or soil properties required. • Training in high-fidelity AGX Dynamics with granular terrain simulation. • Domain randomization of rock geometry, density, and initial states. • 0.8 success rate with stable operation under unseen rocks and materials.

Urban stormwater runoff often contains toxic metals that threaten aquatic environments. Meanwhile, the large quantities of drinking water treatment residuals (DWTRs) generated worldwide offer opportunities for sustainable reuse as pollutant removal materials. In this study, a manganese sand-modified drinking water treatment residual particle (RDP-M) was prepared from DWTRs and manganese sand for Pb(II) removal from water. Characterization by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) showed that RDP-M had a rough surface morphology and abundant oxygen-containing functional groups, which provided adsorption sites. Batch experiments showed that the maximum Pb(II) adsorption capacity of RDP-M reached 2.79 mg g−1 at 298 K and pH 7.0, which was about 48% higher than that of the unmodified particles (RDP). The adsorption process followed the pseudo-second-order kinetic model and the Langmuir isotherm model, indicating a chemisorption-dominated process. Thermodynamic analysis further showed that the process was spontaneous and exothermic. RDP-M maintained stable Pb(II) removal over a wide pH range, showed low sensitivity to coexisting ions, and retained high efficiency during repeated use. These results demonstrate that RDP-M has potential as a sustainable granular material for stormwater treatment and waste resource valorization.

Hoppers are expected to play an essential role in handling of lunar regolith for future lunar exploration missions from collection and storage to in situ resource utilization. This study presents a parametric experimental investigation of regolith discharge dynamics by using the LHS-1 simulant. Results show that vertical vibrations significantly affect the regularity of the flow of granular material through the orifice of the hopper, the average mass flow rate, the spatio-temporal patterning of the material displacement, and the occurrence of jamming (clogging) phenomena. While the average mass flow rate is consistently smaller than that obtained in purely gravitational flow, vibrations induce a significant reduction in the probability of arching and make the overall flow of material much more regular and spatially uniform. Four different flow configurations are identified accordingly in the entire space of parameters, i.e., “funnel,” “mass,” “asymmetric,” and “ratholing” flow. The “funnel” is the most common, while asymmetric and ratholing regimes are only attained for relatively high shaking frequency and amplitude. Low frequencies universally promote arching due to insufficient energy to disrupt force chains within the material. In contrast, the role of high frequencies is more complex, with clogging re-emerging at certain thresholds, particularly at low acceleration amplitude. Increasing the vibration amplitude generally mitigates blockage, but its effectiveness weakens with sample mass growth, indicating that additional factors, such as gravity-induced compaction and related particle rearrangement dynamics also play a significant role in governing such events.

Granular rheology is of interest in many geophysical and industrial applications that require precise handling of particulate materials, including conveying, dosing, spreading, compaction, and other operations. The capability to handle dense flows is important for process throughput and efficiency. In this context, we explore oscillatory rheometry for dense granular flow using a chute-flow rheometer (CFR) having multimodal sensing capability. The CFR applies oscillatory shear in a Couette gap with measurements of torque, wall pressure, and axial flow. The resulting cyclic data were deconstructed into elastic and viscous components using Fourier transforms. Torque data were normalized to the active mass of granular material in the CFR, converted to specific torque and shear stress, and analyzed using Lissajous–Bowditch (LJB) plots. Viscoelastic crossovers were observed at relatively low shear rates consistent with quasistatic (i.e., friction-like) flows. At higher shear rates, secondary loops were observed in elastic (γ˙,τ) LJB plots, consistent with transition to dense inertial (i.e., fluid-like) flow. These rheological markers are discussed in terms of dense flow transitions. Further analysis considered inertial number scaling in the μ(I) granular rheology, comparing specific torque with the conventional definition using pressure and bulk density. Finally, a contour diagram summarizes the coupling of shear and normal forces in the CFR, where the wall pressure sensor detects the first normal force and the second normal force is in the direction of axial flow. The results suggest characterization criteria that are relevant to managing dense granular flows in quasistatic and dense inertial regimes.

A BSTRACT Pulmonary alveolar proteinosis (PAP) is an uncommon condition make distinctive presence of granular eosinophilic material within alveolar spaces. PAP is also known as pulmonary alveolar lipoproteinosis, showing abundant lipids within granular exudate. Bronchoalveolar lavage (BAL) is helpful in both terms of therapeutic, as well as diagnostic point of view. Whole lung lavage given in patients of PAP feel dramatically better with improvement in exertional dyspnoea.

The present research work involves the placing of a small quantity of molten steel into the gap among the components to be connected, subsequently positioning them together during solidification. The heat sources utilized in the welding process include the electric arc. The result is a variant of arc welding in which the cost is determined by the flux utilized during the process. The submerged arc welding technique (SAW) technique has been utilized for the rapid process that involves physical, mechanical, and chemical interactions. When the metal arc is shielded, the spatter from the arc is contained by granular fusible material, which safeguards the weld from ambient contamination. Flux plays a major role in SAW welding and welding cost depends upon recycled slag as recycled slag as flux consumption. This flux gets converted into a shielded layer as slag on the weld bead after solidification. The slag from submerged arc welding is thrown away as trash. According to the investigation, this welding is based on factors such as welding current, speed voltage, and stick out depending on the consumption of recycled slag. The box-Behnken-based designed experimental model has been used while RSM has been effectively employed to examine the causation and influence of process elements on responses for optimization. For the model to be deemed significant, its calculated F-ratio must surpass the standard tabulated F-ratio for a specified confidence level (i.e., 95%). In submerged arc welding, the consumption of slag flux escalates with an increase in current and voltage. As welding speed and nozzle-to-plate distance increase, the consumption of slag as flux diminishes. A weighing machine has been utilized to measure the recycled flux consumption before and after each weld bead. Even yet, extensive research has been done on the physical and chemical characteristics of welding fluxes as well as the factors that influence their use.

Broadcast seeders are commonly used in Poland for fertilisation, but they do not ensure precise and uniform fertiliser distribution. Strip-tillage systems utilise mechanical and pneumatic seeders, which allow seeds to be placed at the appropriate depth and in even rows. However, these devices follow the surface of the ground and are therefore susceptible to uneven fertiliser distribution depending on the terrain (slope). Uneven fertiliser distribution results in localised overfertilisation or nutrient deficiencies (nitrogen, phosphorus, potassium); the former, if excessive, can lead to plant lodging or frost damage, while the latter can lead to weakened plant growth and reduced yields. Competition between plants for sunlight and water can further inhibit the development of weaker individuals. This article presents the results of research on the effect of the tilt of the seed hopper and the measuring system (ranging from -15° to +15°, with 5° intervals) on the dose of granular material sown. Negative angles refer to uphill travel, while positive angles refer to downhill travel. Simulation and laboratory studies have shown that when going uphill, the amount of material spread increases by 5.45% (simulation studies) and 7.86% (laboratory studies). When going downhill, the amounts decrease by 11.63% and 11.86%, respectively. Simulation studies were conducted using Ansys Rocky 2024 software (version R1), based on the discrete element method. The boundary conditions for the simulation, including the static and dynamic friction coefficients and the restitution coefficient of the test object (granular mineral fertiliser in the form of urea), were obtained from literature data. In the first phase of the study, the computational space modelled according to the dimensions of the seeder was unfavourable. Significant improvement in the agreement between the simulation and laboratory data was achieved by increasing the size of the computational space. The simulation results were validated using a laboratory test stand built based on the simulation model. The results were subjected to ANOVA statistical analysis, which confirmed that the effect of the slope on the seeding dose is statistically significant with a significance level of p = 0.000. Based on the obtained simulation and laboratory test results, a mathematical equation was generated to calculate the dose distribution depending on the slope of the terrain. After applying the Wilcoxon signed-rank test, it was confirmed, with a significance level of p = 0.173, that the discrete element method can be used successfully to simulate the dosing (seeding) process with sufficient accuracy.

A stability study of granular seabed subjected to cyclic wave loading and seismic actions, based on limit analysis in terms of effective stress, was conducted. Seismic loading is considered using the pseudo-static method, while wave loading is modeled by the first-order Stokes theory. The adopted formulation incorporates the effects of seepage forces arising from pore pressure gradients induced both by wave pressure oscillations and by soil densification due to cyclic shearing of the granular material. The analysis is conducted using the kinematic approach, based on representative failure mechanisms, and the Mohr-Coulomb strength criterion is adopted. Numerical results highlight the significant destabilizing influence of seismic loading, especially when combined with wave-induced cyclic loading.

During the drilling process of petroleum wellbores, a bit tool uses a rotary motion combined with axial pressure to break the rock formation of the well walls into cuttings. The gravel needs removing; otherwise, it tends to pile up at the bottom of the well, and accumulated rocks can lead to prolonged execution times, increased pressure, and eventually render the well inoperative. The rock pieces extracted from the drilling process have complex geometries; therefore, groups of less complex particles, such as ellipsoidal particles, can model the granular material. Due to the high complexity of solving these flows with immersed particles, numerical simulations are powerful tools to assess the behavior of such flows. One method of studying the transport of particles is the coupling of the lattice Boltzmann method (LBM) and the immersed boundary method (IBM). The LBM employs a mesoscopic approach to describe the fluid as a population of particles evolving over time, where the Boltzmann equation governs the evolution, which contains a collision operator responsible for changes in the velocity and direction of the particles. The IBM uses the force density in the Navier-Stokes equation to mimic a boundary condition, its basis is a two-node system, where an Eulerian grid defined by the LBM is stationary, and the IBM marker points are Lagrangian nodes that are not bound to the Eulerian grid and can move freely. The main goal of this work is to assess the influence of the velocity, through the Reynolds number, on the cleaning of petroleum wellbores. To analyze this phenomenon, we evaluated the transport of 40 prolate particles in a duct filled with glycerin (4 °C). The density ratio was 2.14, the particles' aspect ratio was 2, a geometric mean radius of 25 mm, and their diameter ratio to the duct diameter was 1:10. In the Reynolds range analyzed, from 100 to 250, we observed that in some cases, there was a negative particle mass transport rate (the particles settle faster than they can be transported), passing through zero, and then, for higher Reynolds numbers, presenting a positive mass transport rate.

Metaldehyde is commonly used as a molluscicide, and accidental ingestion in dogs is a recognized toxicologic emergency with potentially fatal outcomes. A 4-month-old female Pit Bull was presented to a veterinary emergency after ingesting an unknown amount of a 5% metaldehyde-based slug bait (Metarex®). Clinical signs began within minutes and included stupor, hypersalivation, and generalized tonic-clonic seizures. Supportive care was provided, including anesthetic coma with propofol and isoflurane, gastric lavage, diazepam, N-acetylcysteine, and oxygen therapy; however, the animal died in eight hours. At necropsy, the stomach and intestines contained abundant blue-to-green amorphous and finely granular material, as well as plastic fragments consistent with Metarex® packaging. No significant microscopic alterations were observed in internal organs. The diagnosis was based on the clinical course, history of exposure, and characteristic gastrointestinal contents. In suspected cases, identification of metaldehyde in the gastrointestinal tract can aid diagnosis when toxicologic confirmation is unavailable.

Three-dimensional (3D), axisymmetric hoppers are widely used in industries for generating smooth outflow of granular materials from storage bins and it is well known that their discharge behavior is governed by the local dynamics at the orifice. Measuring the details of the outflow from a 3D hopper is challenging due to the fact that the flow is dense and the granular material is opaque. In this paper, x-ray tomography is used to image the cross sectionnear the orifice opening. We investigate the vertical velocity, volume fraction, and particle orientations of spherical, oblate (lentil-shaped), and prolate (rice-shaped) particles for various hopper angles. We create a three-dimensional respresentation by time stacking the cross sections. We process these 3D images using standard image filtration techniques and propose simple experimental models to extract the velocity, volume fraction, and orientation angles of the particles based on their shape. We found that the hopper inclination influences both the velocity and volume fraction profiles in such a way that the magnitude of both profiles increases with increasing hopper inclination. Moreover, lentil-shaped particles achieve the highest velocity and pack more densely than the other two particles. In addition, the latter packed more orderly than the prolate (rice-shaped) particles. Finally, it is found that the independently measured experimental discharge rate has a good agreement with the discharge rate obtained from the velocity and volume fraction profiles for sphere and lentil-shaped particles.

Abstract Investigating tsunamigenic landslides via physical experiments is important to increase the understanding of these often devastating events for improving disaster prevention. Landslide masses often consist of granular material, which usually is characterized by non‐uniform grain size distributions, irregular shape and pronounced surface roughness. These material properties have not been comprehensively tested in laboratory experiments on landslide‐induced tsunamis so far. The present study aims to investigate the effect of grain size distribution, particle shape and surface roughness on landslide induced tsunami generation via systematic laboratory experiments. A total of 43 2D flume experiments were performed, using gravity‐accelerated granular slides in a reservoir with a constant water depth, while a 30 slope angle was maintained for the slide. Three granular materials were tested, with individual grain surfaces ranging from very smooth surface, uniform grain size distribution and spherical shape to very rough surface, non‐uniform grain size distribution and irregularly shaped particles. For the rough material, four different grain diameters were tested. The results show that slide impact velocity and maximum wave amplitude were reduced significantly for the rougher materials compared to smooth glass beads, and that the wave amplitude reduction along the flume distance was larger for rough materials. Minor variations in surface roughness had negligible impact on wave amplitude, suggesting that grain roughness is not a primary controlling factor unless substantially reduced. With the exception of the first gauge, a correlation between grain size and wave amplitude can be observed at all gauges along the flume.

Abstract Granular material with different particle shapes is exposed to continuous shear in a cylindrical shell with a special double-shear geometry. Instead of the classical split-bottom cell with a moving disk, we use a rotating ring at the bottom, with the central and peripheral parts of the bottom plate fixed in a static position. Then, two shear zones are formed with different radii of curvature and qualitatively different features. We compare the behavior of spherical grains to that of elongated spherocylinders, and find significant differences in the formation of secondary flow structures.

Abstract Dense particle‐liquid flows are common in natural flows processes. A primary challenge lies in the effective modeling of the granular stress, which is intrinsically related to the flowing state of the granular material. By developing non‐invasive experimental technique and measurement methods for internal observations based on the refractive index matching (RIM) technique, the internal flow information of the particle‐liquid channel flows over a bumpy bed is obtained. The flow shear and fluctuation are strong near the bottom while vanishing near the surface, with the interparticle interactions dominated by collision and friction, respectively, and a transitional layer in between. The granular rheology is controlled by the Bagnold number and presents a coexistence of frictional, viscous, and inertial regimes, corresponding to the granular quasi‐static, liquid‐like, and gas‐like states, respectively. The multi‐state stress can be modeled by integrating a frictional stress described by a rate‐independent model and a collisional stress described by kinetic theory. The latter helps to explain the flow structure‐dependence of the friction coefficient discovered in the heterogeneous flows studied here.

The accumulation of plastic waste represents a significant environmental challenge worldwide, and its reuse in construction materials offers a sustainable management alternative. This study investigates the use of recycled high-density polyethylene (HDPE) and polypropylene (PP) granules as partial volumetric replacements (10%, 20%, and 30%) for limestone aggregate in mortar mixtures. A total of seven mixtures were produced and evaluated in terms of flow value, unit weight, water absorption, porosity, compressive strength, flexural strength, and capillary water absorption. In comparison to the control mixture, it was found that the use of plastic aggregate improved the workability. It was found that the flexural and compressive strengths of mixtures decrease when plastic aggregate is added. Additionally, it was understood that utilization of plastic aggregate in mixtures caused an increase in water absorption rate and porosity values. HDPE and PP plastic aggregates increased flow by 9% to 13% and reduced unit weight by 15 to 15.3%, while compressive and flexural strengths decreased by 48 to 30% and 46 to 54%, respectively. The optimum replacement level was 10% for both HDPE and PP mixtures.

This study investigates the behavior of four unreinforced embankments on soft soils through numerical and parametric analyses. The embankments, composed of granular material, are 3.5 m in height and 17 m in width, and are modeled over a clay layer extending 30 m horizontally, with thicknesses of 5, 10, 15, and 20 m. The soft soil was simulated with the modified Cam Clay model, and the embankment fill with the Mohr–Coulomb criterion. Forty Abaqus simulations were performed, varying soil thickness, overconsolidation ratio (OCR), recompression index (κ ), and critical state line slope (M). The analyses evaluated settlement, horizontal displacement, pore pressure, effective vertical stress and mobilized soil volume, applying multiple normalization approaches. Results highlight the strong influence of soil thickness and κ on deformation and pore pressure, the limited effect of M and OCR for thicker layers and confirm the usefulness of mobilized volume criteria for stability evaluation.