Simulating industrial scenarios with the open-source software MercuryDPM

Creating predictive computer simulations, i.e. virtual prototypes, of complex granular industrial processes has many challenges. In this paper we review recent advances in creating such virtual prototypes. We introduce the open-source code MercuryDPM [1], which is often applied to complex industrial applications via the spin-off company MercuryLab. We briefly discuss how to import complex industrial geometries and how to deal with large numbers of particles and wide size-distributions. Then we focus on how to create a computer representation of an actual granular material, the so-called model calibration. For calibration, we start by reviewing what parameters need to be measured and what experimental characterisation machines are available. We present an industrially practical calibration method, where certain parameters are directly measured and others are indirectly calibrated, using a variety of machine-learning techniques, implemented in the open-source codes GrainLearning [2], TensorFlow [3] and scikit-learn [4]. With GrainLearning, one can find local optima in only two to three iterations, even for complex contact models with many microscopic parameters. On the other hand, TensorFlow and scikit-learn use two popular supervised learning algorithms, Neural Network (NN) and Random Forest (RF) regression, respectivly. After a training period consisting of hundreds of particle simulations, NN and RF are capable of providing a mapping between the micro-parameters and the bulk behaviour, which can be used to find the optimal micro-parameters that correspond to the experimentally observed behaviour

Variations of X Chromosome Inactivation Occur in Early Passages of Female Human Embryonic Stem Cells

X chromosome inactivation (XCI) is a dosage compensation mechanism essential for embryonic development and cell physiology. Human embryonic stem cells (hESCs) derived from inner cell mass (ICM) of blastocyst stage embryos have been used as a model system to understand XCI initiation and maintenance. Previous studies of undifferentiated female hESCs at intermediate passages have shown three possible states of XCI; 1) cells in a pre-XCI state, 2) cells that already exhibit XCI, or 3) cells that never undergo XCI even upon differentiation. In this study, XCI status was assayed in ten female hESC lines between passage 5 and 15 to determine whether XCI variations occur in early passages of hESCs. Our results show that three different states of XCI already exist in the early passages of hESC. In addition, we observe one cell line with skewed XCI and preferential expression of X-linked genes from the paternal allele, while another cell line exhibits random XCI. Skewed XCI in undifferentiated hESCs may be due to clonal selection in culture instead of non-random XCI in ICM cells. We also found that XIST promoter methylation is correlated with silencing of XIST transcripts in early passages of hESCs, even in the pre-XCI state. In conclusion, XCI variations already take place in early passages of hESCs, which may be a consequence of in vitro culture selection during the derivation process. Nevertheless, we cannot rule out the possibility that XCI variations in hESCs may reflect heterogeneous XCI states in ICM cells that stochastically give rise to hESCs

Arc is a flexible modular protein capable of reversible self-oligomerization

The immediate early gene product Arc (activity-regulated cytoskeleton-associated protein) is posited as a master regulator of long-term synaptic plasticity and memory. However, the physicochemical and structural properties of Arc have not been elucidated. In the present study, we expressed and purified recombinant human Arc (hArc) and performed the first biochemical and biophysical analysis of hArc's structure and stability. Limited proteolysis assays and MS analysis indicate that hArc has two major domains on either side of a central more disordered linker region, consistent with in silico structure predictions. hArc's secondary structure was estimated using CD, and stability was analysed by CD-monitored thermal denaturation and differential scanning fluorimetry (DSF). Oligomerization states under different conditions were studied by dynamic light scattering (DLS) and visualized by AFM and EM. Biophysical analyses show that hArc is a modular protein with defined secondary structure and loose tertiary structure. hArc appears to be pyramid-shaped as a monomer and is capable of reversible self-association, forming large soluble oligomers. The N-terminal domain of hArc is highly basic, which may promote interaction with cytoskeletal structures or other polyanionic surfaces, whereas the C-terminal domain is acidic and stabilized by ionic conditions that promote oligomerization. Upon binding of presenilin-1 (PS1) peptide, hArc undergoes a large structural change. A non-synonymous genetic variant of hArc (V231G) showed properties similar to the wild-type (WT) protein. We conclude that hArc is a flexible multi-domain protein that exists in monomeric and oligomeric forms, compatible with a diverse, hub-like role in plasticity-related processes

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer’s disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer’s disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer’s disease and other tau-mediated neurodegenerative diseases

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction:Plasma biomarkers for Alzheimer’s disease (AD) diagnosis/stratification are a“Holy Grail” of AD research and intensively sought; however, there are no well-established plasmamarkers.Methods:A hypothesis-led plasma biomarker search was conducted in the context of internationalmulticenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL;259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.Results:Ten analytes showed significant intergroup differences. Logistic regression identified five(FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD andCTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI(AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Twoanalytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).Discussion:Plasma markers of inflammation and complement dysregulation support diagnosis andoutcome prediction in AD and MCI. Further replication is needed before clinical translatio

Antianemic Treatment of Cancer Patients in German Routine Practice: Data from a Prospective Cohort Study—The Tumor Anemia Registry

The aim of this prospective cohort study was to assess current antianemic treatment of cancer patients in German routine practice, including diagnostics, treatments, and quality of life (QoL). 88 study sites recruited 1018 patients at the start of antianemic treatment with hemoglobin (Hb) levels <11 g/dL (females) or <12 g/dL (males). Patients were followed up for 12 weeks. 63% of the patients had inoperable solid tumors, 22% operable solid tumors, and 15% hematological malignancies. Over 85% received chemotherapy. Median age was 67 years; 48% were male. Red blood cell transfusions (RBCTx) were given to 59% of all patients and to 55% of the patients with Hb ≥8 g/dL on day 1 of the observation period (day 1 treatment). Erythropoiesis-stimulating agents (ESAs) were the second most frequently applied day 1 treatment (20%), followed by intravenous (IV) iron (15%) and ESA + IV iron (6%). Only about a third of patients were tested for blood serum iron parameters at the start of treatment. Overall, more than half of the patients had long-term responses to antianemic therapy. Our data suggest that in routine practice diagnostics for treatable causes of anemia are underused. A high proportion of cancer patients receive RBCTx. It should be discussed whether thorough diagnostics and earlier intervention could decrease the need for RBCTx. This trial is registered with NCT01795690

Using AI and Gd-EOB-DTPA-enhanced MR imaging to assess liver function, comparing the MELIF score with the ALBI score

Abstract Monitoring disease progression is particularly important for determining the optimal treatment strategy in patients with liver disease. Especially for patients with diseases that have a reversible course, there is a lack of suitable tools for monitoring liver function. The development and establishment of such tools is very important, especially in view of the expected increase in such diseases in the future. Image-based liver function parameters, such as the T1 relaxometry-based MELIF score, are ideally suited for this purpose. The determination of this new liver function score is fully automated by software developed with AI technology. In this study, the MELIF score is compared with the widely used ALBI score. The ALBI score was used as a benchmark, as it has been shown to better capture the progression of less severe liver disease than the MELD and Child‒Pugh scores. In this study, we retrospectively determined the ALBI and MELIF scores for 150 patients, compared these scores with the corresponding MELD and Child‒Pugh scores (Pearson correlation), and examined the ability of these scores to discriminate between good and impaired liver function (AUC: MELIF 0.8; ALBI 0.77) and to distinguish between patients with and without cirrhosis (AUC: MELIF 0.83, ALBI 0.79). The MELIF score performed more favourably than the ALBI score and may also be suitable for monitoring mild disease progression. Thus, the MELIF score is promising for closing the gap in the available early-stage liver disease monitoring tools (i.e., identification of liver disease at a potentially reversible stage before chronic liver disease develops)

MELIF, a Fully Automated Liver Function Score Calculated from Gd-EOB-DTPA-Enhanced MR Images: Diagnostic Performance vs. the MELD Score

In the management of patients with chronic liver disease, the assessment of liver function is essential for treatment planning. Gd-EOB-DTPA-enhanced MRI allows for both the acquisition of anatomical information and regional liver function quantification. The objective of this study was to demonstrate and evaluate the diagnostic performance of two fully automatically generated imaging-based liver function scores that take the whole liver into account. T1 images from the native and hepatobiliary phases and the corresponding T1 maps from 195 patients were analyzed. A novel artificial-intelligence-based software prototype performed image segmentation and registration, calculated the reduction rate of the T1 relaxation time for the whole liver (rrT1(liver)) and used it to calculate a personalized liver function score, then generated a unified score-the MELIF score-by combining the liver function score with a patient-specific factor that included weight, height and liver volume. Both scores correlated strongly with the MELD score, which is used as a reference for global liver function. However, MELIF showed a stronger correlation than the rrT1(liver) score. This study demonstrated that the fully automated determination of total liver function, regionally resolved, using MR liver imaging is feasible, providing the opportunity to use the MELIF score as a diagnostic marker in future prospective studies

Single-cell analysis of the developing human testis reveals somatic niche cell specification and fetal germline stem cell establishment.

Human testis development in prenatal life involves complex changes in germline and somatic cell identity. To better understand, we profiled and analyzed ∼32,500 single-cell transcriptomes of testicular cells from embryonic, fetal, and infant stages. Our data show that at 6-7&nbsp;weeks postfertilization, as the testicular cords are established, the Sertoli and interstitial cells originate from a common heterogeneous progenitor pool, which&nbsp;then resolves into fetal Sertoli cells (expressing tube-forming genes) or interstitial cells (including Leydig-lineage cells expressing steroidogenesis genes). Almost 10&nbsp;weeks later, beginning at 14-16&nbsp;weeks postfertilization, the male primordial germ cells exit mitosis, downregulate pluripotent transcription factors, and transition into cells that strongly resemble the state 0 spermatogonia originally defined in the infant and adult testes. Therefore, we called these fetal spermatogonia "state f0." Overall, we reveal multiple insights into the coordinated and temporal development of the embryonic, fetal, and postnatal male germline together with the somatic niche

Characterization of mAb dimers reveals predominant dimer forms common in therapeutic mAbs

The formation of undesired high molecular weight species such as dimers is an important quality attribute for therapeutic monoclonal antibody formulations. Therefore, the thorough understanding of mAb dimerization and the detailed characterization mAb dimers is of great interest for future pharmaceutical development of therapeutic antibodies. In this work, we focused on the analyses of different mAb dimers regarding size, surface properties, chemical identity, overall structure and localization of possible dimerization sites. Dimer fractions of different mAbs were isolated to a satisfactory purity from bulk material and revealed two predominant overall structures, namely elongated and compact dimer forms. The elongated dimers displayed one dimerization site involving the tip of the Fab domain. Depending on the stress applied, these elongated dimers are connected either covalently or non-covalently. In contrast, the compact dimers exhibited non-covalent association. Several interaction points were detected for the compact dimers involving the hinge region or the base of the Fab domain. These results indicate that mAb dimer fractions are rather complex and may contain more than one kind of dimer. Nevertheless, the overall appearance of mAb dimers suggests the existence of two predominant dimeric structures, elongated and compact, which are commonly present in preparations of therapeutic mAbs