Towards a predictive multi-phase model for alpine mass movements and process cascades

Alpine mass movements can generate process cascades involving different materials including rock, ice, snow, and water. Numerical modelling is an essential tool for the quantification of natural hazards, but state-of-the-art operational models reach their limits when facing unprecedented or complex events. Here, we advance our predictive capabilities for process cascades on the basis of a three-dimensional numerical model, coupling fundamental conservation laws to finite strain elastoplasticity. Through its hybrid Eulerian-Lagrangian character, our approach naturally reproduces fractures and collisions, erosion/deposition phenomena, and multi-phase interactions, which finally grant very accurate simulations of complex dynamics. Four benchmark simulations demonstrate the physical detail of the model and its applicability to real-world full-scale events, including various materials and ranging through four orders of magnitude in volume. In the future, our model can support risk-management strategies through predictions of the impact of potentially catastrophic cascading mass movements at vulnerable sites.

A Formal Framework for Complex Event Recognition

Complex event recognition (CER) has emerged as the unifying field for technologies that require processing and correlating distributed data sources in real time. CER finds applications in diverse domains, which has resulted in a large number of proposals for expressing and processing complex events. Existing CER languages lack a clear semantics, however, which makes them hard to understand and generalize. Moreover, there are no general techniques for evaluating CER query languages with clear performance guarantees. In this article, we embark on the task of giving a rigorous and efficient framework to CER. We propose a formal language for specifying complex events, called complex event logic (CEL), that contains the main features used in the literature and has a denotational and compositional semantics. We also formalize the so-called selection strategies, which had only been presented as by-design extensions to existing frameworks. We give insight into the language design trade-offs regarding the strict sequencing operators of CEL and selection strategies. With a well-defined semantics at hand, we discuss how to efficiently process complex events by evaluating CEL formulas with unary filters. We start by introducing a formal computational model for CER, called complex event automata (CEA), and study how to compile CEL formulas with unary filters into CEA. Furthermore, we provide efficient algorithms for evaluating CEA over event streams using constant time per event followed by output-linear delay enumeration of the results.

Cycles in Earth Sciences, Quo Vadis? Essay on Cyclicity Concepts in Geological Thinking and their Historical Influence on Stratigraphic Practices

The archetype of a cycle has played an essential role in explaining observations of nature over thousands of years. At present, this perception significantly influences the worldview of modern societies, including several areas of science. In Earth sciences, the concept of cyclicity offers simple analytical solutions in the face of complex events and their respective products, both in time and space. Current stratigraphic research integrates several methods to identify repetitive patterns in the stratigraphic record and to interpret oscillatory geological processes. This essay proposes a historical review of the cyclic conceptions from the earliest phases in Earth sciences to their subsequent evolution into current stratigraphic principles and practices, contributing to identifying opportunities in integrating methodologies and developing future research mainly associated with quantitative approaches.

Multi-Target Directed Ligands (MTDLs): Promising Coumarin Hybrids for Alzheimer's Disease

: Alzheimer's disease (AD) is an age-associated neurodegenerative disorder and is one of the common health issues around the globe. It is characterized by memory loss and a decline in other cog- nitive domains, including executive function. The progression of AD is associated with complex events, and the exact pathogenesis is still unrevealed. Various mechanisms which are thought to be associated with the initiation of AD include a decreased concentration of acetylcholine (ACh), deposi- tion of amyloid-β (Aβ)peptide, dyshomeostasis of redox metal ions, and prolonged oxidative stress. Due to the simultaneous progression of diverse pathogenetic pathways, no ideal therapeutic agent has been developed to date. The drugs which are available against AD provide only symptomatic benefits and do not have disease-modifying activity. Therefore, in search of ideal therapeutic candidates, the concept of molecular hybrids has been under keen investigation for the past few years. Hybrid mole- cules are able to inhibit or activate or modify the physiology of more than one target simultaneously. Coumarin scaffolds have shown the excellent potential of ACh esterase inhibition, MAO-B inhibition, and anti-Aβ aggregation. In the present review, we have focused on different reported coumarin hy- brids as multi-target-directed agents against AD. These include hybrids of coumarin with carbazole, benzofuran, dithiocarbamate, quinoline, pargyline, tacrine, N-benzyl pyridinium, donepezil, purine, piperidine, morpholine, aminophenol, benzylamino, halophenylalkylamidic, thiazole, thiourea, hy- droxypyridinone, triazole, piperazine, chalcone, etc. Along with the therapeutic potentials of these hy- brids, important clinical investigations and the structure-activity relationship has also been discussed in this compilation.

Molecular Evolution of Classical Hodgkin Lymphoma Revealed Though Whole Genome Sequencing of Hodgkin and Reed-Sternberg Cells

Introduction: Classical Hodgkin lymphoma (cHL) is characterized by a small fraction of Hodgkin and Reed-Sternberg (HRS) tumor cells (~1%) which are surrounded by an extensive immune infiltrate. The rare nature of HRS cells limits the ability to study the genomics of cHL using standard platforms. To circumvent this, our group has optimized fluorescence-activated cell sorting to isolate HRS cells and intratumor B- and T- cells and to perform whole exome sequencing (WES; Reichel, Blood 2015). To date, however, there have been no reports on whole genome sequencing (WGS) of cHL. Methods: We performed flow-sorting of HRS cells and WGS to define the genomic landscape of cHL including: i) mutational processes involved in pathogenesis, ii) large and focal copy number variants, iii) structural variants including complex events, iv) the sequence and evolution of molecular events in cHL. We interrogated WGS from 25 cases of cHL: 10 pediatric patients (age<18), 9 adolescents and young adults (AYA, age 18-40), and 6 older adults (age>40). Intra-tumoral T-cells were used as germline control. An additional 36 cHL cases were evaluated by WES. Results: The average depth of coverage among the 25 WGS cases was 27.5x. After having identified and removed amplification-based palindromic sequencing artifacts, we observed a median of 5006 single base substitutions (SBS; range 1763-18436). Pediatric and AYA patients had a higher SBS burden compared to older adults (median 5279 vs. 2945, p=0.009). Five main SBS signatures were identified: SBS1 and SBS5 (aging), SBS2 and SBS13 (APOBEC), and SBS25 (chemotherapy, in a relapsed case). A dNdScv driver discovery analysis performed on the combined WES and WGS cases identified 24 driver genes including BCL7A and CISH which had not been previously reported as drivers in cHL. An investigation of copy number alterations (CNAs) confirmed high ploidy in cHL (median 2.95, range 1.66-5.33). Whole genome duplication was identified in 64% cases. We also observed clear evidence of complex events such as chromothripsis (n=4), double minutes (dm, n=2), breakage-fusion-bridge (bfb; n=4). Some of these events were responsible for the acquisition of distinct drivers. For example, we observed one dm and one bfb responsible for CD274 and REL gains, respectively (>10 copies). Leveraging the high prevalence of large chromosomal gains, we performed an investigation of the relative timing of acquisition of driver mutations. Clonal mutations within chromosomal gains can be defined as duplicated (VAF~66%; acquired before the gain) or non-duplicated (VAF~33%; acquired before or after the gain). Sixty-one percent (152/249) of driver genes were duplicated suggesting that they were acquired prior to large chromosomal gains. Next, we used the corrected ratio between duplicated and non-duplicated mutations within large chromosomal gains to estimate the molecular time of each duplicated segment (Rustad, Nat Comm 2020). In 11/22 genomes the final CNA profile was acquired through at least two temporally distinct events. To convert these relative estimations into absolute timing (i.e., the age at which events occurred), we leveraged the clock-like mutation signatures (SBS1, SBS5). We first confirmed that the SBS1 and SBS5 mutation rate were constant over time (R 2=0.84; p<0.0001 in Peds/AYA; R 2 =0.82; p=0.002 in older adults). We observed a higher mutation rate in Pediatric/AYA cases compared to older adults (p=0.01), which is consistent with the higher mutational burden observed in this age group. By estimating the SBS1- and SBS5-based molecular time for large chromosomal gains and converting relative estimates to absolute time, we are able to estimate the age in years at the time of the first multi-chromosomal gain event. We observed that the first multi-chromosomal gain in cHL is often acquired several years before the diagnosis/sample collection: median latency of 19.5 (range 12-27) and 5.6 (range 1.8-16) years in older adults and pediatric/AYA patients respectively. Conclusion: Here we report the first WGS in cHL. We identify novel drivers and genomic mechanisms involved in cHL pathogenesis. We found that mutations in driver genes are often acquired earlier then chromosomal gains, potentially preceding the cHL diagnosis by several years. In addition, we observed key differences in biology of cHL across age groups including accelerated mutagenesis and increased mutational burden among younger patients. Disclosures Maura: OncLive: Honoraria; Medscape: Consultancy, Honoraria. Oberley: Caris LIfe Science: Current Employment. Lim: EUSA Pharma: Honoraria. Landgren: Janssen: Other: IDMC; Celgene: Research Funding; Janssen: Honoraria; Amgen: Honoraria; Janssen: Research Funding; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Moskowitz: Merck & Co., Inc.: Research Funding. Roshal: Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Physicians' Education Resource: Other: Provision of services. Elemento: Owkin: Consultancy, Other: Current equity holder; AstraZeneca: Research Funding; Champions Oncology: Consultancy; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; One Three Biotech: Consultancy, Other: Current equity holder; Eli Lilly: Research Funding; Johnson and Johnson: Research Funding; Freenome: Consultancy, Other: Current equity holder in a privately-held company; Janssen: Research Funding. Roth: Janssen: Consultancy; Merck: Consultancy.

Magnetic Helicity Estimations in Models and Observations of the Solar Magnetic Field. IV. Application to Solar Observations

In this ISSI-supported series of studies on magnetic helicity in the Sun, we systematically implement different magnetic helicity calculation methods on high-quality solar magnetogram observations. We apply finite-volume, discrete flux tube (in particular, connectivity-based) and flux-integration methods to data from Hinode’s Solar Optical Telescope. The target is NOAA Active Region 10930 during a 1.5-day interval in 2006 December that included a major eruptive flare (SOL2006-12-13T02:14X3.4). Finite-volume and connectivity-based methods yield instantaneous budgets of the coronal magnetic helicity, while the flux-integration methods allow an estimate of the accumulated helicity injected through the photosphere. The objectives of our work are twofold: a cross-validation of methods, as well as an interpretation of the complex events leading to the eruption. To the first objective, we find (i) strong agreement among the finite-volume methods, (ii) a moderate agreement between the connectivity-based and finite-volume methods, (iii) an excellent agreement between the flux-integration methods, and (iv) an overall agreement between finite-volume- and flux-integration-based estimates regarding the predominant sign and magnitude of the helicity. To the second objective, we are confident that the photospheric helicity flux significantly contributed to the coronal helicity budget and that a right-handed structure erupted from a predominantly left-handed corona during the X-class flare. Overall, we find that the use of different methods to estimate the (accumulated) coronal helicity may be necessary in order to draw a complete picture of an active region corona, given the careful handling of identified data (preparation) issues, which otherwise would mislead the event analysis and interpretation.

Extracellular Vesicles in Regeneration and Rehabilitation Recovery after Stroke

Patients that survive after a stroke event may present disabilities that can persist for a long time or permanently after it. If stroke prevention fails, the prompt and combinatorial intervention with pharmacological and rehabilitation therapy is pivotal for the optimal recovery of patients and the reduction of disabilities. In the present review, we summarize some key features of the complex events that occur in the brain during and after the stroke event, with a special focus on extracellular vesicles (EVs) and their role as both carriers of biomarkers and potential therapeutics. EVs have already demonstrated their ability to be used for diagnostic purposes for multiple brain disorders and could represent valuable tools to track the regenerative and inflammatory processes occurring in the injured brain after stroke. Last, but not least, the use of artificial or stem cell-derived EVs were proved to be effective in stimulating brain remodeling and ameliorating recovery after stroke. Still, effective biomarkers of recovery are needed to design robust trials for the validation of innovative therapeutic strategies, such as regenerative rehabilitation approaches.

The Application of Single-Cell RNA Sequencing in Mammalian Meiosis Studies

Meiosis is a cellular division process that produces gametes for sexual reproduction. Disruption of complex events throughout meiosis, such as synapsis and homologous recombination, can lead to infertility and aneuploidy. To reveal the molecular mechanisms of these events, transcriptome studies of specific substages must be conducted. However, conventional methods, such as bulk RNA-seq and RT-qPCR, are not able to detect the transcriptional variations effectively and precisely, especially for identifying cell types and stages with subtle differences. In recent years, mammalian meiotic transcriptomes have been intensively studied at the single-cell level by using single-cell RNA-seq (scRNA-seq) approaches, especially through two widely used platforms, Smart-seq2 and Drop-seq. The scRNA-seq protocols along with their downstream analysis enable researchers to accurately identify cell heterogeneities and investigate meiotic transcriptomes at a higher resolution. In this review, we compared bulk RNA-seq and scRNA-seq to show the advantages of the scRNA-seq in meiosis studies; meanwhile, we also pointed out the challenges and limitations of the scRNA-seq. We listed recent findings from mammalian meiosis (male and female) studies where scRNA-seq applied. Next, we summarized the scRNA-seq analysis methods and the meiotic marker genes from spermatocytes and oocytes. Specifically, we emphasized the different features of the two scRNA-seq protocols (Smart-seq2 and Drop-seq) in the context of meiosis studies and discussed their strengths and weaknesses in terms of different research purposes. Finally, we discussed the future applications of scRNA-seq in the meiosis field.

Constructing Theory-Informed Relational and Verifiable Protest Event Data

Protest event data are both undertheorized and riddled with inconsistencies and errors. We call for modifying standard practices in the collection and construction of protest event data from electronic archives of news sources to both improve verifiability of data and integrate theory with data construction. The key change is a relational data structure that maintains strong links between events identified by coders and the underlying textual sources. This allows study of the relation between events and news coverage of those events. An additional change is to record data on the relations among events, including both recognition of complex events involving multiple actors, dates, action forms, or locations and explicit acknowledgement of the connection of events to specific protest campaigns or episodes of contention. We present preliminary illustrative data about Black protests from these new procedures to demonstrate the value of this approach. NOTE: This is a working paper. Comments and feedback are appreciated.