The Meaning of This Time and Place: Address to American Catholic Bishops and American Rabbis

Jews and Christians are both witnesses to the reality of God and his moral law on earth. That is why if Hitler had succeeded in destroying the Jewish people, he would have begun destroying the Church next. The Nazis ultimately wanted to tear up the taproot of the Christian faith and to replace it with a faith of their own invention. It was the profound tragedy of the Shoah that convinced the Church to reevaluate its teachings and relationship with the Jewish people. Out of this horror came the seeds of Jewish-Christian healing and the beginning a new era of fraternity—and we are only at the beginning of this reconciliation. This healing between the Church and the Jewish people is no small measure of meaning in the midst of the unspeakable devastation and desecration. Perhaps it points the way to a new era of faith for all of us and renewed commitment to sanctify life, to heal the world, and to protect God’s moral values for all of his children. Rabbi Eugene Korn is Executive Director of the Center for Christian-Jewish Understanding of Sacred Heart University. This address was delivered in Krakow, Poland, on September 2, 2007, as part of the U.S. Bishops and Rabbis Study Tour sponsored by the CCJU

The Latin Liturgy and the Jews

Pope Benedict XVI\u27s recent letter to bishops authorizing wider use of the 1962 Roman Missal, commonly referred to as the Latin Mass, has provoked strong reactions from Jews and Catholics worldwide who are committed to furthering the historic work of reconciliation begun at the Second Vatican Council with the “Declaration on the Relation of the Church to Non-Christian Religions” (Nostra Aetate, 1965). Many are concerned that some language in the missal harkens back to the Adversus Judaeos tradition within Christianity, which for some 18 centuries saw Jews as a threat to Christian society. This tradition was forthrightly and courageously rejected at Vatican II. Yet we and many others in the interfaith community believe these issues can be addressed while still honoring the pope’s laudable desire to reach out to those Catholics who feel a special connection to the Latin rite. There is much to learn from the present controversy. Indeed, it is a crucial moment in the history of Jewish-Catholic dialogue, a test of how far our relations have progressed

QSAR Modeling of SARS-CoV Mpro Inhibitors Identifies Sufugolix, Cenicriviroc, Proglumetacin, and other Drugs as Candidates for Repurposing against SARS-CoV-2

The main protease (Mpro) of the SARS-CoV-2 has been proposed as one of the major drug targets for COVID-19. We have identified the experimental data on the inhibitory activity of compounds tested against the closely related (96% sequence identity, 100% active site conservation) Mpro of SARS-CoV. We developed QSAR models of these inhibitors and employed these models for virtual screening of all drugs in the DrugBank database. Similarity searching and molecular docking were explored in parallel, but docking failed to correctly discriminate between experimentally active and inactive compounds, so it was not relied upon for prospective virtual screening. Forty-two compounds were identified by our models as consensus computational hits. Subsequent to our computational studies, NCATS reported the results of experimental screening of their drug collection in SARS-CoV-2 cytopathic effect assay (https://opendata.ncats.nih.gov/covid19/). Coincidentally, NCATS tested 11 of our 42 hits, and three of them, cenicriviroc (AC50 of 8.9 μM), proglumetacin (tested twice independently, with AC50 of 8.9 μM and 12.5 μM), and sufugolix (AC50 12.6 μM), were shown to be active. These observations support the value of our modeling approaches and models for guiding the experimental investigations of putative anti-COVID-19 drug candidates. All data and models used in this study are publicly available via Supplementary Materials, GitHub (https://github.com/alvesvm/sars-cov-mpro), and Chembench web portal (https://chembench.mml.unc.edu/)

ExEmPLAR (Extracting, Exploring, and Embedding Pathways Leading to Actionable Research): a user-friendly interface for knowledge graph mining

SUMMARY: Knowledge graphs are being increasingly used in biomedical research to link large amounts of heterogenous data and facilitate reasoning across diverse knowledge sources. Wider adoption and exploration of knowledge graphs in the biomedical research community is limited by requirements to understand the underlying graph structure in terms of entity types and relationships, represented as nodes and edges, respectively, and learn specialized query languages for graph mining and exploration. We have developed a user-friendly interface dubbed ExEmPLAR (Extracting, Exploring, and Embedding Pathways Leading to Actionable Research) to aid reasoning over biomedical knowledge graphs and assist with data-driven research and hypothesis generation. We explain the key functionalities of ExEmPLAR and demonstrate its use with a case study considering the relationship of Trypanosoma cruzi, the etiological agent of Chagas disease, to frequently associated cardiovascular conditions. AVAILABILITY AND IMPLEMENTATION: ExEmPLAR is freely accessible at https://www.exemplar.mml.unc.edu/. For code and instructions for the using the application, see: https://github.com/beasleyjonm/AOP-COP-Path-Extractor

COVID-KOP: integrating emerging COVID-19 data with the ROBOKOP database

SUMMARY: In response to the COVID-19 pandemic, we established COVID-KOP, a new knowledgebase integrating the existing Reasoning Over Biomedical Objects linked in Knowledge Oriented Pathways (ROBOKOP) biomedical knowledge graph with information from recent biomedical literature on COVID-19 annotated in the CORD-19 collection. COVID-KOP can be used effectively to generate new hypotheses concerning repurposing of known drugs and clinical drug candidates against COVID-19 by establishing respective confirmatory pathways of drug action. AVAILABILITY AND IMPLEMENTATION: COVID-KOP is freely accessible at https://covidkop.renci.org/. For code and instructions for the original ROBOKOP, see: https://github.com/NCATS-Gamma/robokop

Correlation Between Structure And C-Afm Contrast Of 180-Degree Domain Walls In Rhombohedral Bati03

Using Landau-Ginzburg-Devonshire theory we describe 180-degree domain wall structure, intrinsic energy and carrier accumulation in rhombohedral phase of BaTiO3 as a function of the wall orientation and flexoelectric coupling strength. Two types of domain wall structures (phases of the wall) exist depending on the wall orientation. The low-energy 'achiral' phase occurs in the vicinity of the {110} wall orientation and has odd polarization profile invariant with respect to inversion about the wall center. The second 'chiral' phase occurs around {211} wall orientations and corresponds to mixed parity domain walls that may be of left-handed or right-handed chirality. The transformation between the phases is abrupt, accompanied with 20-30% change of the domain wall thickness and can happen at fixed wall orientation with temperature change. We suggest that the phase transition may be detected through domain wall thickness change or by c-AFM. The structure of the domain wall is correlated to its conductivity through polarization component normal to the domain wall, which causes free carriers accumulation. Depending on the temperature and flexoelectric coupling strength relative conductivity of the wall becomes at least one order of magnitude higher than in the single-domain region, creating c-AFM contrast enhancement pronounced and detectable.Comment: 31 pages, 10 figures, Supplementary material

Thermodynamics of nanodomain formation and breakdown in Scanning Probe Microscopy: Landau-Ginzburg-Devonshire approach

Thermodynamics of tip-induced nanodomain formation in scanning probe microscopy of ferroelectric films and crystals is studied using the Landau-Ginzburg-Devonshire phenomenological approach. The local redistribution of polarization induced by the biased probe apex is analyzed including the effects of polarization gradients, field dependence of dielectric properties, intrinsic domain wall width, and film thickness. The polarization distribution inside subcritical nucleus of the domain preceding the nucleation event is very smooth and localized below the probe, and the electrostatic field distribution is dominated by the tip. In contrast, polarization distribution inside the stable domain is rectangular-like, and the associated electrostatic fields clearly illustrate the presence of tip-induced and depolarization field components. The calculated coercive biases of domain formation are in a good agreement with available experimental results for typical ferroelectric materials. The microscopic origin of the observed domain tip elongation in the region where the probe electric field is much smaller than the intrinsic coercive field is the positive depolarization field in front of the moving counter domain wall. For infinitely thin domain walls local domain breakdown through the sample depth appears. The results obtained here are complementary to the Landauer-Molotskii energetic approach.Comment: 35 pages, 8 figures, suplementary attached, to be submitted to Phys. Rev.

Knowledge-based approaches to drug discovery for rare diseases

The conventional drug discovery pipeline has proven to be unsustainable for rare diseases. Herein, we discuss recent advances in biomedical knowledge mining applied to discovering therapeutics for rare diseases. We summarize current chemogenomics data of relevance to rare diseases and provide a perspective on the effectiveness of machine learning (ML) and biomedical knowledge graph mining in rare disease drug discovery. We illustrate the power of these methodologies using a chordoma case study. We expect that a broader application of knowledge graph mining and artificial intelligence (AI) approaches will expedite the discovery of viable drug candidates against both rare and common diseases

Learning from history: do not flatten the curve of antiviral research!

Here, we explore the dynamics of the response of the scientific community to several epidemics, including Coronavirus Disease 2019 (COVID-19), as assessed by the numbers of clinical trials, publications, and level of research funding over time. All six prior epidemics studied [bird flu, severe acute respiratory syndrome (SARS), swine flu, Middle East Respiratory Syndrome (MERS), Ebola, and Zika] were characterized by an initial spike of research response that flattened shortly thereafter. Unfortunately, no antiviral medications have been discovered to date as treatments for any of these diseases. By contrast, the HIV/AIDS pandemic has garnered consistent research investment since it began and resulted in drugs being developed within 7 years of its start date, with many more to follow. We argue that, to develop effective treatments for COVID-19 and be prepared for future epidemics, long-term, consistent investment in antiviral research is needed

STopTox: An in Silico Alternative to Animal Testing for Acute Systemic and Topical Toxicity

BACKGROUND: Modern chemical toxicology is facing a growing need to Reduce, Refine, and Replace animal tests (Russell 1959) for hazard identification. The most common type of animal assays for acute toxicity assessment of chemicals used as pesticides, pharmaceuticals, or in cosmetic products is known as a "6-pack" battery of tests, including three topical (skin sensitization, skin irritation and corrosion, and eye irritation and corrosion) and three systemic (acute oral toxicity, acute inhalation toxicity, and acute dermal toxicity) end points. METHODS: We compiled, curated, and integrated, to the best of our knowledge, the largest publicly available data sets and developed an ensemble of quantitative structure-activity relationship (QSAR) models for all six end points. All models were validated according to the Organisation for Economic Co-operation and Development (OECD) QSAR principles, using data on compounds not included in the training sets. RESULTS: In addition to high internal accuracy assessed by cross-validation, all models demonstrated an external correct classification rate ranging from 70% to 77%. We established a publicly accessible Systemic and Topical chemical Toxicity (STopTox) web portal (https://stoptox.mml.unc.edu/) integrating all developed models for 6-pack assays. CONCLUSIONS: We developed STopTox, a comprehensive collection of computational models that can be used as an alternative to in vivo 6-pack tests for predicting the toxicity hazard of small organic molecules. Models were established following the best practices for the development and validation of QSAR models. Scientists and regulators can use the STopTox portal to identify putative toxicants or nontoxicants in chemical libraries of interest. https://doi.org/10.1289/EHP9341