Screening Of Interactions Research Articles

Revisiting ‘blackboard’: Transformation of medium, space and pedagogy in school education

Appeared as a ‘low-tech’ yet significant teaching aid in the modern classroom, the blackboard has greatly shaped the medium, space and pedagogy of school education. Over the past two centuries, ‘blackboard’ itself has also been constantly remoulded in terms of its colour, material and function, from the traditional black wooden surface to the interactive digital screen, which requires comprehensive investigations from historical, technological and educational perspectives. This essay synthesizes approaches applied in three dimensions. First is the material and technological aspect, tracing the transformation of such ‘boards’ from stone/wood to plastic/steel to digital/online forms and their functions extended; then it focuses on the etymological and lexicographical dimension, comparatively analysing the definitions of blackboard, chalkboard and whiteboard in the representative dictionaries; moreover, an educational perspective is employed throughout the whole investigation, especially on how the invention and involution of ‘blackboard’ shaped the class space, teacher-student relationship and subject pedagogy. Beyond the concern of technology, this essay reserves due attention to the epistemological issue in dealing with the presentation, transmission and acquisition of knowledge under different cognitive contexts.

Identification of Plant Co-regulatory Modules Using CoReg.

Regulatory network is often characterized by complex interactions between transcription factors (TFs) and target genes. The synergistic regulations among multiple TFs may co-induce/co-suppress the expressions of the similar target genes. Such information is important for understanding stress response signaling pathways in plants. In this chapter, we present a computational tool, CoReg, for mining co-regulatory gene modules from network topology. The analysis results can be used to interpret co-regulation effects in regulatory networks generated by high-through TF-DNA interaction screenings such as yeast-one-hybrid, ChIP-seq, and DAP-seq.

Drug-gene Interaction Screens Coupled to Tumor Data Analyses Identify the Most Clinically Relevant Cancer Vulnerabilities Driving Sensitivity to PARP Inhibition.

This study identifies tumor genetic backgrounds where to expand the use of PARPis beyond mutations in BRCA1 or BRCA2. This is achieved by combining the output of unbiased genome-wide loss-of-function CRISPR-Cas9 genetic screens with bioinformatics analysis of biallelic losses of the identified genes in public tumor datasets, unveiling loss of the DNA repair gene XRCC3 as a potential biomarker of PARPi sensitivity in prostate cancer.

Conical Intersections in Solution with Polarizable Embedding: Integral-Exact Direct Reaction Field.

A common strategy to exploring the properties and reactivity of complex systems is to use quantum mechanics/molecular mechanics (QM/MM) embedding, wherein a QM region is defined and treated with electronic structure theory, and the remainder of the system is treated with a force field. Important to the description of electronic excited states, especially those of charge-transfer character, is the treatment of the coupling between the QM and MM subsystems. The state of the art is to use a polarizable force field for the MM region and mutually couple the QM wavefunction and MM induced dipoles, in addition to the usual electrostatic embedding, yielding a polarizable embedding (QM/MM-Pol) approach. However, we showed previously that current popular QM/MM-Pol approaches exhibit issues of root flipping and/or incorrect descriptions of electronic crossings in multistate calculations [J. Chem. Theory Comput. 14, 2137 (2018)]. Here, we demonstrate a solution to these problems with an integral-exact reformulation of the direct reaction field approach of Thole and Van Duijnen (QM/MM-IEDRF). The resulting embedding potential includes one- and two-electron operators and many-body dipole-induced dipole interactions and thus includes a natural description of the screening of electron-electron interactions by the MM induced dipoles. Pauli repulsion from the environment is mimicked by effective core potentials on the MM atoms. Inherent to the DRF approach is the assumption that MM dipoles respond instantaneously to the positions of the QM electrons; therefore, dispersion interactions are captured approximately. All electronic states are eigenfunctions of the same Hamiltonian, while the polarization induced in the environment and the associated energetic stabilization are unique to each state. This allows for a consistent definition of transition properties and state crossings. We demonstrate QM/MM-IEDRF by exploring the influence of a (polarizable) inert xenon matrix environment on the conical intersection underlying the photoisomerization of ethylene.

QED medium effects in (anti)neutrino-nucleus and electron-nucleus scattering: Elastic scattering on nucleons

Interpretation of current and future neutrino oscillation and electron scattering experiments requires knowledge of lepton-nucleon and lepton-nucleus interactions at the percent level. We study the exchange of photons between charged particles and the nuclear medium for (anti)neutrino-, electron-, and muon-induced reactions inside a large nucleus. While quantum electrodynamics (QED)-medium contributions are formally suppressed by two powers of the electromagnetic coupling constant α when compared to the leading-order cross sections, low-energy modes and the nuclear size enhance the effect by orders of magnitude. They require a proper infrared regularization, which we implement as a screening of the electromagnetic interactions at atomic length scales or above. We provide approximate analytic expressions for the distortion of (anti)neutrino-nucleus and charged lepton-nucleus cross sections and evaluate the QED-medium effects for realistic values of the screening scale on the example of elastic scattering with nucleons inside the nucleus. We find new permille- to percent-level effects, which were not considered in either (anti)neutrino-nucleus or electron-nucleus scattering.

AI-Based Protein Interaction Screening and Identification (AISID).

In this study, we presented an AISID method extending AlphaFold-Multimer’s success in structure prediction towards identifying specific protein interactions with an optimized AISIDscore. The method was tested to identify the binding proteins in 18 human TNFSF (Tumor Necrosis Factor superfamily) members for each of 27 human TNFRSF (TNF receptor superfamily) members. For each TNFRSF member, we ranked the AISIDscore among the 18 TNFSF members. The correct pairing resulted in the highest AISIDscore for 13 out of 24 TNFRSF members which have known interactions with TNFSF members. Out of the 33 correct pairing between TNFSF and TNFRSF members, 28 pairs could be found in the top five (including 25 pairs in the top three) seats in the AISIDscore ranking. Surprisingly, the specific interactions between TNFSF10 (TNF-related apoptosis-inducing ligand, TRAIL) and its decoy receptors DcR1 and DcR2 gave the highest AISIDscore in the list, while the structures of DcR1 and DcR2 are unknown. The data strongly suggests that AlphaFold-Multimer might be a useful computational screening tool to find novel specific protein bindings. This AISID method may have broad applications in protein biochemistry, extending the application of AlphaFold far beyond structure predictions.

AN EPIDEMIC WITHIN A PANDEMIC: CYBERBULLYING IN CHILDREN AND ADOLESCENTS

With a quick look into your waiting room, it’s evident that most tweens and teens are glued to an electronic device. They are most likely using some form of social media as a way to reach out to others or as a platform of self-expression while they wait for their appointment. There is so much to cover from discussing mood and anxiety to screening for substance use and physical aggression. However, realistically, you will not have time to discuss your patient’s social media use and screen for healthy cyber interactions.

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform.

Secreted proteins, which include cytokines, hormones, and growth factors, are extracellular ligands that control key signaling pathways mediating cell-cell communication within and between tissues and organs. Many drugs target secreted ligands and their cell surface receptors. Still, there are hundreds of secreted human proteins that either have no identified receptors ('orphans') or are likely to act through cell surface receptors that have not yet been characterized. Discovery of secreted ligand-receptor interactions by high-throughput screening has been problematic, because the most commonly used high-throughput methods for protein-protein interaction (PPI) screening are not optimized for extracellular interactions. Cell-based screening is a promising technology for the deorphanization of ligand-receptor interactions, because multimerized ligands can enrich for cells expressing low affinity cell surface receptors, and such methods do not require purification of receptor extracellular domains. Here, we present a proteo-genomic cell-based CRISPR activation (CRISPRa) enrichment screening platform employing customized pooled cell surface receptor sgRNA libraries in combination with a magnetic bead selection-based enrichment workflow for rapid, parallel ligand-receptor deorphanization. We curated 80 potentially high-value orphan secreted proteins and ultimately screened 20 secreted ligands against two cell sgRNA libraries with targeted expression of all single-pass (TM1) or multi-pass transmembrane (TM2+) receptors by CRISPRa. We identified previously unknown interactions in 12 of these screens, and validated several of them using surface plasmon resonance and/or cell binding assays. The newly deorphanized ligands include three receptor protein tyrosine phosphatase (RPTP) ligands and a chemokine-like protein that binds to killer immunoglobulin-like receptors (KIRs). These new interactions provide a resource for future investigations of interactions between the human-secreted and membrane proteomes.

Uncovering the pharmacology of Ginkgo biloba folium in the cell-type-specific targets of Parkinson's disease.

Parkinson’s disease (PD) is the second most common neurodegenerative disease with a fast-growing prevalence. Developing disease-modifying therapies for PD remains an enormous challenge. Current drug treatment will lose efficacy and bring about severe side effects as the disease progresses. Extracts from Ginkgo biloba folium (GBE) have been shown neuroprotective in PD models. However, the complex GBE extracts intertwingled with complicated PD targets hinder further drug development. In this study, we have pioneered using single-nuclei RNA sequencing data in network pharmacology analysis. Furthermore, high-throughput screening for potent drug-target interaction (DTI) was conducted with a deep learning algorithm, DeepPurpose. The strongest DTIs between ginkgolides and MAPK14 were further validated by molecular docking. This work should help advance the network pharmacology analysis procedure to tackle the limitation of conventional research. Meanwhile, these results should contribute to a better understanding of the complicated mechanisms of GBE in treating PD and lay the theoretical ground for future drug development in PD.

Interactions of Isoquinoline Alkaloids with Transition Metals Iron and Copper.

Data on alkaloid interactions with the physiologically important transition metals, iron and copper, are mostly lacking in the literature. However, these interactions can have important consequences in the treatment of both Alzheimer’s disease and cancer. As isoquinoline alkaloids include galanthamine, an approved drug for Alzheimer’s disease, as well as some potentially useful compounds with cytostatic potential, 28 members from this category of alkaloids were selected for a complex screening of interactions with iron and copper at four pathophysiologically relevant pH and in non-buffered conditions (dimethyl sulfoxide) by spectrophotometric methods in vitro. With the exception of the salts, all the alkaloids were able to chelate ferrous and ferric ions in non-buffered conditions, but only five of them (galanthine, glaucine, corydine, corydaline and tetrahydropalmatine) evoked some significant chelation at pH 7.5 and only the first two were also active at pH 6.8. By contrast, none of the tested alkaloids chelated cuprous or cupric ions. All the alkaloids, with the exception of the protopines, significantly reduced the ferric and cupric ions, with stronger effects on the latter. These effects were mostly dependent on the number of free aromatic hydroxyls, but not other hydroxyl groups. The most potent reductant was boldine. As most of the alkaloids chelated and reduced the ferric ions, additional experimental studies are needed to elucidate the biological relevance of these results, as chelation is expected to block reactive oxygen species formation, while reduction could have the opposite effect.

Optimized Rhombic Experimental Dynamic Checkerboard Designs to Elucidate Pharmacodynamic Drug Interactions of Antibiotics

PurposeQuantification of pharmacodynamic interactions is key in combination therapies, yet conventional checkerboard experiments with up to 10 by 10 combinations are labor-intensive. Therefore, this study provides optimized experimental rhombic checkerboard designs to enable an efficient interaction screening with significantly reduced experimental workload.MethodsBased on the general pharmacodynamic interaction (GPDI) model implemented in Bliss Independence, a novel rhombic ‘dynamic’ checkerboard design with quantification of bacteria instead of turbidity as endpoint was developed. In stochastic simulations and estimations (SSE), the precision and accuracy of interaction parameter estimations and classification rates of conventional reference designs and the newly proposed rhombic designs based on effective concentrations (EC) were compared.ResultsAlthough a conventional rich design with 20-times as many combination scenarios provided estimates of interaction parameters with higher accuracy, precision and classification rates, the optimized rhombic designs with one natural growth scenario, three monotherapy scenarios per combination partner and only four combination scenarios were still superior to conventional reduced designs with twice as many combination scenarios. Additionally, the rhombic designs were able to identify whether an interaction occurred as a shift on maximum effect or EC50 with > 98%. Overall, effective concentration-based designs were found to be superior to traditional standard concentrations, but were more challenged by strong interaction sizes exceeding their adaptive concentration ranges.ConclusionThe rhombic designs proposed in this study enable a reduction of resources and labor and can be a tool to streamline higher throughput in drug interaction screening.

Ca2+-dependent phosphorylation of NRAMP1 by CPK21 and CPK23 facilitates manganese uptake and homeostasis in Arabidopsis

Homeostasis of the essential micronutrient manganese (Mn) is crucially determined through availability and uptake efficiency in all organisms. Mn deficiency of plants especially occurs in alkaline and calcareous soils, seriously restricting crop yield. However, the mechanisms underlying the sensing and signaling of Mn availability and conferring regulation of Mn uptake await elucidation. Here, we uncover that Mn depletion triggers spatiotemporally defined long-lasting Ca2+ oscillations in Arabidopsis roots. These Ca2+ signals initiate in individual cells, expand, and intensify intercellularly to transform into higher-order multicellular oscillations. Furthermore, through an interaction screen we identified the Ca2+-dependent protein kinases CPK21 and CPK23 as Ca2+ signal-decoding components that bring about translation of these signals into regulation of uptake activity of the high-affinity Mn transporter natural resistance associated macrophage proteins 1 (NRAMP1). Accordingly, a cpk21/23 double mutant displays impaired growth and root development under Mn-limiting conditions, while kinase overexpression confers enhanced tolerance to low Mn supply to plants. In addition, we define Thr498 phosphorylation within NRAMP1 as a pivot mechanistically determining NRAMP1 activity, as revealed by biochemical assays and complementation of yeast Mn uptake and Arabidopsis nramp1 mutants. Collectively, these findings delineate the Ca2+-CPK21/23-NRAMP1 axis as key for mounting plant Mn homeostasis.

Assessment of the Second-Order Statically Screened Exchange Correction to the Random Phase Approximation for Correlation Energies.

With increasing interelectronic distance, the screening of the electron–electron interaction by the presence of other electrons becomes the dominant source of electron correlation. This effect is described by the random phase approximation (RPA) which is therefore a promising method for the calculation of weak interactions. The success of the RPA relies on the cancellation of errors, which can be traced back to the violation of the crossing symmetry of the 4-point vertex, leading to strongly overestimated total correlation energies. By the addition of second-order screened exchange (SOSEX) to the correlation energy, this issue is substantially reduced. In the adiabatic connection (AC) SOSEX formalism, one of the two electron–electron interaction lines in the second-order exchange term is dynamically screened (SOSEX(W, vc)). A related SOSEX expression in which both electron–electron interaction lines are statically screened (SOSEX(W(0), W(0))) is obtained from the G3W2 contribution to the electronic self-energy. In contrast to SOSEX(W, vc), the evaluation of this correlation energy expression does not require an expensive numerical frequency integration and is therefore advantageous from a computational perspective. We compare the accuracy of the statically screened variant to RPA and RPA+SOSEX(W, vc) for a wide range of chemical reactions. While both methods fail for barrier heights, SOSEX(W(0), W(0)) agrees very well with SOSEX(W, vc) for charged excitations and noncovalent interactions where they lead to major improvements over RPA.

Biomolecular Complexation on the "Wrong Side": A Case Study of the Influence of Salts and Sugars on the Interactions between Bovine Serum Albumin and Sodium Polystyrene Sulfonate.

In the protein purification, drug delivery, food industry, and biotechnological applications involving protein–polyelectrolyte complexation, proper selection of co-solutes and solution conditions plays a crucial role. The onset of (bio)macromolecular complexation occurs even on the so-called “wrong side” of the protein isoionic point where both the protein and the polyelectrolyte are net like-charged. To gain mechanistic insights into the modulatory role of salts (NaCl, NaBr, and NaI) and sugars (sucrose and sucralose) in protein–polyelectrolyte complexation under such conditions, interaction between bovine serum albumin (BSA) and sodium polystyrene sulfonate (NaPSS) at pH = 8.0 was studied by a combination of isothermal titration calorimetry, fluorescence spectroscopy, circular dichroism, and thermodynamic modeling. The BSA–NaPSS complexation proceeds by two binding processes (first, formation of intrapolymer complexes and then formation of interpolymer complexes), both driven by favorable electrostatic interactions between the negatively charged sulfonic groups (−SO3–) of NaPSS and positively charged patches on the BSA surface. Two such positive patches were identified, each responsible for one of the two binding processes. The presence of salts screened both short-range attractive and long-range repulsive electrostatic interactions between both macromolecules, resulting in a nonmonotonic dependence of the binding affinity on the total ionic strength for both binding processes. In addition, distinct anion-specific effects were observed (NaCl < NaBr < NaI). The effect of sugars was less pronounced: sucrose had no effect on the complexation, but its chlorinated analogue, sucralose, promoted it slightly due to the screening of long-range repulsive electrostatic interactions between BSA and NaPSS. Although short-range non-electrostatic interactions are frequently mentioned in the literature in relation to BSA or NaPSS, we found that the main driving force of complexation on the “wrong side” are electrostatic interactions.

Influence of denaturants on amyloid β42 aggregation kinetics.

Amyloid formation is linked to devastating neurodegenerative diseases, motivating detailed studies of the mechanisms of amyloid formation. For Aβ, the peptide associated with Alzheimer’s disease, the mechanism and rate of aggregation have been established for a range of variants and conditions in vitro and in bodily fluids. A key outstanding question is how the relative stabilities of monomers, fibrils and intermediates affect each step in the fibril formation process. By monitoring the kinetics of aggregation of Aβ42, in the presence of urea or guanidinium hydrochloride (GuHCl), we here determine the rates of the underlying microscopic steps and establish the importance of changes in relative stability induced by the presence of denaturant for each individual step. Denaturants shift the equilibrium towards the unfolded state of each species. We find that a non-ionic denaturant, urea, reduces the overall aggregation rate, and that the effect on nucleation is stronger than the effect on elongation. Urea reduces the rate of secondary nucleation by decreasing the coverage of fibril surfaces and the rate of nucleus formation. It also reduces the rate of primary nucleation, increasing its reaction order. The ionic denaturant, GuHCl, accelerates the aggregation at low denaturant concentrations and decelerates the aggregation at high denaturant concentrations. Below approximately 0.25 M GuHCl, the screening of repulsive electrostatic interactions between peptides by the charged denaturant dominates, leading to an increased aggregation rate. At higher GuHCl concentrations, the electrostatic repulsion is completely screened, and the denaturing effect dominates. The results illustrate how the differential effects of denaturants on stability of monomer, oligomer and fibril translate to differential effects on microscopic steps, with the rate of nucleation being most strongly reduced.

Compound Interaction Screen on a Photoactivatable Cellulose Membrane (CISCM) Identifies Drug Targets.

Identifying the protein targets of drugs is an important but tedious process. Existing proteomic approaches enable unbiased target identification but lack the throughput needed to screen larger compound libraries. Here, we present a compound interaction screen on a photoactivatable cellulose membrane (CISCM) that enables target identification of several drugs in parallel. To this end, we use diazirine-based undirected photoaffinity labeling (PAL) to immobilize compounds on cellulose membranes. Functionalized membranes are then incubated with protein extract and specific targets are identified via quantitative affinity purification and mass spectrometry. CISCM reliably identifies known targets of natural products in less than three hours of analysis time per compound. In summary, we show that combining undirected photoimmobilization of compounds on cellulose with quantitative interaction proteomics provides an efficient means to identify the targets of natural products.

Oral oncolytic monitoring pilot with patient-reported outcomes and adherence assessments.

Patients on oral oncolytics are responsible for self-monitoring adherence and adverse drug reactions (ADRs). Oncology pharmacists are in position to focus on quality and safety of care for patients on oncolytics while providing communication between the patient, physician, and specialty pharmacies. This pilot aimed to monitor patients treated by our leukemia team initiated on oral oncolytics. From July 2020 to February 2021, patients treated by our leukemia team newly started on oncolytics were included. Pharmacists performed medication reconciliation and drug interaction screening on initiation of oral oncolytic. Pharmacists followed up at predefined intervals. On follow up adherence was assessed using the Morisky Medication Adherence Scale-8 (MMAS-8) and patient reported outcomes (PROs) were assessed using the revised Edmonton Symptom Assessment Scale (ESAS-r). After each follow-up, a note was placed in the chart with assessment scores and recommendations. A total of 32 patients were screened with 19 patients included. Oral oncolytics included: imatinib (4), dasatinib (5), ponatinib (1), gilteritinib (2), enasidenib (1), and venetoclax (6). Fourteen drug interactions were identified, 11 medications discontinued, nine medications added, and two medications doses were changed. Twenty-six adherence assessments were performed with 21, 4, and 1 assessment demonstrating adherence, medium adherence, and low adherence, respectively. 62 ESAS-r assessments were performed with 64% reported as no symptoms, 17% as mild, 13% as moderate, and 5% as severe symptoms. Twenty laboratory tests were ordered from pharmacist recommendation on initiation and follow-up. This pilot demonstrated the role pharmacists play in oral oncolytic monitoring and symptom management.

Interactions between O2 Nanobubbles and the Pulmonary Surfactant in the Presence of Inhalation Medicines.

A dispersion of oxygen nanobubbles (O2-NBs) is an extraordinary gas–liquid colloidal system where spherical gas elements can be considered oxygen transport agents. Its conversion into inhalation aerosol by atomization with the use of nebulizers, while maintaining the properties of the dispersion, gives new opportunities for its applications and may be attractive as a new concept in treating lung diseases. The screening of O2-NBs interactions with lung fluids is particularly needed in view of an O2-NBs application as a promising aerosol drug carrier with the additional function of oxygen supplementation. The aim of the presented studies was to investigate the influence of O2-NBs dispersion combined with the selected inhalation drugs on the surface properties of two types of pulmonary surfactant models (lipid and lipid–protein model). The characteristics of the air–liquid interface were carried out under breathing-like conditions using two selected tensiometer systems: Langmuir–Wilhelmy trough and the oscillating droplet tensiometer. The results indicate that the presence of NBs has a minor effect on the dynamic characteristics of the air–liquid interface, which is the desired effect in the context of a potential use in inhalation therapies.

Screening of the Coulomb interaction in C3N: Reduced dimensionality and electronic structure effects

Coulomb interactions in two-dimensional semimetals like graphene are not screened in the usual way, and sizable long-range interaction has been found. With the aim of achieving new materials with nonconventional screening, as well as, in order to investigate various effects such as reduced dimensionality and electronic band dispersion, we calculate the strength of the effective Coulomb interaction $U$ between ${p}_{z}$ electrons in recently developed hexagonal ${\mathrm{C}}_{3}\mathrm{N}$ materials from the first principles using the constrained random-phase approximation. We find that the calculated parameters in the monolayer of the ${\mathrm{C}}_{3}\mathrm{N}$ are larger than the ones in graphene and remain sizable even in metallic bilayers. Nonlocal Coulomb interactions $U(r)$ in nonmetallic ${\mathrm{C}}_{3}\mathrm{N}$ nanoribbons are almost 1 eV smaller than the ones for ${\mathrm{C}}_{3}\mathrm{N}$ monolayer. Our results show that similar to graphene, screening in hexagonal ${\mathrm{C}}_{3}\mathrm{N}$ is also nonconventional. This controversial screening of Coulomb interaction stems from the electronic structure and massless Dirac dispersion below Fermi energy, which has to be preserved for symmetry reasons in hexagonal ${\mathrm{C}}_{3}\mathrm{N}$ layers.

VRPharmer: bringing virtual reality into pharmacophore-based virtual screening with interactive exploration and realistic visualization

Current pharmacophore-based virtual screening (VS) software has limited interactive capabilities and less intuitive screening processes. In this study, a novel tool named VRPharmer is proposed to perform the entire VS workflow in VR environments. VRPharmer enables users to interactively perceive computation processes and immersively observe molecular structures. Besides a typical screening mode (OPT mode), VRPharmer provides a unique interactive screening mode (SCORE mode) for freely exploring the optimal binding poses. Pharmacophore models are editable to study the impact of each feature and further refine the screening results. Moreover, molecular rendering algorithms are improved for precise representations. VRPharmer is open-source software under the MIT license. The released version is available at https://github.com/VRPharmer/VRPharmer. Supplementary data are available at Bioinformatics online.