Large Interactive Surfaces Research Articles

Supporting Mixed-Presence Awareness across Wall-Sized Displays Using a Tracking Pipeline based on Depth Cameras

One of the main benefits of large interactive surfaces (e.g. wall-sized displays) lies in their support for collocated collaboration by facilitating simultaneous interactions with the displays and high awareness of other group members' actions. In the context of remote collaboration, this awareness information needs to be acquired through digital means such as video feeds, which typically offer very limited information on non-verbal communication aspects, including on workspace awareness. We describe a new approach we have implemented to tackle that challenge through a multimodal pipeline that deals with tracking, attributing, transmitting, and visualising non-verbal information through what we refer to as workspace awareness cues, across wall-sized displays placed at distant locations. Our approach relies on commodity depth cameras combined with screen configuration information to generate deictic cues such as pointing targets and gaze direction. It also leverages recent artificial intelligence breakthroughs to attribute such cues to identified individuals and augment them with additional gestural interactions. In the present paper, we expand on the details and rationale behind our approach, describe its technical implementation, validate its novelty with regards to the existing literature, and report on early but promising results from an evaluation we conducted based on a mixed-presence decision-making scenario across two distant wall-sized displays.

Leveraging Bidirectional Nature of Allostery To Inhibit Protein-Protein Interactions (PPIs): A Case Study of PCSK9-LDLR Interaction.

The protein PCSK9 (proprotein convertase subtilisin/Kexin type 9) negatively regulates the recycling of LDLR (low-density lipoprotein receptor), leading to an elevated plasma level of LDL. Inhibition of PCSK9-LDLR interaction has emerged as a promising therapeutic strategy to manage hypercholesterolemia. However, the large interaction surface area between PCSK9 and LDLR makes it challenging to identify a small molecule competitive inhibitor. An alternative strategy would be to identify distal cryptic sites as targets for allosteric inhibitors that can remotely modulate PCSK9-LDLR interaction. Using several microseconds long molecular dynamics (MD) simulations, we demonstrate that on binding with LDLR, there is a significant conformational change (population shift) in a distal loop (residues 211-222) region of PCSK9. Consistent with the bidirectional nature of allostery, we establish a clear correlation between the loop conformation and the binding affinity with LDLR. Using a thermodynamic argument, we establish that the loop conformations predominantly present in the apo state of PCSK9 would have lower LDLR binding affinity, and they would be potential targets for designing allosteric inhibitors. We elucidate the molecular origin of the allosteric coupling between this loop and the LDLR binding interface in terms of the population shift in a set of salt bridges and hydrogen bonds. Overall, our work provides a general strategy toward identifying allosteric hotspots: compare the conformational ensemble of the receptor between the apo and bound states of the protein and identify distal conformational changes, if any. The inhibitors should be designed to bind and stabilize the apo-specific conformations.

Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death.

Proteolysis-targeting chimera (PROTAC) has emerged as a promising strategy for degrading proteins of interest. Peptide-based PROTACs offer several advantages over small-molecule-based PROTACs, such as high specificity, low toxicity, and large protein-protein interaction surfaces. However, peptide-based PROTACs have several intrinsic shortcomings that strongly limit their application including poor cell permeability and low stability and potency. Herein, we designed a nanosized hybrid PROTAC (GNCTACs) to target and degrade human epidermal growth factor receptor 2 (HER2) in tumor cells. Gold nanoclusters (GNCs) were utilized to connect HER2-targeting peptides and cereblon (CRBN)-targeting ligands. GNCTACs could overcome the intrinsic barriers of peptide-based PROTACs, efficiently delivering HER2-targeting peptides in the cytoplasm and protecting them from degradation. Furthermore, a fasting-mimicking diet was applied to enhance the cellular uptake and proteasome activity. Consequently, more than 95% of HER2 in SKBR3 cells was degraded by GNCTACs, and the degradation lasted for at least 72 h, showing a catalytic-like reaction.

Deep Sequencing of a Systematic Peptide Library Reveals Conformationally-Constrained Protein Interface Peptides that Disrupt a Protein-Protein Interaction.

Disrupting protein-protein interactions is difficult due to the large and flat interaction surfaces of the binding partners. The BLIP and BLIP-II proteins are unrelated in sequence and structure and yet each potently inhibit β-lactamases. High-throughput oligonucleotide synthesis was used to construct a 12,470-member library containing overlapping linear and cyclic peptides ranging in size from 6 to 21 amino acids that scan through the sequences of BLIP and BLIP-II. Phage display affinity selections and deep sequencing revealed that, despite the differences in interaction surfaces with β-lactamases, rapid enrichment of consensus peptide regions originating from both BLIP and BLIP-II contact residues in the binding interface occurred. BLIP and BLIP-II peptides that were enriched by affinity selection were shown to bind β-lactamases and disrupt the BLIP/β-lactamase interaction. The results suggest that peptides that bind at and disrupt PPI interfaces can be identified through systematic peptide library construction, affinity selection, and deep sequencing.

Passively mode-locked fiber laser based on graphene covered single-mode fiber with inner short waveguides

A saturable absorber based on graphene film covered single-mode fiber with inner short waveguides is proposed and demonstrated for passively mode-locked laser operation. The output laser pulses produced have the center wavelength of 1556.9 nm and pulse width of 830.5 fs at the fundamental repetition rate of 18.7 MHz. Such a saturable absorber is highly robust as the graphene film is covered on the surface of single-mode fiber, instead on tapered fiber or side-polished fiber. Moreover, compared with the saturable absorber based on clamping the graphene film between the two fiber connectors in a fiber adaptor, our device provides a large interaction surface area, thus effectively avoiding the thermal damage and ensuring a long time and stable system operation. The device is attractive for high power ultra-short laser pulse generation.

Spatiotemporal dynamics of nanowire growth in a microfluidic reactor

Co-integration of nanomaterials into microdevices poses several technological challenges and presents numerous scientific opportunities that have been addressed in this paper by integrating zinc oxide nanowires (ZnO-NWs) into a microfluidic chamber. In addition to the applications of these combined materials, this work focuses on the study of the growth dynamics and uniformity of nanomaterials in a tiny microfluidic reactor environment. A unique experimental platform was built through the integration of a noninvasive optical characterization technique with the microfluidic reactor. This platform allowed the unprecedented demonstration of time-resolved and spatially resolved monitoring of the in situ growth of NWs, in which the chemicals were continuously fed into the microfluidic reactor. The platform was also used to assess the uniformity of NWs grown quickly in a 10-mm-wide microchamber, which was intentionally chosen to be 20 times wider than those used in previous attempts because it can accommodate applications requiring a large surface of interaction while still taking advantage of submillimeter height. Further observations included the effects of varying the flow rate on the NW diameter and length in addition to a synergetic effect of continuous renewal of the growth solution and the confined environment of the chemical reaction.

Abstract 2471: IDP-121, a first in class staple peptide targeting c-MYC

Abstract MYC is a transcription factor involved in fundamental cellular functions such as proliferation, apoptosis, differentiation, metabolism and, as lately discovered, immune response. [1,2] It is deregulated in a wide variety of aggressive human cancers and its overexpression is one of the most common events associated with tumorigenesis, making it one of the most attractive yet challenging targets in oncology.[3] c-MYC protein structure is mostly disordered in its monomeric state, and assumes a helix-loop-helix fold upon binding to its protein partner MAX. The absence of clefts or hydrophobic pockets (typical of enzymes) and the large protein-protein interaction surface formed in the c-MYC/MAX complex represent a challenge for the design of small molecule inhibitors. Moreover, the intra-nuclear localization of c-MYC renders the use of antibodies impossible. Hence, it is not surprising that conventional drug development has failed and no therapeutic has yet progressed into clinical trials.[4] Here we describe IDP-121, a stapled peptide specifically designed to target c-MYC protein. A library based on c, l, n-MYC and MAX druggable regions was designed, with a bias towards disruption of c-MYC (residual) intra-protein interactions. The primary goal in the initial screen was to identify compounds able to block c-MYC's fold-like state that allows binding to MAX. A functional (cellular) assay was used for our screening program to ensure cell and nuclear penetration. Stapling technology was implemented to overcome the lack of stability and cell permeability common to unmodified peptides, whilst retaining c-MYC specificity and a large surface coverage. The lead compound, IDP-121, is stable to proteolysis and is rapidly internalized into cells, distributing efficiently into the nucleus (see Abstract 3). The interaction with c-MYC was characterized by HSQC-NMR, Fluorescence Polarization (FP) and Surface Plasmon Resonance (SPR). IDP-121 binds specifically to c-MYC, with a Kd of 400 nM, an affinity ten-fold higher than c-MYC/MAX interaction, allowing IDP-121 to displace MAX from the binding site. SAR studies were conducted to tailor the elements essential for its biological function. Isolated protein complex (ELISA), and pull-down and FRET experiments confirmed disruption of the c-MYC/MAX complex by IDP-121 (see Abstracts 2). The drug-like properties and efficacy in hematological and solid tumors of IDP-121 have been demonstrated in vivo (see Abstracts 2 and 3). In addition, IDP-121 has progressed through GLP toxicology studies without evidence of major systemic toxicity, allowing for the first viable Myc-targeted therapy to enter Phase 1 clinical trials in 2021. 1.Casey S.C. et al. Science 2016; 352 (6282): 227–231 2.Casey S.C. et al. Blood 2018; 131 (18): 2007-20153.Dang CV. Cell. 2012;149(1):22-35.4. Whitfield J. R., Front. Cell Dev. Biol. 2017 Citation Format: Carmen Calvis, Andreas Beier, Michael Feichtinger, Theresa Höfurthner, Miguel Moreno, Ramon Messeguer, Robert Konrat, Santiago Esteban, Laura Nevola. IDP-121, a first in class staple peptide targeting c-MYC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2471.

Partial Least-Squares Discriminant Analysis and Ensemble-Based Flexible Docking of PD-1/PD-L1 Inhibitors: A Pilot Study.

Although mAbs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have achieved remarkable therapeutic potential against multiple types of cancer, it is still of great interest for researchers to develop small-molecule PD-1/PD-L1 inhibitors without the mAb-related disadvantages of no oral bioavailability and poor solid tumor penetration. However, targeting the PD-1/PD-L1 pathway with small molecules is normally considered challenging because of the flat and large interaction surface of the PD-1/PD-L1 complex. In this paper, a total of 2558 PD-1/PD-L1 inhibitors were compiled from recent patents and literatures and then used for exploring the chemical space and structural features of PD-1/PD-L1 inhibitors by partial least-squares discriminant analysis. The results showed that intramolecular H bond, amphotericity indices, radius of gyration, nonbond electrostatic energy, fractional van der Waals surface area of H-bond donors, octanol–water partition coefficient, and molecular weight are the seven key features discriminating the PD-1/PD-L1 inhibitors from noninhibitors, with the prediction accuracy larger than 0.90. Based on the seven crystal structures of the PD-L1 dimer complexed with the patent BristolMyers Squibb (BMS) inhibitors, the feasibility of molecular docking for this unconventional binding pocket was further investigated. The results showed that the ensemble-based flexible docking protocol can reproduce the near-native binding conformations of the BMS inhibitors with a strong correlation between the IC50 values and ligand–receptor interaction energies (R = 0.81). In general, this paper delineates, for the first time, the characteristic features of the PD-1/PD-L1 inhibitors as well as a high-quality flexible docking strategy for the unconventional binding pocket of the PD-L1 dimer.

Blocking of the High-Affinity Interaction-Synapse Between SARS-CoV-2 Spike and Human ACE2 Proteins Likely Requires Multiple High-Affinity Antibodies: An Immune Perspective.

The pandemic of Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has induced global eagerness to develop vaccines and therapeutics for treating COVID-19, including neutralizing antibodies. To develop effective therapeutic antibodies against SARS-CoV-2, it is critical to understand the interaction between viral and host's proteins. The human ACE2 (hACE2) protein is the crucial target for the SARS-CoV's Spike protein that allows the virus to adhere to host epithelial cells. X-ray crystal structures and biophysical properties of protein-protein interactions reveal a large interaction surface with high binding-affinity between SARS-CoV-2 and hACE2 (18 interactions), at least 15-fold stronger than between SARS-CoV-1 and hACE2 (eight interactions). This suggests that antibodies against CoV-1 infection might not be very efficient against CoV-2. Furthermore, interspecies comparisons indicate that ACE2 proteins of man and cat are far closer than dog, ferret, mouse, and rat with significant differences in binding-affinity between Spike and ACE2 proteins. This strengthens the notion of productive SARS-CoV-2 transmission between felines and humans and that classical animal models are not optimally suited for evaluating therapeutic antibodies. The large interaction surface with strong affinity between SARS-CoV-2 and hACE2 (dG−12.4) poses a huge challenge to develop reliable antibody therapy that truly blocks SARS-CoV-2 adherence and infection. We gauge that single antibodies against single epitopes might not sufficiently interfere with the strong interaction-synapse between Spike and hACE2 proteins. Instead, appropriate combinations of high-affinity neutralizing antibodies against different epitopes might be needed, preferably of IgA-class for optimal and prolonged activity at epithelial layers of respiratory and intestine tracts.

Identification and molecular analysis of interaction sites in the MtSEO-F1 protein involved in forisome assembly

Forisomes are large mechanoprotein complexes found solely in legumes such as Medicago truncatula. They comprise several “sieve element occlusion by forisome” (SEO-F) subunits, with MtSEO-F1 as the major structure-forming component. SEO-F proteins possess three conserved domains –an N-terminal domain (SEO-NTD), a potential thioredoxin fold, and a C-terminal domain (SEO-CTD)– but structural and biochemical data are scarce and little is known about the contribution of these domains to forisome assembly. To identify key amino acids involved in MtSEO-F1 dimerization and complex formation, we investigated protein-protein interactions by bimolecular fluorescence complementation and the analysis of yeast two-hybrid and random mutagenesis libraries. We identified a SEO-NTD core region as the major dimerization site, with abundant hydrophobic residues and rare charged residues suggesting dimerization is driven by the hydrophobic effect. We also found that ~45% of the full-length MtSEO-F1 sequence must be conserved for higher-order protein assembly, indicating that large interaction surfaces facilitate stable interactions, contributing to the high resilience of forisome bodies. Interestingly, the removal of 62 amino acids from the C-terminus did not disrupt forisome assembly. This is the first study unraveling interaction sites and mechanisms within the MtSEO-F1 protein at the level of dimerization and complex formation.

Hot-spot guided design of macrocyclic inhibitors of the LSD1-CoREST1 interaction

New modalities such as cyclic peptides are attractive structures to inhibit challenging targets. The interaction between LSD1 and CoREST1 is required for histone demethylation and represents an attractive therapeutic target. The large interaction surface between these two proteins was analyzed by virtual alanine scanning using DrugScore PPI and a cluster of hot-spot residues was identified on CoREST1. The cluster was converted into a series of cyclic peptides and the inhibitory potency was optimized by stereochemical inversion at one of the amino acids alpha carbons combined with modification of amino acid side chains. Active peptides were further studied by variable temperature 1H NMR and docking to evaluate the effect of conformation on binding. Potent inhibitors of the challenging PPI were obtained and will allow future optimization into more druglike structures.

FRET-based analysis and molecular modeling of the human GPN-loop GTPases 1 and 3 heterodimer unveils a dominant-negative protein complex.

GPN-loop GTPases 1 and 3 are required for RNA polymerase II (RNAPII) nuclear import. Gpn1 and Gpn3 display some sequence similarity, physically associate, and their protein expression levels are mutually dependent in human cells. We performed here Fluorescence Resonance Energy Transfer (FRET), molecular modeling, and cell biology experiments to understand, and eventually disrupt, human Gpn1-Gpn3 interaction in live HEK293-AD cells. Transiently expressed EYFP-Gpn1 and Gpn3-CFP generated a strong FRET signal, indicative of a very close proximity, in the cytoplasm of HEK293-AD cells. Molecular modeling of the human Gpn1-Gpn3 heterodimer based on the crystallographic structure of Npa3, the Saccharomyces cerevisiae Gpn1 ortholog, revealed that human Gpn1 and Gpn3 associate through a large interaction surface formed by internal α-helix 7, insertion 2, and the GPN-loop from each protein. In site-directed mutagenesis experiments of interface residues, we identified the W132D and M227D EYFP-Gpn1 mutants as defective to produce a FRET signal when coexpressed with Gpn3-CFP. Simultaneous but not individual expression of Gpn1 and Gpn3, with either or both proteins fused to EYFP, retained RNAPII in the cytoplasm and markedly inhibited global transcription in HEK293-AD cells. Interestingly, the W132D and M227D Gpn1 mutants that showed an impaired ability to interact with Gpn3 by FRET were also unable to delocalize RNAPII in this assay, indicating that an intact Gpn1-Gpn3 interaction is required to display the dominant-negative effect on endogenous Gpn1/Gpn3 function we described here. Altogether, our results suggest that a Gpn1-Gpn3 strong interaction is critical for their cellular function.

Structure-based design of potent linear peptide inhibitors of the YAP-TEAD protein-protein interaction derived from the YAP omega-loop sequence.

The YAP-TEAD protein-protein interaction is a potential therapeutic target to treat cancers in which the Hippo signaling pathway is deregulated. However, the extremely large surface of interaction between the two proteins presents a formidable challenge for a small molecule interaction disrupter approach. We have accomplished progress towards showing the feasibility of this approach by the identification of a 15-mer peptide able to potently (nanomolar range) disrupt the YAP-TEAD interaction by targeting only one of the two important sites of interaction. This peptide, incorporating non-natural amino acids selected by structure-based design, is derived from the Ω-loop sequence 85-99 of YAP.

Proteomic Analysis of Endothelial Cells Exposed to Ultrasmall Nanoparticles Reveals Disruption in Paracellular and Transcellular Transport.

The large interactive surfaces of nanoparticles (NPs) increase the opportunities to develop NPs for vascular targeting. Proteomic analysis of endothelial cells exposed to NPs reveals the cellular response and turns the focus into the impairment of the endothelial permeability. Here, quantitative proteomics and transcriptome sequencing are combined to evaluate the effects of exposure to sub-lethal concentrations of TiO2 -USNPs and TiO2 -NPs on human dermal microvascular endothelial cells. Endothelial cells react to preserve the semi-permeable properties that are essential for vascular tissue fluid homeostasis, vascular development, and angiogenesis. The main impact of the exposure was alteration of functional complexes involved in cell adhesion, vesicular transport, and cytoskeletal structure. Those are the core cellular structures that are linked to the permeability and the integrity of the endothelial tissue. Moreover, the extracellular proteins uptake along wih the NPs into the endothelial cells escape the lysosomal degradation pathway. These findings improve the understanding of the interaction of NPs with endothelial cell. The effects of the studied NPs modulating cell-cell adhesion and vesicular transport can help to evaluate the distribution of NPs via intravenous administration.

High‐Performance PE‐BN/PVDF‐HFP Bilayer Separator for Lithium‐Ion Batteries

AbstractHighly efficient and thermally stable polyethylene‐hexagonal boron nitride/poly(vinylidene fluoride‐hexafluoropropylene) (PE‐BN/PVDF‐HFP) bilayer separator with microporous structure is prepared, for the first time with a wet chemistry method. The incorporation of hexagonal boron nitride particles in PE matrix promotes the interfacial interaction between PE and PVDF‐HFP layers to prevent separation of layers and supresses dendrite growth owing to the strong adsorption energy with polymers, large interactive surface area, and superior mechanical capability. The PVDF‐HFP layer provides additional thermally stable backbone while its inherent hydrophilic property and highly porous structure improve the overall performance of the separator. The bilayer separator owns a high electrolyte uptake of 348% and a thermal shrinkage of 6.6% upon annealing at 140 °C for 1 h. The lithium iron phosphate/lithium cell with the as‐prepared separator owns a high ionic conductivity up to 4.4 × 10−4 S cm−1, and a room‐temperature capacity of 120 mAh g−1 at 2 C with a 95% capacity retention after 500 cycles and a capability of 108 mAh g−1 at 4 C. The PE‐BN/PVDF‐HFP separator is a promising alternative of traditional multilayer separators for high‐performance lithium‐ion batteries.

New Impressions in Interaction Design: A Task Taxonomy for Elastic Displays

Abstract Novel shape-changing interfaces promise to provide a rich haptic experience for human-computer interaction. As a specific instance of shape-changing interfaces, Elastic Displays provide large interaction surfaces that can be temporally deformed using force-touch. The unique property of these displays is that they automatically return to their initial flat state. Recently, several review and position papers have stimulated a discussion towards consolidating the knowledge about shape-changing interfaces. The knowledge about Elastic Displays is similarly scattered across multiple publications from recent years. This paper contributes a task taxonomy based on productive uses of Elastic Displays found in literature, on the web, and in our interaction lab. This taxonomy emphasizes tasks, but also encompasses general aspects regarding content types, visualization technology, and interaction styles. All aspects of the taxonomy are illustrated using case studies from literature.

Nuclear magnetic resonance structure-based drug design.

Nuclear magnetic resonance structure-based drug design.

Investigating large curved interaction devices

Large interactive surfaces enable novel forms of interaction for their users, particularly in terms of collaborative interaction. During longer interactions, the ergonomic factors of interaction systems have to be taken into consideration. Using the full interaction space may require considerable motion of the arms and upper body over a prolonged period of time, potentially causing fatigue. In this work, we present Curved, a large-surface interaction device, whose shape is designed based on the natural movement of an outstretched arm. It is able to track one or two hands above or on its surface by using 32 capacitive proximity sensors. Supporting both touch and mid-air interaction can enable more versatile modes of use. We use image processing methods for tracking the user’s hands and classify gestures based on their motion. Virtual reality is a potential use case for such interaction systems and was chosen for our demonstration application. We conducted a study with ten users to test the gesture tracking performance, as well as user experience and user preference for the adjustable system parameters.

Impact of red giant/AGB winds on active galactic nucleus jet propagation

Dense stellar winds may mass-load the jets of active galactic nuclei, although it is unclear what are the time and spatial scales in which the mixing takes place. We study the first steps of the interaction between jets and stellar winds, and also the scales at which the stellar wind may mix with the jet and mass-load it. We present a detailed two-dimensional simulation, including thermal cooling, of a bubble formed by the wind of a star. We also study the first interaction of the wind bubble with the jet using a three-dimensional simulation in which the star enters the jet. Stability analysis is carried out for the shocked wind structure, to evaluate the distances over which the jet-dragged wind, which forms a tail, can propagate without mixing with the jet flow. The two-dimensional simulations point at quick wind bubble expansion and fragmentation after about one bubble shock crossing time. Three-dimensional simulations and stability analysis point at local mixing in the case of strong perturbations and relatively small density ratios between the jet and the jet dragged-wind, and to a possibly more stable shocked wind structure at the phase of maximum tail mass flux. Analytical estimates also indicate that very early stages of the star jet-penetration time may be also relevant for mass loading. The combination of these and previous results from the literature suggest highly unstable interaction structures and efficient wind-jet flow mixing on the scale of the jet interaction height, possibly producing strong inhomogeneities within the jet. In addition, the initial wind bubble shocked by the jet leads to a transient, large interaction surface. The interaction structure can be a source of significant non-thermal emission.

Curved - free-form interaction using capacitive proximity sensors

Abstract: Large interactive surfaces have found increased popularity in recent years. However, with increased surface size ergonomics become more important, as interacting for extended periods may cause fatigue. Curved is a large-surface interaction device, designed to follow the natural movement of a stretched arm when performing gestures. It tracks one or two hands above the surface, using an array of capacitive proximity sensors and supports both touch and mid-air gestures. It requires specific object tracking methods and the synchronized measurement from 32 sensors. We have created an example application for users wearing a virtual reality headset while seated that may benefit from haptic feedback and ergonomically shaped surfaces. A prototype with adaptive curvature has been created that allows us to evaluate gesture recognition performance and different surface inclinations.