Pair Structure Research Articles

Mathematical topology and geometry-based classification of tauopathies

Neurodegenerative diseases, like Alzheimer’s, are associated with the presence of neurofibrillary lesions formed by tau protein filaments in the cerebral cortex. While it is known that different morphologies of tau filaments characterize different neurodegenerative diseases, there are few metrics of global and local structure complexity that enable to quantify their structural diversity rigorously. In this manuscript, we employ for the first time mathematical topology and geometry to classify neurodegenerative diseases by using cryo-electron microscopy structures of tau filaments that are available in the Protein Data Bank. By employing mathematical topology metrics (Gauss linking integral, writhe and second Vassiliev measure) we achieve a consistent, but more refined classification of tauopathies, than what was previously observed through visual inspection. Our results reveal a hierarchy of classification from global to local topology and geometry characteristics. In particular, we find that tauopathies can be classified with respect to the handedness of their global conformations and the handedness of the relative orientations of their repeats. Progressive supranuclear palsy is identified as an outlier, with a more complex structure than the rest, reflected by a small, but observable knotoid structure (a diagrammatic structure representing non-trivial topology). This topological characteristic can be attributed to a pattern in the beginning of the R3 repeat that is present in all tauopathies but at different extent. Moreover, by comparing single filament to paired filament structures within tauopathies we find a consistent change in the side-chain orientations with respect to the alpha carbon atoms at the area of interaction.

Abstract 1663: Single-cell signaling analysis reveals that major vault protein facilitates RasG12C inhibitor resistance

Abstract Covalent inhibitors of RasG12C are the first clinically-approved drugs for targeting mutant Ras-driven cancers. However, the rapid development of clinical resistance to current Ras G12C inhibitors is common. It has been demonstrated that a subpopulation of cancer cells facilitate drug resistance but the mechanistic basis of this heterogenous response is not well understood. Here, we utilized recently developed Ras sensors to profile the environment of active Ras and to measure the activity of endogenous Ras to pair structure (Ras signalosome) to function (Ras activity), respectively, at a single-cell level. With this approach, we found that a subpopulation of KRasG12C cells treated with RasG12C-GDP inhibitors underwent oncogenic signaling and metabolic changes driven by WT Ras at the golgi and mutant Ras at mitochondria, respectively. Our Ras sensors identified Major Vault Protein (MVP) as a mediator of Ras activation at both subcellular locations by scaffolding Ras signaling pathway components and metabolite channels. We found that recently developed RasG12C-GTP inhibitors also led to MVP-mediated WT Ras signaling at the golgi, demonstrating that this a general mechanism of RasG12C inhibitor resistance. Overall, single-cell analyses enabled the discovery of a RasG12C inhibitor-resistant subpopulation driven by MVP, providing insight into the complex and heterogenous rewiring that confers drug resistance in cancer. Citation Format: Jason Z. Zhang, Shao-En Ong, David Baker, Dustin J. Maly. Single-cell signaling analysis reveals that major vault protein facilitates RasG12C inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1663.

Structures and bonding characteristics of KCl(H2O)n clusters with n = 1-10 based on density functional theory.

Aqueous inorganic salt solutions play a prominent role in both physiological and chemical experiments, and significant attention has been directed toward understanding the mechanisms underlying salt dissolution. In our effort to elucidate the hydration process of potassium chloride, we employed a comprehensive genetic algorithm to explore the structures of KCl(H2O)n (n = 1-10). A series of stable structures were identified by high-level abinitio optimization and single-point energy calculations with a zero-point energy correction. An analysis of the probability distribution of KCl(H2O)1-10 revealed that clusters with high probability at low temperatures exhibit reduced probabilities at higher temperatures, while others become more prevalent. When n = 1-9, the contact ion pair configurations or partially dissociated structures dominate in the system, and the probability distribution plot shows that the proportion of the solvent-separated ion pair (SSIP) structures of KCl(H2O)n is very small, while the SSIP configuration in KCl(H2O)10 becomes a stable structure with increasing temperature. The results from natural bond orbital analysis reveal a stronger interaction between chloride ions and water molecules. These findings provide valuable insights for a more comprehensive understanding of the intricacies of potassium chloride dissolution in water.

Modulating Polarization in Second Harmonic Generation through Symmetry Evolution in Plasmonic Lattices.

We report a strategy for preparing cost-effective plasmonic square lattices with tunable unit structures of circles, crosses, and circle-cross pairs on a centimeter scale. The asymmetrical electromagnetic (EM) field distribution of the lattice enhances second harmonic generation (SHG) under oblique incidence. The SHG signals are progressively strengthened as the unit symmetry decreases from C∞v (circle) to C4v (cross) to C2v (circle-cross pair). The peak SHG signal is observed from the plasmonic lattice with a circle-cross pair, showcasing a conversion efficiency of 1.0 × 10-2, which is a 7.3-fold enhancement relative to the dielectric lattice comprised of circle units. This notably high conversion efficiency of SHG is on par with that of phase-matched bulk nanostructures under normal incidence, benefiting from the Bloch-surface plasmon polariton (Bloch-SPP) modes associated with the distribution of the photonic local density of states (LDOS). Furthermore, the SHG emission exhibits distinctive directional and polarization characteristics as the unit symmetry is reduced. This work offers valuable insights into a structural symmetry-dependent SHG in plasmonic lattices and the way forward for the design of functional nonlinear plasmonic devices.

Expanding FTMap for Fragment-Based Identification of Pharmacophore Regions in Ligand Binding Sites.

The knowledge of ligand binding hot spots and of the important interactions within such hot spots is crucial for the design of lead compounds in the early stages of structure-based drug discovery. The computational solvent mapping server FTMap can reliably identify binding hot spots as consensus clusters, free energy minima that bind a variety of organic probe molecules. However, in its current implementation, FTMap provides limited information on regions within the hot spots that tend to interact with specific pharmacophoric features of potential ligands. E-FTMap is a new server that expands on the original FTMap protocol. E-FTMap uses 119 organic probes, rather than the 16 in the original FTMap, to exhaustively map binding sites, and identifies pharmacophore features as atomic consensus sites where similar chemical groups bind. We validate E-FTMap against a set of 109 experimentally derived structures of fragment-lead pairs, finding that highly ranked pharmacophore features overlap with the corresponding atoms in both fragments and lead compounds. Additionally, comparisons of mapping results to ensembles of bound ligands reveal that pharmacophores generated with E-FTMap tend to sample highly conserved protein-ligand interactions. E-FTMap is available as a web server at https://eftmap.bu.edu.

The Microstructural Investigation and the Temperature-Changing Separation of Brine with a High Mg/Li Ratio

The difficult separation of magnesium–lithium has always been a problem that impedes the comprehensive utilization of salt lake brine resources. In this paper, a method for the separation of magnesium and lithium based on the crystallization of magnesium sulfate at high-temperature supersaturation and a low viscosity was investigated. The microstructure of soluble solutions was analyzed, and the results showed that, in a single-salt solution, controlling the temperature can change the contact ion pair structure of MgSO4 solution, and the arrangement of SO42− and H2O in the second hydration layer changes. In the Li2SO4 solution, the hydrogen bonds between SO42− and H2O break, and the surrounding water structure changes, breaking the similarity of the microstructure of magnesium–lithium and enhancing the separation effect. In a multi-ion system, the change in water structure in the solution decreases with the increase in Cl− concentration. Controlling the temperature of salt lake brine with different magnesium–lithium mass ratios, it was found that the magnesium–lithium mass ratio in the brine could be reduced by one-third; when the magnesium–lithium mass ratio was 10:1~160:1, the loss of lithium could be controlled within 5%, but when the magnesium–lithium mass ratio was 5:1, the loss of lithium was 25.06%. The main reason for lithium loss is that Li2SO4 in the liquid phase enters the solid phase as a cluster and is entrapped during the MgSO4 crystallization process. The entire experiment shows that controlling the temperature process is more suitable for salt lake brine with a high magnesium–lithium ratio.

Structure and large-scale environment of galaxy pairs in the S-PLUS DR4

ABSTRACT In this paper, we use photometric data from the Southern Photometric Local Universe Survey Data Release 4 survey to identify isolated galaxy pairs and analyse their characteristics and properties. Our results align with previous spectroscopic studies, particularly in luminosity function parameters, suggesting a consistent trait among galaxy systems. Our findings reveal a high fraction of red galaxies across all samples, irrespective of projected distance, velocity difference, or luminosity ratio. We found that the proximity of a neighbour to its central galaxy influences its colour due to environmental effects. We also found that central and neighbour have different behaviours: central galaxies maintain a stable red colour regardless of luminosity, while neighbour colours vary based on luminosity ratios. When the central is significantly brighter, the neighbour tends to be less red. According to our division in red, blue, and mixed pairs, we found evidence of galactic conformity. The red pair fractions increase in closer pairs and in pairs of similar luminosity, indicating shared environments promoting red galaxy formation. Analysing local density, the expected colour–density relation is of course recovered, but it is strongly determined by the stellar mass of the pair. In denser environments, the red pair fractions increase, blue pairs decrease, and for the mixed pairs it depends on their stellar mass: more massive mixed pairs decrease their fraction, whereas the less massive ones increase it. These results shed light on the intricate relationship between galaxy pairs, their characteristics, and environmental influences on colour, providing insights into their evolutionary histories.

Intermolecular hydrogen bonding in DNA base pairs interacting with different numbers of bare and hydrated Li+: NBO, QTAIM, and computational spectroscopic studies

In this study, the effect of different numbers of Li+ interacting with various sites of DNA base pairs (adenine–thymine (AT) and cytosine-guanine (GC)) on the base pair structures, the strength of hydrogen bonding between the bases, and spectroscopic properties (IR and absorption spectra) of the base pairs was investigated. Two quantum computational analyses, the natural bonding orbitals (NBO) and the quantum theory of atoms in molecules (QTAIM), were used to follow the change in the strength of hydrogen bonds between the bases in each pair. The type of base pair’s site interacting with Li+ showed different effects on the change in the strength of the hydrogen bonds between the bases. The IR and absorption spectra of the lithiated base pairs were calculated and compared with those of bare base pairs. This comparison provided the changes in the spectra as a fingerprint for the structural identification of different lithiated base pairs. Also, the determination of the change in the strength of hydrogen bonds in the lithiated base pairs compared to their bare base pairs. In the other part of this study, the effect of the hydration of the attached Li+ in the structure of lithiated base pairs on the strength of their hydrogen bonds and spectra was investigated.

Concurrent prediction of RNA secondary structures with pseudoknots and local 3D motifs in an integer programming framework.

The prediction of RNA structure canonical base pairs from a single sequence, especially pseudoknotted ones, remains challenging in a thermodynamic models that approximates the energy of the local 3D motifs joining canonical stems. It has become more and more apparent in recent years that the structural motifs in the loops, composed of noncanonical interactions, are essential for the final shape of the molecule enabling its multiple functions. Our capacity to predict accurate 3D structures is also limited when it comes to the organization of the large intricate network of interactions that form inside those loops. We previously developed the integer programming framework RNA Motifs over Integer Programming (RNAMoIP) to reconcile RNA secondary structure and local 3D motif information available in databases. We further develop our model to now simultaneously predict the canonical base pairs (with pseudoknots) from base pair probability matrices with or without alignment. We benchmarked our new method over the all nonredundant RNAs below 150 nucleotides. We show that the joined prediction of canonical base pairs structure and local conserved motifs (i) improves the ratio of well-predicted interactions in the secondary structure, (ii) predicts well canonical and Wobble pairs at the location where motifs are inserted, (iii) is greatly improved with evolutionary information, and (iv) noncanonical motifs at kink-turn locations. The source code of the framework is available at https://gitlab.info.uqam.ca/cbe/RNAMoIP and an interactive web server at https://rnamoip.cbe.uqam.ca/.

Design and optimization of an octuple-electrode array for micro-particle chain rotation via electrorotation integrated with machine vision technology.

Microparticle rotation is an important process in biomedical engineering, such as biosensors, cell injection or cell morphology. Single particle rotation has been widely investigated, while rotation of particle chains has gained rare attention. In this paper, we utilize a noncontact manipulation method to rotate microparticle chains via electrorotation by designing an octuple-electrode array (OEA). Finite element simulations were conducted for analyzing the desired electrode field and optimizing the structure of microelectrode pairs. The direction of the electric field in the workspace is investigated with different voltage signal inputs through specially designed circuits. In the experiment, microparticles are driven to form several chains in the proposed electrode fields. With the rotation of the electric field, particle chains could be rotated synchronously. Automated rotation and detection of polystyrene microspheres and yeast cell chains are achieved using machine vision technology. Results show that the proposed method could be utilized to rotate ordered microparticles with an appropriate input signal.

Efficient Discovery of Functional Dependencies on Massive Data

Functional dependencies are the most common constraints in the design theory for relational databases, which have very important practical applications in many areas. Different kinds of algorithms are proposed to discover the functional dependencies. However, it is found in this paper that the existing algorithms cannot deal well with massive data which cannot be held entirely in memory due to high memory consumption and high computation cost. In this paper, a novel algorithm FSC is presented to compute functional dependencies on massive data. The two-step execution of FSC relies on a pre-computed update-friendly assistant structure of comparable pairs which reflect the identifier pairs for tuples with at least one equal attribute. In step 1, FSC determines the violated functional dependencies and introduces the selective comparison by comparable pairs to reduce the required pairwise comparison significantly. The direct value-combination compression strategy is devised to process attributes of small cardinality. In step 2, FSC induces the required functional dependencies by the results in step 1. The extensive experimental results, conducted on synthetic and real-life data sets, show that FSC can discover functional dependencies on massive data efficiently.

Commercial air transport in Africa: changing structure and development of country pairs

Commercial air transport in Africa: changing structure and development of country pairs

Ultrasensitive detection of a responsive fluorescent thymidine analogue in DNA via pulse-shaped two-photon excitation.

Fluorescent base analogues (FBAs) are versatile nucleic acid labels that can replace a native nucleobase, while maintaining base pairing and secondary structure. Following the recent demonstration that free FBAs can be detected at the single-molecule level, the next goal is to achieve this level of detection sensitivity in oligonucleotides. Due to the short-wavelength absorption of most FBAs, multiphoton microscopy has emerged as a promising approach to single-molecule detection. We report the multiphoton-induced fluorescence of 5-(5-(4-methoxyphenyl)thiophen-2-yl)-6-aza-uridine (MeOthaU), a polarity-sensitive fluorescent thymidine analogue, as a nucleoside, and in two single-stranded deoxyribo-oligonucleotides, with and without their complementary strands. Ensemble steady-state and time-resolved measurements in dioxane, following one-photon and two-photon excitation, reveals both strongly and weakly emissive species, assigned as rotamers, while in Tris buffer there are additional non-emissive states, which are attributed to tautomeric forms populated in aqueous environments. The two-photon (2P) brightness for MeOthaU is highest as the free nucleoside in dioxane (10 GM) and lowest as the free nucleoside in Tris buffer (0.05 GM). The species-averaged 2P brightness values in DNA are higher for the single strands (0.66 and 0.82 GM for sequence context AXA and AXT, respectively, where X is MeOthaU) than in the duplex (0.31 and 0.25 GM for AXA and AXT, respectively). Using 2P microscopy with pulse-shaped broadband excitation, we were able to detect single- and double-stranded oligos with a molecular brightness of 0.8-0.9 kHz per molecule. This allowed the detection of as few as 7 DNA molecules in the focus, making it the brightest responsive FBA in an oligonucleotide reported to date.

Combining Ti4(embonate)6 anionic cages and π-conjugated coordination cations for highly effective optical limiting.

The integration of anionic Ti4L6 (L = embonate) cages and π-conjugated coordination cations into ordered structures can produce high-performance nonlinear optical (NLO) materials. More specifically, by employing Ti4L6 cages for assembly with mixed N,N-chelated and P,P-chelated type conjugated organic ligands and Ag+ ions, three cage-based structures have been synthesized and structurally characterized. Among them, an ion pair structure with strong π-π accumulation exhibits a significant third-order NLO response, and an excellent optical limiting effect has been experimentally verified. This work provides a promising material for NLO applications.

Human induced pluripotent stem cell-derived cardiac muscle rings for biohybrid self-beating actuator.

Cardiac muscle, a subtype of striated muscle composing our heart, has garnered attention as a source of autonomously driven actuators due to its inherent capability for spontaneous contraction. However, conventional cardiac biohybrid robots have utilized planar (2D) cardiac tissue consisting of a thin monolayer of cardiac myotubes with a thickness of 3-5 μm, which can generate a limited contractile force per unit footprint. In this study, 3D cardiac muscle rings were proposed as robotic actuator units. These units not only exhibit higher contractile force per unit footprint compared to their 2D counterparts due to their increased height, but they can also be integrated into desired 3D configurations. We fabricated cardiac muscle rings from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), evaluated their driving characteristics, and verified the actuation effects by integrating them with artificial components. After the 10th day from culture, the cardiac muscle rings exhibited rhythmic spontaneous contraction and increased contractile force in response to stretching stimuli. Furthermore, after constructing a centimeter-sized biohybrid self-beating actuator with an antagonistic pair structure of cardiac muscle rings, the periodic antagonistic beating motion at its tail portion was confirmed. We believe that 3D cardiac muscle rings, possessing high contractile force and capable of being positioned within limited 3D space, can be used as potent biohybrid robotic actuators.

A highly sensitive torsion sensor based on upright-inverted alternating triangular prism structure on the single-multi-single mode fiber

In this paper, a novel torsion sensor based on Mach-zehnder interferometer (MZI) is proposed and demonstrated. The proposed sensor is fabricated by the single-mode fiber (SMF) and multi-mode fiber (MMF) shear splicing, further employing CO2 laser to modulate the MMF surface into triangular prism form. And compare the number of different triangular prism pairs structure on torsion sensitivity. By increasing the number of triangular prism pairs effectively improve the torsion sensitivity. The experimental results show that in the range of 0–9.617 rad/m, the highest sensitivity fiber sensor can be obtained with a sensitivity of 3.3133 nm/(rad/m). Meanwhile, the temperature characteristic of the sensor is investigated, which presents a sensitivity of 21.67 pm/℃ in the range from 30 ℃ to 100 ℃. Therefore, the temperature crosstalk is 0.0065 (rad/m)/℃, which results in a low temperature crosstalk. In addition, the structure also has the advantages of low cost and simple manufacturing process.

A post-modification strategy to precisely construct dual-atom sites for oxygen reduction electrocatalysis

Dual-atom catalysts (DACs) afford promising potential for oxygen reduction electrocatalysis due to their high atomic efficiency and high intrinsic activity. However, precise construction of dual-atom sites remains a challenge. In this work, a post-modification strategy is proposed to precisely fabricate DACs for oxygen reduction electrocatalysis. Concretely, a secondary metal precursor is introduced to the primary single-atom sites to introduce direct metal–metal interaction, which ensures the formation of desired atom pair structure during the subsequent pyrolysis process and allows for successful construction of DACs. The as-prepared FeCo-NC DAC exhibits superior oxygen reduction electrocatalytic activity with a half-wave potential of 0.91 V vs. reversible hydrogen electrode. Zn–air batteries equipped with the FeCo-NC DAC demonstrate higher peak power density than those with the Pt/C benchmark. More importantly, this post-modification strategy is demonstrated universal to achieve a variety of dual-atom sites. This work presents an effective synthesis methodology for precise construction of catalytic materials and propels their applications in energy-related devices.

Dichotomy of heavy and light pairs of holes in the t−J model

A key step in unraveling the mysteries of materials exhibiting unconventional superconductivity is to understand the underlying pairing mechanism. While it is widely agreed upon that the pairing glue in many of these systems originates from antiferromagnetic spin correlations, a microscopic description of pairs of charge carriers remains lacking. Here we use state-of-the art numerical methods to probe the internal structure and dynamical properties of pairs of charge carriers in quantum antiferromagnets in four-legged cylinders. Exploiting the full momentum resolution in our simulations, we are able to distinguish two qualitatively different types of bound states: a highly mobile, meta-stable pair, which has a dispersion proportional to the hole hopping t, and a heavy pair, which can only move due to spin exchange processes and turns into a flat band in the Ising limit of the model. Understanding the pairing mechanism can on the one hand pave the way to boosting binding energies in related models, and on the other hand enable insights into the intricate competition of various phases of matter in strongly correlated electron systems.

Novel complementary Sziklai pair based high gain low noise small-signal amplifiers

<span lang="EN-US">A new paired configuration of opposite polarity BJTs, the “complementary Sziklai pair” is introduced in the series of multi-BJT-based devices like Darlington and Sziklai pair, and its viability is tested in small-signal common emitter (CE) and common collector (CC) amplifier configurations. The Darlington and Sziklai both face the problem of poor frequency response at a higher frequency which is addressed by the proposed configuration. The proposed pair with CE amplifier holds class-A amplification property with a high voltage gain of 200.05, a high current gain of 11.62, wider bandwidth of 1.64 MHz, and a low THD of 1.29E-6%, hence supports the potential of wide applicability in analog communication. Similarly, the proposed pair with CC configuration produces approximately a unit current gain of 0.99 with wider bandwidth of 1.90 MHz and low THD of 1.76E-6%, therefore it can be used as a current buffer in a generalized current follower circuit. Conclusively, the device structure of this new BJT pair may be considered the third consecutive member of the series of Darlington pair and Sziklai pair. The layout of the proposed CE and CC amplifier occupy small areas of 158.30 μm<sup>2</sup> (10.23×15.47 μm) and 141.16 μm<sup>2</sup> (10.20×13.84 μm) respectively in 180 nm process technology.</span>

Physiological and pathological 3R and 4R tau expression in marmoset brain

AbstractBackgroundCommon marmosets (Callithrix jacchus) have recently emerged as an important model for studying aging and neurodegenerative disorders, including Alzheimer’s disease (AD). Amyloid‐β deposits in the cerebral cortex of marmosets present naturally with aging, which has now been widely reported. However, the role of tau in the marmoset brain has been understudied. The purpose of the present studies was to comprehensively examine 3R and 4R tau isoform expression in the marmoset brain.MethodsThe mRNA expression in the marmoset brain was confirmed by RT‐PCR. The total mRNA was isolated from frozen tissue of various age groups and reverse transcribed to cDNA, which was used for RT‐PCR. The sequence of each fragment was confirmed by the Sanger sequencing method. The tau protein expression in Sarkosyl soluble and insoluble fractions was examined by western blot using tau‐specific antibodies, and expression levels of 3R/4R were quantified by Dot blot. Synaptic tau expression was analyzed from crude synaptosome extractions of the frontal cortex. Pathological tau aggregates in cryo‐slices of a 10‐year‐old marmoset brain were visualized by immunohistochemistry.Results3R and 4R tau were expressed in the marmoset brain, with 3R tau predominately expressed in neonatal brains and 4R tau in adult/aged brains. 3R and 4R tau were also localized in synaptic regions of the frontal cortex. The Sarkosyl soluble tau was phosphorylated on T181, T217, and T231 sites with evidence of oligomers. Insoluble tau was phosphorylated on S396/S404 and S202/S205 sites and contained high molecular weight aggregates comprising 3R and 4R tau. Moreover, a 10‐year‐old marmoset brain case study demonstrated a paired helical filament structure in the hippocampus and intracellular 3R and 4R tau accumulation.ConclusionsOur results reveal physiological and pathological 3R/4R tau distributions in the frontal and temporal cortex of the marmoset brain, confirming the presence of 3R tau and AD‐like pathological tau in aging marmosets. These data support the utility of common marmosets as appropriate models for studying AD and neurodegenerative disorders.