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Targeting neuroplasticity to improve motor recovery after stroke: an artificial neural network model
No full textAfter a neurological injury, people develop abnormal patterns of neural activity that limit motor recovery. Traditional rehabilitation, which concentrates on practicing impaired skills, is seldom fully effective. New targeted neuroplasticity protocols interact with the central nervous system to induce beneficial plasticity in key sites and thereby enable wider beneficial plasticity. They can complement traditional therapy and enhance recovery. However, their development and validation is difficult because many different targeted neuroplasticity protocols are conceivable, and evaluating even one of them is lengthy, laborious, and expensive. Computational models can address this problem by triaging numerous candidate protocols rapidly and effectively. Animal and human empirical testing can then concentrate on the most promising ones. Here, we simulate a neural network of corticospinal neurons that control motoneurons eliciting unilateral finger extension. We use this network to (i) study the mechanisms and patterns of cortical reorganization after a stroke; and (ii) identify and parameterize a targeted neuroplasticity protocol that improves recovery of extension torque. After a simulated stroke, standard training produced abnormal bilateral cortical activation and suboptimal torque recovery. To enhance recovery, we interdigitated standard training with trials in which the network was given feedback only from a targeted population of sub-optimized neurons. Targeting neurons in secondary motor areas on ∼20% of the total trials restored lateralized cortical activation and improved recovery of extension torque. The results illuminate mechanisms underlying suboptimal cortical activity post-stroke; they enable the identification and parameterization of the most promising targeted neuroplasticity protocols. By providing initial guidance, computational models could facilitate and accelerate the realization of new therapies that improve motor recovery
Uncertainty and Bias of Cosmology and Astrophysical Population Model from Statistical Dark Sirens
No full textGravitational-wave (GW) radiation from a coalescing compact binary is a standard siren, as the luminosity distance of each event can be directly measured from the amplitude of the signal. One possibility to constrain cosmology using the GW siren is to perform statistical inference on a population of binary black hole (BBH) events. In essence, this statistical method can be viewed as follows. We can modify the shape of the distribution of observed BBH events by changing the cosmological parameters until it eventually matches the distribution constructed from an astrophysical population model, thereby allowing us to determine the cosmological parameters. In this work, we derive the Cramér–Rao bound for both cosmological parameters and those governing the astrophysical population model from this statistical dark siren method by examining the Fisher information contained in the event distribution. Our study provides analytical insights and enables fast yet accurate estimations of the statistical accuracy of dark siren cosmology. Furthermore, we consider the bias in cosmology due to unmodeled substructures in the merger rate and mass distribution. We find that a 1% deviation in the astrophysical model can lead to a more than 1% error in the Hubble constant. This could limit the accuracy of dark siren cosmology when there are more than 104 BBH events detected
Antibody Recognition of CD4-Induced Open HIV-1 Env Trimers
No full textHuman immunodeficiency virus type 1 (HIV-1) envelope (Env), a heterotrimer of gp120-gp41 subunits, mediates fusion of the viral and host cell membranes after interactions with the host receptor CD4 and a coreceptor. CD4 binding induces rearrangements in Env trimer, resulting in a CD4-induced (CD4i) open Env conformation. Structural studies of antibodies isolated from infected donors have defined antibody-Env interactions, with one class of antibodies specifically recognizing the CD4i open Env conformation. In this study, we characterized a group of monoclonal antibodies isolated from HIV-1 infected donors (V2i MAbs) that displayed characteristics of CD4i antibodies. Binding experiments demonstrated that the V2i MAbs preferentially recognize CD4-bound open Env trimers. Structural characterizations of V2i MAb-Env-CD4 trimer complexes using single-particle cryo-electron microscopy showed recognition by V2i MAbs using different angles of approach to the gp120 V1V2 domain and the β2/β3 strands on a CD4i open conformation Env with no direct interactions of the MAbs with CD4. We also characterized CG10, a CD4i antibody that was raised in mice immunized with a gp120-CD4 complex, bound to an Env trimer plus CD4. CG10 exhibited characteristics similar to those of the V2i antibodies, i.e., recognition of the open Env conformation, but showed direct contacts to both CD4 and gp120. Structural comparisons of these and previously characterized CD4i antibody interactions with Env provide a suggested mechanism for how these antibodies are elicited during HIV-1 infection.
IMPORTANCE: The RV144 HIV-1 clinical vaccination trial showed modest protection against viral infection. Antibody responses to the V1V2 region of HIV-1 Env gp120 were correlated inversely with the risk of infection, and data from three other clinical vaccine trials suggested a similar signal. In addition, antibodies targeting V1V2 have been correlated with protections from simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infections in nonhuman primates. We structurally characterized V2i antibodies directed against V1V2 isolated from HIV-1 infected humans in complex with open Env trimers bound to the host receptor CD4. We also characterized a CD4i antibody that interacts with CD4 as well as the gp120 subunit of an open Env trimer. Our study suggests how V2i and CD4i antibodies were elicited during HIV-1 infection
Thermal Modulation of Gigahertz Surface Acoustic Waves on Lithium Niobate
No full textSurface-acoustic-wave (SAW) devices have a wide range of applications in microwave signal processing. Microwave SAW components benefit from higher quality factors and much smaller crosstalk when compared to their electromagnetic counterparts. Efficient routing and modulation of SAWs are essential for building large-scale and versatile acoustic wave circuits. Here, we demonstrate integrated thermoacoustic modulators using two SAW platforms: bulk lithium niobate and thin-film lithium niobate on sapphire. In both approaches, the gigahertz-frequency SAWs are routed by integrated acoustic waveguides, while on-chip microheaters are used to locally change the temperature, and thus, control the phase of the SAW. Using this approach, we achieve phase changes of over 720° with the responsibility of 2.6°/mW for bulk lithium niobate and 0.52°/mW for lithium niobate on sapphire. Furthermore, we demonstrate amplitude modulation of SAWs using acoustic Mach-Zehnder interferometers. Our thermoacoustic modulators can enable reconfigurable acoustic signal processing for next-generation wireless communications and microwave systems
Influence of lasing parameters on the morphology and electrical resistance of polyimide-based laser-induced graphene (LIG)
No full textLaser-induced graphene (LIG) uses a CO₂ infrared laser scriber for transforming specific polymer substrates into porous graphene. This technique is simple, scalable, low-cost, free of chemicals, and produces a 3D graphene for applications across many fields. However, the resulting 3D graphene is highly sensitive to the lasing parameters used in their production. Here, we report the effects of power, raster speed, number of lasing passes (with and without spot overlapping) on the resulting LIG structure, morphology, and sheet resistance, using a polyimide (PI) substrate. We find that the number of lasing passes, laser spot overlapping and brand of PI used had a strong influence on the quality of the LIG, measured in terms of the I_(G)/I_(D) and I_(2D) Raman bands and sheet resistance. Increasing number of passes and overlapping of laser spots led to increased LIG pore sizes, larger graphene scales, and reduced sheet resistance. Furthermore, the over-the-counter desktop CO₂ aser engraving unit used introduced additional restrictions that limited the quality of the LIG produced, particularly due to inconsistent control of the laser scribing speed and a poor thermal management of the laser unit
Simultaneous mapping of 3D structure and nascent RNAs argues against nuclear compartments that preclude transcription
No full textMammalian genomes are organized into three-dimensional DNA structures called A/B compartments that are associated with transcriptional activity/inactivity. However, whether these structures are simply correlated with gene expression or are permissive/impermissible to transcription has remained largely unknown because we lack methods to measure DNA organization and transcription simultaneously. Recently, we developed RNA & DNA (RD)-SPRITE, which enables genome-wide measurements of the spatial organization of RNA and DNA. Here we show that RD-SPRITE measures genomic structure surrounding nascent pre-mRNAs and maps their spatial contacts. We find that transcription occurs within B compartments—with multiple active genes simultaneously colocalizing within the same B compartment—and at genes proximal to nucleoli. These results suggest that localization near or within nuclear structures thought to be inactive does not preclude transcription and that active transcription can occur throughout the nucleus. In general, we anticipate RD-SPRITE will be a powerful tool for exploring relationships between genome structure and transcription
A Subsurface Magma Ocean on Io: Exploring the Steady State of Partially Molten Planetary Bodies
No full textIntense tidal heating within Io produces active volcanism on the surface, and its internal structure has long been a subject of debate. A recent reanalysis of the Galileo magnetometer data suggested the presence of a high-melt-fraction layer with >50 km thickness in the subsurface region of Io. Whether this layer is a “magmatic sponge” with interconnected solid or a rheologically liquid “magma ocean” would alter the distribution of tidal heating and would also influence the interpretation of various observations. To this end, we explore the steady state of a magmatic sponge and estimate the amount of internal heating necessary to sustain such a layer with a high degree of melting. Our results show that the rate of tidal dissipation within Io is insufficient to sustain a partial-melt layer of ϕ > 0.2 for a wide range of parameters, suggesting that such a layer would swiftly separate into two phases. Unless melt and/or solid viscosities are at the higher end of the estimated range, a magmatic sponge would be unstable, and thus a high-melt-fraction layer suggested in Khurana et al. is likely to be a subsurface magma ocean
Beyond the Monastery Walls: Lay Men and Women in Early Medieval Legal Formularies
No full textOur understanding of life in the early Middle Ages is dominated by Christian churches and monasteries. It is their records and libraries which have survived the centuries, to tell us how the clerics, monks, and nuns who lived and worked within their walls experienced the world around them. We thus see the lay inhabitants of that wider world mostly when they are interacting with the clergy. However, a few sources let us explore lay life in this period more broadly. Beyond the Monastery Walls exploits perhaps the richest of these: manuscript books containing formulas, or models, for documents that do not otherwise survive. Through these books, Warren C. Brown explores the concerns and behavior of lay men and women in this period on their own terms, and casts fresh light on a part of the medieval world that is usually hidden from view. In the process, he shows how early medievalists are winning fresh information from our sources by looking at them in new ways
On stability and instability of C^(1,α) singular solutions to the 3D Euler and 2D Boussinesq equations
No full textSingularity formation of the 3D incompressible Euler equations is known to be extremely challenging. In [18], Elgindi proved that the 3D axisymmetric Euler equations with no swirl and C^(1,α) initial velocity develops a finite time singularity. Inspired by Elgindi's work, we proved that the 3D axisymmetric Euler and 2D Boussinesq equations with C^(1,α) initial velocity and boundary develop a stable asymptotically (or approximately) self-similar finite time singularity [8]. On the other hand, the authors of [35,52] recently showed that blowup solutions to the 3D Euler equations are hydrodynamically unstable. The instability results obtained in [35,52] require some strong regularity assumption on the initial data, which is not satisfied by the C^(1,α) velocity field. In this paper, we generalize the analysis of [8,18,35,52] to show that the blowup solutions of the 3D Euler and 2D Boussinesq equations with C^(1,α) velocity are unstable under the notion of stability introduced in [35,52]. These two seemingly contradictory results reflect the difference of the two approaches in studying the stability of 3D Euler blowup solutions. The stability analysis of the blowup solution obtained in [8,18] is based on the stability of a dynamically rescaled blowup profile in space and time, which is nonlinear in nature. The linear stability analysis in [35,52] is performed by directly linearizing the 3D Euler equations around a blowup solution in the original variables. It does not take into account the changes in the blowup time, the dynamic changes of the rescaling rate of the perturbed blowup profile and the blowup exponent of the original 3D Euler equations using a perturbed initial condition when there is an approximate self-similar blowup profile. Such information has been used in an essential way in establishing the nonlinear stability of the blowup profile in [8,18,19]
Retrieval-based Controllable Molecule Generation
No full textGenerating new molecules with specified chemical and biological properties via generative models has emerged as a promising direction for drug discovery. However, existing methods require extensive training/fine-tuning with a large dataset, often unavailable in real-world generation tasks. In this work, we propose a new retrieval-based framework for controllable molecule generation. We use a small set of exemplar molecules, i.e., those that (partially) satisfy the design criteria, to steer the pre-trained generative model towards synthesizing molecules that satisfy the given design criteria. We design a retrieval mechanism that retrieves and fuses the exemplar molecules with the input molecule, which is trained by a new self-supervised objective that predicts the nearest neighbor of the input molecule. We also propose an iterative refinement process to dynamically update the generated molecules and retrieval database for better generalization. Our approach is agnostic to the choice of generative models and requires no task-specific fine-tuning. On various tasks ranging from simple design criteria to a challenging real-world scenario for designing lead compounds that bind to the SARS-CoV-2 main protease, we demonstrate our approach extrapolates well beyond the retrieval database, and achieves better performance and wider applicability than previous methods