Miracle-dz/UniFAR-FTUs huggingface dataset:
Neuron‐Derived Misfolded α‐Synuclein in Blood: A Potential Biomarker for Parkinson's Disease?

To date, the clinical diagnosis of Parkinson’s disease (PD) is based on the assessment of motor and nonmotor symptoms, risk factors, and the response to levodopa. However, many patients with PD suffer from a late and often uncertain diagnosis. In the future, successful treatment of the disease will depend essentially on our ability to facilitate early diagnosis and to detect even presymptomatic disease manifestations. The pathology of PD is associated with misfolded and aggregated α-synuclein protein. Thus, its detection in peripheral tissue or biofluids would represent a promising biomarker; however, inconsistent reports of α-synuclein levels have so far compromised this approach. In an attempt to address this challenge, Kluge and colleagues report that the detection of pathological α-synuclein conformers from neuronderived extracellular vesicles (EVs) in blood plasma samples allows for a reliable discrimination between patients and control subjects. Released from almost all types of cells, EVs are lipid bilayer structures carrying nucleic acids, lipids, and proteins, and they are able to pass the blood–brain barrier. They are important means of intercellular communication and potentially contribute to the pathogenesis of neurodegenerative diseases by spreading neuropathological proteins, for example, misfolded α-synuclein. Kluge and colleagues carried out a proof-of-concept study including 30 patients with idiopathic PD and 50 control subjects to detect misfolded α-synuclein in blood. They isolated EVs from plasma samples through gradual centrifugation and precipitation. From this pool, neuron-derived EVs were isolated through immunoprecipitation with an antibody against a neuronal marker. Soluble higher-molecular-weight forms of α-synuclein are thought to mediate neurotoxicity. Consequently, the authors used a structure-specific α-synuclein antibody to probe for these conformers in the soluble fraction of the neuron-derived EV lysates under nondenaturing conditions. Most importantly, they detected significantly increased α-synuclein signal intensities in the neuron-derived EVs from patients with PD compared with control subjects. Moreover, the pathological folding potential of the isolated α-synuclein species was subsequently confirmed in a seeding assay, exhibiting characteristic β-sheet-rich structures and a fibrillary appearance. This highly promising study provides the basis for a reliable and standardized blood test for PD. The experimental approach in its current form is technically challenging for routine diagnostics. However, once a simplified version has been established, this test may have an important impact on the (1) diagnostic accuracy, (2) determination and in-depth characterization of presymptomatic disease stage in a personalized fashion, and (3) application of interceptive medicine in the future to prevent irreparable brain damage.
Geometric integrators for multiple time-scale simulation

In this paper, we review and extend recent research on averaging integrators for multiple time-scale simulation such as are needed for physical N-body problems including molecular dynamics, materials modelling and celestial mechanics. A number of methods have been proposed for direct numerical integration of multiscale problems with special structure, such as the mollified impulse method (Garcia-Archilla, Sanz-Serna and Skeel 1999 SIAM J. Sci. Comput. 20 930–63) and the reversible averaging method (Leimkuhler and Reich 2001 J. Comput. Phys. 171 95–114). Features of problems of interest, such as thermostatted coarse-grained molecular dynamics, require extension of the standard framework. At the same time, in some applications the computation of averages plays a crucial role, but the available methods have deficiencies in this regard. We demonstrate that a new approach based on the introduction of shadow variables, which mirror physical variables, has promised for broadening the usefulness of multiscale methods and enhancing accuracy of or simplifying computation of averages. The shadow variables must be computed from an auxiliary equation. While a geometric integrator in the extended space is possible, in practice we observe enhanced long-term energy behaviour only through use of a variant of the method which controls drift of the shadow variables using dissipation and sacrifices the formal geometric properties such as time-reversibility and volume preservation in the enlarged phase space, stabilizing the corresponding properties in the physical variables. The method is applied to a gravitational three-body problem as well as a partially thermostatted model problem for a dilute gas of diatomic molecules.
Signature of viscous flow units in apparent elastic regime of metallic glasses

We characterize and identify the flow units in two typical metallic glasses (MGs), which have markedly different β-relaxation behaviors and mechanical properties. The viscoelastic hysteresis loops are found in the cyclic deformation in the nominal elastic regime of the metallic glasses. We show that the hysteresis loops are related to the activation of the flow units in metallic glasses, and a model is proposed to describe the flow units. We demonstrate that the flow units are both the deformation units of the anelastic and plastic deformation behaviors and the structural origin of the β-relaxation in metallic glasses.
A Camptothetin Analog, Topotecan, Promotes HIV Latency via Interference with HIV Transcription and RNA Splicing

HIV survives in a state of very low activity, called latency, for long periods in persons with HIV on antiretroviral therapy. This low activity of HIV is linked to residual inflammation and associated diseases, such as heart disease and cancer. ABSTRACT Low level HIV transcription during modern antiretroviral therapy (ART) in persons with HIV is linked to residual inflammation and associated diseases, like cardiovascular disease and cancer. The “block and lock” approach to hold HIV in a state of deep latency may help decrease residual inflammation in a person with HIV on ART and thus improve health. A camptothecin analog topotecan (TPT) was previously implicated as an inhibitor of active HIV replication. Using an in vitro primary T cell model of HIV latency, we demonstrated that (i) TPT reduces HIV transcriptional activity in latently infected cells; (ii) downregulation of HIV RNA by TPT cannot be reversed by latency reversing agents; (iii) several primary and secondary mechanism of action of TPT may be involved in control of HIV replication; (iv) regulation of HIV RNA by TPT is dependent on splicing complexity; (v) increase in proportion of unspliced HIV transcripts was facilitated by intron retention and upregulation of splicing factors, specifically SRSF6, by TPT. Although high TPT dosing (10 μM) was needed to achieve the observed effects, viability of primary CD4+ T cells was not greatly affected. Because toxicity can be observed with TPT in persons with cancer, TPT is unlikely to be used as an anti-HIV agent in clinic, but our study provides proof that camptothetin has “block and lock” activity. Other camptothetin analogs, which are less toxic than TPT, should be designed and tested as HIV “block and lock” agents. IMPORTANCE HIV survives in a state of very low activity, called latency, for long periods in persons with HIV on antiretroviral therapy. This low activity of HIV is linked to residual inflammation and associated diseases, such as heart disease and cancer. New strategies are being explored to further silence the HIV provirus and suppress residual inflammation. This study provides strong evidence that the camptothetin analog, Topotecan, can reduce residual activity of HIV in an experimental model of HIV latency. While Topotecan itself is likely not suitable for use in the clinic due to its toxicity, other camptothetin analogs should be designed and investigated as “block and lock” agents.
Multiple Gaussian process models for direct time series forecasting

This paper focuses on the problem of time series forecasting using the Gaussian process models. The Gaussian process model is a nonparametric model and the output of the model has Gaussian distribution with mean and variance. The multiple Gaussian process models as every step ahead predictors are used for time series forecasting in accordance with the direct approach. The separable least‐squares approach that combines the genetic algorithm with the linear least‐squares method is applied to train these Gaussian process models. Simulation results are shown to illustrate the effectiveness of the proposed direct forecasting method. © 2011 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Disordered region encodes α-crystallin chaperone activity toward lens client γD-crystallin

Significance Humans express 10 ATP-independent protein chaperones called small heat-shock proteins (sHSPs). The highly abundant sHSP chaperone present in eye lens, α-crystallin, delays lens protein aggregation and, therefore, development of cataract, over an individual’s lifetime. α-Crystallin components, HSPB4 and HSPB5, are highly similar to each other yet differ in their chaperone activity toward a lens protein proxy that mimics a UV-damaged, aggregate-prone species. We identified the source of the differential activity as a short sequence within the large intrinsically-disordered regions of the two sHSPs. This stretch determines local secondary structure and dynamics throughout the disordered region and modulates chaperone activity. Our findings support the notion that short segments within highly variable disordered regions of sHSPs can control chaperone function.
BRD4‐PRC2 represses transcription of T‐helper 2‐specific negative regulators during T‐cell differentiation

BRD4 is a well‐recognized transcriptional activator, but how it regulates gene transcriptional repression in a cell type‐specific manner has remained elusive. In this study, we report that BRD4 works with Polycomb repressive complex 2 (PRC2) to repress transcriptional expression of the T‐helper 2 (Th2)‐negative regulators Foxp3 and E3‐ubiqutin ligase Fbxw7 during lineage‐specific differentiation of Th2 cells from mouse primary naïve CD4+ T cells. Brd4 binds to the lysine‐acetylated‐EED subunit of the PRC2 complex via its second bromodomain (BD2) to facilitate histone H3 lysine 27 trimethylation (H3K27me3) at target gene loci and thereby transcriptional repression. We found that Foxp3 represses transcription of Th2‐specific transcription factor Gata3, while Fbxw7 promotes its ubiquitination‐directed protein degradation. BRD4‐mediated repression of Foxp3 and Fbxw7 in turn promotes BRD4‐ and Gata3‐mediated transcriptional activation of Th2 cytokines including Il4, Il5, and Il13. Chemical inhibition of the BRD4 BD2 induces transcriptional de‐repression of Foxp3 and Fbxw7, and thus transcriptional downregulation of Il4, Il5, and Il13, resulting in inhibition of Th2 cell lineage differentiation. Our study presents a previously unappreciated mechanism of BRD4's role in orchestrating a Th2‐specific transcriptional program that coordinates gene repression and activation, and safeguards cell lineage differentiation.
A relaxation scheme to approximate the 10-moment Gaussian closure

A relaxation scheme is derived to approximate the weak solutions of the 10-moment gaussian closure system. This model is governed by an hyperbolic system of conservation laws supplemented by entropy inequalities. The proposed relaxation scheme is proved to satisfy both needed positiveness property and all discrete entropy inequalities. Numerical experiments illustrate the interest of the method.
Levinson theorem for the Dirac equation in the presence of solitons in (1+1) dimensions

We study the Levinson theorem in (1 1+ 1) dimensions for a Dirac particle coupled to a background pseudo-scalar field, which is allowed to evolve into a soliton with arbitrary topological charge. We demonstrate the difficulty with defining the phase shifts when solitons are present, and then present a prescription for defining the phase shifts when the background field has arbitrary boundary values. We find that a modified form of the Levinson theorem holds, in which half the total number of threshold bound states at zero strength of the potential needs to be subtracted from the total number of bound states. We then present the Levinson theorem in a form that is universal to both relativistic and nonrelativistic quantum mechanics, which also includes all the exceptional cases. We also find generalizations to the Levinson theorem by finding relations between the bound states and the values of the phase shifts at each boundary of the continua separately. We relate the values of the phase shifts at the boundaries of a given continuum to the spectral deficiency in that continuum. We also relate the values of phase shifts at infinite energies to the topological charge of the solitons and their adiabatic contribution to the vacuum polarization that they induce.
Exploring the Lipid World Hypothesis: A Novel Scenario of Self-Sustained Darwinian Evolution of the Liposomes

According to the Lipid World hypothesis, life on Earth originated with the emergence of amphiphilic assemblies in the form of lipid micelles and vesicles (liposomes). However, the mechanism of appearance of the information molecules (ribozymes/RNA) accompanying that process, considered obligatory for Darwinian evolution, is unclear. We propose a novel scenario of self-sustained Darwinian evolution of the liposomes driven by ever-present natural phenomena: solar UV radiation, day/night cycle, gravity, and the formation of liposomes in an aqueous media. The central tenet of this scenario is the liposomes' encapsulation of the heavy solutes, followed by their gravitational submerging in the water. The submerged liposomes, being protected from the damaging UV radiation, acquire the longevity necessary for autocatalytic replication of amphiphiles, their mutation, and the selection of those amphiphilic assemblies that provide the greatest membrane stability. These two sets of adaptive compositional information (heavy content and amphiphilic assemblies design) generate a population of liposomes with self-replication/reproduction properties, which are amendable to mutation, inheritance, and selection, thereby establishing Darwinian progression. Temporary and spatial expansion of this liposomal population will provide the basis for the next evolutionary step—a transition of accidentally entrapped RNA precursor molecules into complex functional molecules, such as ribozymes/RNA.
CO (3–2) and CO (2–1) Detections in a z = 1.3 Hyper-Luminous Starburst Galaxy

We present an ∼ 2′′ resolution image of the CO (2–1) emission and an ∼ 4′′ resolution image of the CO (3–2) emission in the z = 1.3 hyper-luminous starburst galaxy MIPS J142824.0+352619, obtained at the Nobeyama Radio Observatory. Our new CO (3–2) and CO (2–1) emission detections yield LCO(3–2) = 1.4 (±0.5)×1011 and LCO(2–1) = 1.2 (±0.3)× 1011 K km s−1 pc2, which translate to a molecular gas mass of ∼ 1011 M , assuming a CO to H2 conversion factor appropriate for ULIRGs. The derived high CO luminosities place this source as being one of the brightest galaxies detected in CO to date. The CO (3–2) and CO (2–1) derived redshifts are 1.3248± 0.0002 and 1.3250± 0.0002. If the bulk of the molecular gas traced in these lines is completely thermalized, as suggested by LCO(3–2)/L ′ CO(2–1) ∼ 1, a constraint to the gas density of n 103 cm−3 is obtained from our Large Velocity Gradient (LVG) analysis. If a significant fraction of the bright FIR luminosity of LFIR = (3.2± 0.7)× 1013L arises from starburst activity, then the Star Formation Efficiency (SFE) is 320L M−1 . The size constraint of 1. ′′3 given by the CO (2–1) map provides an upper limit to the lensing magnification factor of μ 8, which further supports the earlier claim that the magnification of this source is only modest.
Alterations of mesenchymal stem cells on regulating Th17 and Treg differentiation in severe aplastic anemia

Immune-mediated hematopoietic destruction is a key factor in idiopathic severe aplastic anemia (SAA). With great immunomodulatory functions, mesenchymal stem cells (MSCs) are important for bone marrow niche. While the underlying etiology of immunologic changes in SAA bone marrow remains unknown, dysfunctional MSCs are implicated as a major cause. To provide evidence for their defects in immunomodulation, alterations of SAA MSCs in regulating T cell differentiation were determined. During differentiation from CD4+ T cells into T helper 17 (Th17) cells under polarization conditions, impaired inhibition on IL-17 and IL-1β production was noted when cocultured with SAA MSCs compared to control MSCs (P < 0.05). After stimulation of Th17 activation, the percentage of IL-17-secreting cells was significantly increased in the SAA group (9.1 ± 1.5% vs 6.6 ± 0.4%, P < 0.01). Under regulatory T (Treg) polarization, a higher percentage of CD4+CD25+FoxP3+ Treg cells was detected when cocultured with SAA MSCs compared to control MSCs (8.1 ± 0.5% vs 5.8 ± 0.8%, P < 0.01). Inconsistently, transforming growth factor-β (TGF-β) concentrations in the culture supernatant were decreased and IL-1β concentrations were elevated in the SAA group. Our data indicated impaired inhibition of SAA MSCs on Th17 activation and aberrant regulation of SAA MSCs on Treg differentiation. Increased IL-17 and IL-1β levels with decreased TGF-β levels in the supernatant suggested the potential of SAA MSCs for triggering a hyperinflammatory environment. Dysfunctional MSCs could contribute to the lack of immunoprotection in the bone marrow, which may be associated with SAA.
Strains Colonizing Different Intestinal Sites within an Individual Are Derived from a Single Founder Population

By reconstructing bacterial genomes from samples taken from specific sites within the human intestines, via aspiration, we show that strains at specific intestinal sites are genetically distinct yet interrelated and are derived from a single founder population. Organ-specific metagenomic information represents a powerful tool to generate insights into gastrointestinal diseases, which involve only a part of the intestine, such as inflammatory bowel disease. ABSTRACT Metagenomics has improved our understanding of commensal bacteria that colonize human intestines yet relies almost exclusively on fecal samples. Thus, spatial information about the niche range of these gut microbes and the level of specialized adaptation that they undergo has been inaccessible to fecal metagenomic studies. Here, we leveraged metagenomic data obtained through colonoscopy aspirates from three intestinal sites of healthy adults, and reconstructed metagenome-assembled genomes of several common gut bacteria to address intestinal site-specific evolution. We show that the genomes of bacterial strains at specific intestinal sites are clearly distinct yet are interrelated and are derived from a single founder strain colonizing multiple sites. We also reveal that within those intestinal sites, purifying selection is the dominant evolutionary force acting on Escherichia coli genomes within human hosts. Importantly, no site-specific adaptations at the level of accessory genes were detected, implying that these commensals are well-adapted to several host microniches and can therefore colonize multiple intestinal sites with high efficiency. Nevertheless, bacterial in situ growth rates differ markedly across different sections of the intestine. Metagenomics of aspirate samples can reveal unique strain- and intestinal tissue-specific genomic information. Such information may be critical for understanding bacterial contribution to gastrointestinal diseases, which involve only a part of the intestine, as is often the case in inflammatory bowel disease. IMPORTANCE By reconstructing bacterial genomes from samples taken from specific sites within the human intestines, via aspiration, we show that strains at specific intestinal sites are genetically distinct yet interrelated and are derived from a single founder population. Organ-specific metagenomic information represents a powerful tool to generate insights into gastrointestinal diseases, which involve only a part of the intestine, such as inflammatory bowel disease.
Collision-aware In-hand 6D Object Pose Estimation using Multiple Vision-based Tactile Sensors

In this paper, we address the problem of estimating the in-hand 6D pose of an object in contact with multiple vision-based tactile sensors. We reason on the possible spatial configurations of the sensors along the object surface. Specifically, we filter contact hypotheses using geometric reasoning and a Convolutional Neural Network (CNN), trained on simulated object-agnostic images, to promote those that better comply with the actual tactile images from the sensors. We use the selected sensors configurations to optimize over the space of 6D poses using a Gradient Descent-based approach. We finally rank the obtained poses by penalizing those that are in collision with the sensors. We carry out experiments in simulation using the DIGIT vision-based sensor with several objects, from the standard YCB model set. The results demonstrate that our approach estimates object poses that are compatible with actual object-sensor contacts in 87.5% of cases while reaching an average positional error in the order of 2 centimeters. Our analysis also includes qualitative results of experiments with a real DIGIT sensor.
Spin echo of spins diffusing in a bounded medium

The effect of reflecting boundaries on the spin echo measurement of diffusion in a geometrically bounded medium is calculated by considering the accumulation of phase shifts during the spin echo process. The distribution of phase shifts is shown to be Gaussian in the limits when the time between pulses is either long or short compared to the time required for a spin to diffuse from one boundary to another. The distribution is assumed to be Gaussian in the intermediate case, and the problem is reduced to the calculation of the mean square phase change due to diffusion. Expressions for spin echo amplitudes are derived for the cases of planar, spherical, and cylindrical boundaries, and forms are derived that are valid when the time of the measurement is very long or very short compared with the time required for diffusion between boundaries.
Microstructure and Electrical Properties of Lead-free Piezoelectric Ba-excess (Ba0.85(1+0.7%)Ca0.15)(Ti0.9Zr0.1)O3 Ceramics by Microwave Sintering

Microwave sintering was applied to manufacture fine-grained Ba-excess (Ba0.85(1+0.7%) Ca0.15)(Ti0.9Zr0.1)O3 (BCTZ) lead-free piezoceramics from nanometer grinded 0.20 μm particles. The sintering condition dependences of microstructure, density, dielectric constants and piezoelectric properties were investigated. With increasing microwave sintering temperature or soaking time, grain size increases as well as piezoelectric properties. The grain size of BCTZ ceramics by microwave sintering and subsequent high temperature treatment homogeneously increases and the samples show much better piezoelectric properties than those without high temperature treatment.