Miracle-dz/UniFAR-FTUs huggingface dataset:
Changing electrical nature of Saturn's rings: Implications for spoke formation

During Cassini's orbit insertion at Saturn, the trajectory took the spacecraft overtop the planet's famed ring system. At this time, the Cassini Radio and Plasma Wave Science (RPWS) instrument obtained unprecedented observations of electron density in the vicinity of the rings. Using this information and a model of photoemission anticipated from the rings, we demonstrate that the ring surface potential undergoes a seasonal change in electrical configuration, being primarily unipolar (of one charge polarity/potential) during the Voyager era and now bipolar (two separate polarities/potentials) during the Cassini era. We calculate the approximate ring/sun opening angle required for the transition from unipolar to bipolar configuration. Using electron density profiles, we explicitly examine the conditions for current balance on the B ring and show which regions are most likely to charge to positive potentials and those that may remain negative as a function of ring opening angle relative to the sun. Finally, we demonstrate that the current body of observations of Saturn ring spokes is consistent with their formation only on negatively‐charged surfaces, and suggest future times and locations to look for spoke activity based upon the model.
Explorer Satisfiability on Mixed Instances

The study of the worst-case complexity of the Boolean Satisfiability (SAT) problem has seen considerable progress in recent years, for various types of instances including CNFs [16, 15, 20, 21], Boolean formulas [18] and constant-depth circuits [6]. We systematically investigate the complexity of solving mixed instances, where different parts of the instance come from different types. Our investigation is motivated partly by practical contexts such as SMT (Satisfiability Modulo Theories) solving, and partly by theoretical issues such as the exact complexity of graph problems and the desire to find a unifying framework for known satisfiability algorithms. We investigate two kinds of mixing: conjunctive mixing, where the mixed instance is formed by taking the conjunction of pure instances of different types, and compositional mixing, where the mixed instance is formed by the composition of different kinds of circuits. For conjunctive mixing, we show that non-trivial savings over brute force search can be obtained for a number of instance types in a generic way using the paradigm of subcube partitioning. We apply this generic result to show a meta-algorithmic result about graph optimisation problems: any optimisation problem that can be formalised in Monadic SNP can be solved exactly with exponential savings over brute-force search. This captures known results about problems such as Clique, Independent Set and Vertex Cover, in a uniform way. For certain kinds of conjunctive mixing, such as mixtures of k-CNFs and CNFs of bounded size, and of k-CNFs and Boolean formulas, we obtain improved savings over subcube partitioning by combining existing algorithmic ideas in a more fine-grained way. We use the perspective of compositional mixing to show the first non-trivial algorithm for satisfiability of quantified Boolean formulas, where there is no depth restriction on the formula. We show that there is an algorithm which for any such formula with a constant number of quantifier blocks and of size n, where c < 5/4, solves satisfiability in time 2n−n Ω(1) .
Precise levels of Nectin-3 and an interaction with Afadin are required for proper synapse formation in postnatal visual cortex

Background Developing cortical neurons express a tightly choreographed sequence of cytoskeletal and transmembrane proteins to form and strengthen specific synaptic connections during circuit formation. Nectin-3 is a cell-adhesion molecule with previously described roles in synapse formation and maintenance. This protein and its binding partner, Nectin-1, are selectively expressed in upper-layer neurons of mouse visual cortex, but their role in the development of cortical circuits is unknown. Methods Here we block Nectin-3 expression (via shRNA) or overexpress Nectin-3 in developing layer 2/3 visual cortical neurons using in utero electroporation. We then assay dendritic spine densities at three developmental time points: eye opening (postnatal day (P)14), one week following eye opening after a period of heightened synaptogenesis (P21), and at the close of the critical period for ocular dominance plasticity (P35). Results Knockdown of Nectin-3 beginning at E15.5 or ∼P19 increased dendritic spine densities at P21 or P35, respectively. Conversely, overexpressing full length Nectin-3 at E15.5 led to decreased dendritic spine densities when all ages were considered together. Interestingly, an even greater decrease in dendritic spine densities, particularly at P21, was observed when we overexpressed Nectin-3 lacking its Afadin binding domain, indicating Afadin may facilitate spine morphogenesis after eye opening. Conclusion These data collectively suggest that the proper levels of Nectin-3, as well as the interaction of Nectin-3 with Afadin, facilitate normal synapse formation after eye opening in layer 2/3 visual cortical neurons.
LRRC8A regulates hypotonicity-induced NLRP3 inflammasome activation

The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered a therapeutic target. However, there is much regarding the mechanism of NLRP3 activation that remains unknown. Chloride efflux is suggested as an important step in NLRP3 activation, but the identity of which chloride channels are involved is still unknown. We used chemical, biochemical, and genetic approaches to establish the importance of Cl- channels in the regulation of NLRP3 activation. Specifically we identify LRRC8A, an essential component of volume-regulated anion channels (VRAC), as a vital regulator of hypotonicity-induced, but not DAMP-induced, NLRP3 inflammasome activation. Although LRRC8A was dispensable for canonical DAMP-dependent NLRP3 activation, this was still sensitive to Cl- channel inhibitors, suggesting there are additional and specific Cl- sensing and regulating mechanisms controlling NLRP3.
Human Domain Antibodies to Conserved Epitopes on HER2 Potently Inhibit Growth of HER2-Overexpressing Human Breast Cancer Cells In Vitro

The FDA approval of two anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, and an antibody-drug conjugate, trastuzumab emtansine, has transformed clinical practice for HER2-positive cancers. However, not all patients respond to therapy, and the majority of responders eventually develop resistance. In addition, cardiotoxicity is a major safety concern for their clinical use. Thus, there remains a need for the discovery and development of novel classes of HER2-targeted therapeutics with high efficacy and specificity. In this study, we report the identification and characterization of fully human single-domain antibodies (dAbs) targeting HER2 epitopes that are highly conserved among various species and non-overlapping with those of trastuzumab and pertuzumab. An Fc-fusion protein of the best binder demonstrated much higher inhibitory activity against HER2-amplified human breast cancer cell lines than trastuzumab and pertuzumab. Unlike the latter, however, it did not have an effect on gastric and ovarian cancer cell lines with HER2 overexpression. The dAb-Fc fusion protein showed poor pharmacokinetics in mice, thus limiting its potential for therapeutic use. It could be useful as an agent for the exploration of functionally important conserved structures on HER2 with implications for the design of novel therapeutics and elucidation of mechanisms of HER2-mediated tumorigenesis.
Bridging scales in scattering tissues via multifocal two-photon microscopy

Imaging biological systems at subcellular resolution and across scales is essential to under-standing how cells form tissues, organs, and organisms. However, existing large-scale optical techniques often require harsh tissue-clearing methods that cause significant morphological changes, compromise the integrity of cell membranes, and reduce the signal of fluorescent proteins. Here, we demonstrate multifocal two-photon microscopy that enables imaging mesoscopic scattering samples in their native tissue environment at high resolution and high speed.
Studying the Interrelationship amongst Various Barriers in Adoption of BIM in Developing Countries using ISM Methodology

Building Information Modelling is an emerging area of technology which deals with the process of creating and using design models for design, construction and operation of projects. However, it is still in its nascent stage in developing countries and suffers due to various barriers which hinder its development and adoption. Present research work deals with recognizing such barriers in adoption of BIM in developing countries like India and further studying the inter-relationships amongst them using ISM methodology.
Electromechanics of lipid-modulated gating of Kv channels

Experimental studies reveal that anionic lipid POPA and non-phospholipid cholesterol inhibit the gating of voltage-sensitive potassium (Kv) channels at 5–10% molar concentrations. Intriguingly, other anionic lipids similar to POPA, like POPG, have minimal impact on the gating of the same channels for reasons that remain obscure. Our long-timescale atomistic simulations show that POPA preferentially solvates the voltage sensor domains of Kv channels by direct electrostatic interactions between the positively charged arginine and negatively charged phosphate groups. Cholesterol solvates the voltage sensor domains through CH-π interactions between the cholesterol rings and the aromatic side chains of phenylalanine and tyrosine residues. A continuum electromechanical model predicts that POPA lipids may restrict the vertical motion of voltage-sensor domain through direct electrostatic interactions, while cholesterol may oppose the radial motion of the pore domain of the channel by increasing the mechanical rigidity of the membrane. The electromechanical model predictions are consistent with measurements of the activation curves of Kv channels for various lipids. The atomistic simulations also suggest that the solvation due to POPG is much weaker likely due to its bigger head-group size. Thus the channel activity appears to be tied to the local lipid environment, allowing lipids to regulate channel gating in low concentrations.
Group A Streptococcus Infection of the Nasopharynx Requires Proinflammatory Signaling through the Interleukin-1 Receptor

Group A Streptococcus (GAS) is the etiologic agent of numerous high-morbidity and high-mortality diseases. Infections are typically highly proinflammatory. During the invasive infection necrotizing fasciitis, this is in part due to the GAS protease SpeB directly activating interleukin-1β (IL-1β) independent of the canonical inflammasome pathway. The upper respiratory tract is the primary site for GAS colonization, infection, and transmission, but the host-pathogen interactions at this site are still largely unknown. ABSTRACT Group A Streptococcus (GAS) is the etiologic agent of numerous high-morbidity and high-mortality diseases. Infections are typically highly proinflammatory. During the invasive infection necrotizing fasciitis, this is in part due to the GAS protease SpeB directly activating interleukin-1β (IL-1β) independent of the canonical inflammasome pathway. The upper respiratory tract is the primary site for GAS colonization, infection, and transmission, but the host-pathogen interactions at this site are still largely unknown. We found that in the murine nasopharynx, SpeB enhanced IL-1β-mediated inflammation and the chemotaxis of neutrophils. However, neutrophilic inflammation did not restrict infection and instead promoted GAS replication and disease. Inhibiting IL-1β or depleting neutrophils, which both promote invasive infection, prevented GAS infection of the nasopharynx. Mice pretreated with penicillin became more susceptible to GAS challenge, and this reversed the attenuation from neutralization or depletion of IL-1β, neutrophils, or SpeB. Collectively, our results suggest that SpeB is essential to activate an IL-1β-driven neutrophil response. Unlike during invasive tissue infections, this is beneficial in the upper respiratory tract because it disrupts colonization resistance mediated by the microbiota. This provides experimental evidence that the notable inflammation of strep throat, which presents with significant swelling, pain, and neutrophil influx, is not an ineffectual immune response but rather is a GAS-directed remodeling of this niche for its pathogenic benefit.
Direct RNA sequencing reveals structural differences between transcript isoforms

The ability to correctly assign structure information to an individual transcript in a continuous and phased manner is critical to understanding RNA function. RNA structure play important roles in every step of an RNA’s lifecycle, however current short-read high throughput RNA structure mapping strategies are long, complex and cannot assign unique structures to individual gene-linked isoforms in shared sequences. To address these limitations, we present an approach that combines structure probing with SHAPE-like compound NAI-N3, nanopore direct RNA sequencing, and one-class support vector machines to detect secondary structures on near full-length RNAs (PORE-cupine). PORE-cupine provides rapid, direct, accurate and robust structure information along known RNAs and recapitulates global structural features in human embryonic stem cells. The majority of gene-linked isoforms showed structural differences in shared sequences both local and distal to the alternative splice site, highlighting the importance of long-read sequencing for phasing of structures. Structural differences between gene-linked isoforms are associated with differential translation efficiencies globally, highlighting the role of structure as a pervasive mechanism for regulating isoform-specific gene expression inside cells.
Philanthrocapitalism: Promoting Global Health but Failing Planetary Health

Focusing on the Bill and Melinda Gates Foundation (BMGF) as a case study, this paper explores the relationship between philanthrocapitalism, economic history, and global and planetary health. The Wellcome Trust is also briefly discussed, chiefly in the context of planetary health. The paper argues that in the last 45 years there has been an increased preference for market-based approaches, often called neoliberalism, particularly in the U.S. and its allies. This has generated greater inequality in many high-income settings and weakened the norm of taxation. This has provided a setting in which philanthrocapitalism has flourished, including the BMGF. The latter has in turn become an important actor for global health, partially balancing the adverse consequences of neoliberalism. Planetary health is here defined as the interaction between global health and global environmental change, including to the climate and other elements of the Earth System. Although the Wellcome Trust has recently made funds available for ecological health research, it continues to invest in fossil fuels. The Gates Foundation provide no or minimal grants for ecological or planetary health but appear to have recently substantially divested from fossil fuels, for unclear reasons. The paper concludes that these large philanthrocapitalist organizations partly compensate for the decline in attention to global health driven by market-preferring solutions, but remain insufficiently proactive in the face of the great dangers associated with declining planetary health.
Spatiotemporal Dynamics of Sound Representations reveal a Hierarchical Progression of Category Selectivity

As the human brain transforms incoming sounds, it remains unclear whether semantic meaning is assigned via distributed, domain-general architectures or specialized hierarchical streams. Here we show that the spatiotemporal progression from acoustic to semantically dominated representations is consistent with a hierarchical processing scheme. Combining magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) patterns, we found superior temporal responses beginning ~80 ms post-stimulus onset, spreading to extratemporal cortices by ~130 ms. Early acoustically-dominated representations trended systematically toward semantic category dominance over time (after ~200 ms) and space (beyond primary cortex). Semantic category representation was spatially specific: vocalizations were preferentially distinguished in temporal and frontal voice-selective regions and the fusiform face area; scene and object sounds were distinguished in parahippocampal and medial place areas. Our results are consistent with an extended auditory processing hierarchy in which acoustic representations give rise to multiple streams specialized by category, including areas typically considered visual cortex.
The Artemis Rover as an Example for Model Based Engineering in Space Robotics

Future application of robotic missions in the space context will require the systems to have both mobility and manipulation capabilities. The limited direct communication with the systems due to visibility, and severe time delays also make it a requirement for the system to perform its actions mainly autonomously. The increasing complexity of the task, as well as the strict requirements for reliability and fault tolerance pose a significant challenge to both engineering and research activities. The SpaceBot Cup was held in November 2013 to probe those capabilities in the context of a competition. In this paper we present the Artemis rover and its software architecture as well as the competition results and lessons learned. Special attention is given to the modular design based on the Robot Construction Kit (Rock) framework – a component based software framework, which uses a component model based on the Orocos Real-Time-Toolkit (RTT).
Computation noise promotes cognitive resilience to adverse conditions during decision-making

Random noise in information processing systems is widely seen as detrimental to function. But despite the large trial-to-trial variability of neural activity and behavior, humans and other animals show a remarkable adaptability to unexpected adverse events occurring during task execution. This cognitive ability, described as constitutive of general intelligence, is missing from current artificial intelligence (AI) systems which feature exact (noise-free) computations. Here we show that implementing computation noise in recurrent neural networks boosts their cognitive resilience to a variety of adverse conditions entirely unseen during training, in a way that resembles human and animal cognition. In contrast to artificial agents with exact computations, noisy agents exhibit hallmarks of Bayesian inference acquired in a ‘zero-shot’ fashion – without prior experience with conditions that require these computations for maximizing rewards. We further demonstrate that these cognitive benefits result from free-standing regularization of activity patterns in noisy neural networks. Together, these findings suggest that intelligence may ride on computation noise to promote near-optimal decision-making in adverse conditions without any engineered cognitive sophistication.
Microglial activation results in neuron-type-specific increase in mPFC GABAergic transmission and abnormal behavior in mice

Neuroinflammation and synaptic dysfunction are two early symptoms of most neurological diseases. However, the mechanisms underlying microglia-associated neuroinflammation in the regulation of synaptic activity remain obscure. We report here that acute neuroinflammation induced by a single-dose proinflammatory cytokine inducer, lipopolysaccharide (LPS), results in enhanced inhibitory postsynaptic currents (IPSCs) of glutamatergic neurons, upregulated levels of GABAAR subunits, glutamine synthetase (GS) and vGAT, and downregulated BDNF and pTrkB levels, due to enhanced activation of microglia in the medial prefrontal cortex (mPFC). Blockage of microglial activation by minocycline ameliorated LPS-induced aberrant mIPSCs and associated aberrant protein expression and behavior. Exogenous application of BDNF prior to LPS challenge also ameliorated LPS-induced abnormal mIPSCs. Thus, this study elucidates a critical role for microglia in the neurobiology of GABAergic synaptic dysfunction induced by neuroinflammation, revealing a novel GABAergic signaling pathway that might be targeted therapeutically to treat neuroinflammation-induced abnormal synaptic activity and associated aberrant behavior.
Effects of a Contusive Spinal Cord Injury on Spinal Motor Neuron Activity and Conduction Time in Rats

Objective The purpose of this study was to determine the effects of spinal cord injury (SCI) on spike activity evoked in the hindlimb spinal cord of the rat from cortical electrical stimulation. Approach Adult, male, Sprague Dawley rats were randomly assigned to a Healthy or SCI group. SCI rats were given a 175 kDyn dorsal midline contusion injury at the level of the T8 vertebrae. At four weeks post-SCI, intracortical microstimulation (ICMS) was delivered at several sites in the hindlimb motor cortex of anesthetized rats, and evoked neural activity was recorded from corresponding sites throughout the dorsoventral depths of the spinal cord and EMG activity from hindlimb muscles. Main results In healthy rats, post-ICMS spike histograms showed reliable, evoked spike activity during a short-latency epoch 10-12 ms after the initiation of the ICMS pulse train (short). Longer latency spikes occurred between ~20-60 ms, generally following a Gaussian distribution, rising above baseline at time LON, followed by a peak response (Lp), and then falling below baseline at time LOFF. EMG responses occurred between LON and Lp (25-27 ms). In SCI rats, short-latency responses were still present, long-latency responses were disrupted or eliminated, and EMG responses were never evoked. The retention of the short-latency responses indicates that spared descending spinal fibers, most likely via the cortico-reticulospinal pathway, can still depolarize spinal cord motor neurons after a dorsal midline contusion injury. Significance This study provides novel insights into the role of alternate pathways for voluntary control of hindlimb movements after SCI that disrupts the corticospinal tract in the rat.
Dendritic cell actin dynamics controls T cell priming efficiency at the immunological synapse

Dendritic cells (DCs) are crucial for the priming of naïve T cells and the initiation of adaptive immunity. Priming is initiated at a heterologous cell-cell contact, the immunological synapse (IS). While it is established that actin dynamics regulates signalling at the T cell side of the contact, little is known about the cytoskeletal contribution on the DC side. We show that that the DC cytoskeleton is decisive for the formation of a multifocal synaptic structure, which correlates with T cell priming efficiency. We demonstrate that DC actin appears in transient foci at the IS and that these foci are dynamized by the WAVE complex. Absence of WAVE in DCs leads to stabilized contacts with T cells, caused by an increase in ICAM1-integrin mediated cell-cell adhesions. This results in a lower number of activated and proliferating T cells. Our results reveal an important role of DC actin in the regulation of synaptic contacts with crucial relevance for full T cell expansion.