Miracle-dz/UniFAR-FTUs huggingface dataset:
CCL2 Mediates Neuron–Macrophage Interactions to Drive Proregenerative Macrophage Activation Following Preconditioning Injury

CNS neurons in adult mammals do not spontaneously regenerate axons after spinal cord injury. Preconditioning peripheral nerve injury allows the dorsal root ganglia (DRG) sensory axons to regenerate beyond the injury site by promoting expression of regeneration-associated genes. We have previously shown that peripheral nerve injury increases the number of macrophages in the DRGs and that the activated macrophages are critical to the enhancement of intrinsic regeneration capacity. The present study identifies a novel chemokine signal mediated by CCL2 that links regenerating neurons with proregenerative macrophage activation. Neutralization of CCL2 abolished the neurite outgrowth activity of conditioned medium obtained from neuron–macrophage cocultures treated with cAMP. The neuron–macrophage interactions that produced outgrowth-promoting conditioned medium required CCL2 in neurons and CCR2/CCR4 in macrophages. The conditioning effects were abolished in CCL2-deficient mice at 3 and 7 d after sciatic nerve injury, but CCL2 was dispensable for the initial growth response and upregulation of GAP-43 at the 1 d time point. Intraganglionic injection of CCL2 mimicked conditioning injury by mobilizing M2-like macrophages. Finally, overexpression of CCL2 in DRGs promoted sensory axon regeneration in a rat spinal cord injury model without harmful side effects. Our data suggest that CCL2-mediated neuron–macrophage interaction plays a critical role for amplification and maintenance of enhanced regenerative capacity by preconditioning peripheral nerve injury. Manipulation of chemokine signaling mediating neuron–macrophage interactions may represent a novel therapeutic approach to promote axon regeneration after CNS injury. SIGNIFICANCE STATEMENT CNS axons do not regenerate spontaneously after injury. However, preconditioning peripheral nerve injury enables dorsal root ganglia sensory neurons to regenerate central axons beyond spinal lesion. The exact mechanism by which the conditioning injury enhances axon regeneration capacity remains elusive. We report here that neuronal CCL2 induced by conditioning injury mediates neuron–macrophage interactions, resulting in accumulation of perineuronal macrophages with a proregenerative phenotype. Genetic or immunological inhibition of CCL2 abolished conditioning effects in vitro and in vivo, indicating that CCL2-mediated activation of proregenerative macrophages is essential in the conditioning injury-induced enhanced regenerative capacity. Intraganglionic CCL2 gene delivery recapitulates conditioning effects after spinal cord injury, suggesting that a chemokine signal mediating neuron–macrophage interaction may be a novel target for axon regeneration therapeutics.
Heuristic-based model refinement for FLAVERS

FLAVERS is a finite-state verification approach that allows an analyst to incrementally add constraints to improve the precision of the model of the system being analyzed. Except for trivial systems, however, it is impractical to compute which constraints should be selected to produce precise results for the least cost. Thus, constraint selection has been a manual task, guided by the intuition of the analyst. In this paper, we investigate several heuristics for selecting task automaton constraints, a kind of constraint that tends to reduce infeasible task interactions. We describe an experiment showing that one of these heuristics is extremely effective at improving the precision of the analysis results without significantly degrading performance.
Rewriting complex SPARQL analytical queries for efficient cloud-based processing

Many emerging Semantic Web applications combine and aggregate data across domains for analysis. Such analytical queries compute aggregates over multiple groupings of data, resulting in query plans with complex grouping-aggregation constraints. In the context of an RDF analytical query, each such grouping maps to a graph pattern subquery with multiple join operations, and related groups often result in overlapping graph patterns within the same query. In this paper, we propose a holistic approach to optimize RDF analytical queries by refactoring queries to achieve shared execution of common subexpressions that enables parallel evaluation of groupings as well as aggregations. Such a rewriting enables shorter execution workflows, particularly beneficial for scale-out processing on distributed Cloud systems with multiple I/O phases. Experiments on real-world and synthetic benchmarks confirm that such a rewriting can achieve more efficient execution plans when compared to relational-style SPARQL query plans executed on popular Cloud systems.
Optimization of nanofibrous silk fibroin scaffold as a delivery system for bone marrow adherent cells: in vitro and in vivo studies

Electrospun silk fibroin nanofibrous scaffolds (ESFNSs) were successfully prepared by electrospinning of various Bombyx mori silk fibroin concentrations (10, 12, and 14% in formic acid). After characterizing the purified silk fibroin, the morphology, porosity, fibers’ diameter, and uniformity of the prepared scaffolds were examined in detail. In addition, biological responses such as effects on bone marrow cell viability, cytotoxicity, and cell adhesion were evaluated in vitro. Biocompatibility and bioactivity properties of the ESFNSs were evaluated in vitro and in vivo by cell culturing and subcutaneous implantation in rat models for 7 and 28 days, respectively. According to the obtained results, no beaded fibers were seen in any of the prepared scaffolds, whereas ESFNS‐10% provided more uniformity and porosity with nanoscaled fibers (90 ± 0.021 nm). Furthermore, the scaffolds also showed good cell adhesion and spreading (68.7 ± 11.8 and 7.6 ± 3.3 total length and width, respectively) with no detectable effect on cell viability and cytotoxicity. The in vivo biocompatibility evaluation indicated that the scaffolds did not stimulate detectable cellular inflammatory response (lymphocytes) and increased the total cell number (cellularity) in the implantation area. Furthermore, the results suggest the potential use of the prepared ESFNS‐10% bone marrow cell constructs in direct implantation for tissue engineering applications.
Aphid amino acid transporter regulates glutamine supply to intracellular bacterial symbionts

Significance Nutritional bacterial endosymbionts are housed in specialized host cells and are partitioned from the host cell cytoplasm by a host-derived symbiosomal membrane. This cellular organization isolates bacterial symbionts from nutrient pools in the host cell and makes possible host control of nutrient supply to bacterial symbionts. Here, using the aphid–Buchnera nutritional endosymbiosis, we demonstrate that the most active host glutamine (precursor) transporter, Acyrthosiphon pisum glutamine transporter 1, is competitively inhibited by arginine (a Buchnera-synthesized end product). We propose a model of endosymbiosis regulation in which precursor transport is regulated by a symbiont-synthesized end product. Thus, we provide insights into the molecular mechanism of host control of bacterial endosymbiont essential nutrient biosynthesis. Endosymbiotic associations have played a major role in evolution. However, the molecular basis for the biochemical interdependence of these associations remains poorly understood. The aphid–Buchnera endosymbiosis provides a powerful system to elucidate how these symbioses are regulated. In aphids, the supply of essential amino acids depends on an ancient nutritional symbiotic association with the gamma-proteobacterium Buchnera aphidicola. Buchnera cells are densely packed in specialized aphid bacteriocyte cells. Here we confirm that five putative amino acid transporters are highly expressed and/or highly enriched in Acyrthosiphon pisum bacteriocyte tissues. When expressed in Xenopus laevis oocytes, two bacteriocyte amino acid transporters displayed significant levels of glutamine uptake, with transporter ACYPI001018, LOC100159667 (named here as Acyrthosiphon pisum glutamine transporter 1, ApGLNT1) functioning as the most active glutamine transporter. Transporter ApGLNT1 has narrow substrate selectivity, with high glutamine and low arginine transport capacity. Notably, ApGLNT1 has high binding affinity for arginine, and arginine acts as a competitive inhibitor for glutamine transport. Using immunocytochemistry, we show that ApGLNT1 is localized predominantly to the bacteriocyte plasma membrane, a location consistent with the transport of glutamine from A. pisum hemolymph to the bacteriocyte cytoplasm. On the basis of functional transport data and localization, we propose a substrate feedback inhibition model in which the accumulation of the essential amino acid arginine in A. pisum hemolymph reduces the transport of the precursor glutamine into bacteriocytes, thereby regulating amino acid biosynthesis in the bacteriocyte. Structural similarities in the arrangement of hosts and symbionts across endosymbiotic systems suggest that substrate feedback inhibition may be mechanistically important in other endosymbioses.
An Online Social Network-based Recommendation System

We present a social network-based recommendation system that uses data from user profiles and user-to-user connections. We adapted our implementation to use data from the BoardGameGeek (BGG) website. The end result system will be usable by members of BGG to get recommendations given both their ratings history and their friend relationships. At this stage, we have gathered all of the needed data from the BGG website, and we have started to run the algorithm for our recommendation service. The remaining steps are to run experiments to determine suitable parameter settings for the algorithm, and create a web-based application.
KNoCEmu: High Speed FPGA Emulator for Kilo-node Scale NoCs

Many-core architectures are becoming mainstream in both processor designs and System-on-Chip (SoC) designs. With the growing number of cores on a chip, Network-on-Chip (NoC) has become the de-facto on-chip communication infrastructure. Since it is believed that the near future many-core architectures will have thousands of cores integrated on a single chip, it is essential to have both full-system simulators and stand-alone NoC simulators for supporting architectural design exploration and performance evaluation of such kilo scale many-core systems. This paper proposes KNoCEmu, an FPGA emulator which can achieve fast and cycle-accurate Kilo-Node scale NoC simulations. To overcome the limitation of FPGA resources, we propose a method which reduces the amount of required FPGA resources while maintaining the simulation accuracy. The time-division multiplexing technique is adopted to emulate the behavior of the entire network using one or several physical nodes. Our design is optimized to efficiently use FPGA resources such as block RAM and distributed RAM. We have implemented KNoCEmu for emulating a 32×32 mesh NoC with the conventional input buffer router on a Virtex 7 XC7VX485T FPGA and evaluated the amount of occupied FPGA resources and the simulation speedup over a software-based software simulator. The evaluation results show that KNoCEmu can achieve 134× simulation speedup over the software-based simulator while using less than 8% of the total number of available slices of the Virtex 7 XC7VX485T FPGA.
A unifying treatise on variational principles for gradient and micromorphic continua

The effective macroscopic behaviour of most materials depends significantly on the structure exhibited at the microscopic level. In recent decades, considerable effort has thus been directed towards the development of continuum theories accounting for the inherent microstructure of materials. A unified theory is, however, not yet available. A reliable and efficient use of microstructured materials would benefit from the former, which is also the foundation of any subsequent numerical analysis. Focusing on two kinds of microstructured materials (gradient continua, micromorphic continua), an attempt is made to identify their role and their potential with regard to numerical implementations in a generic theory. An analysis of both continua in the framework of various variational formulations based on the Dirichlet principle shows that they are closely related (which is intuitively not obvious): a gradient continuum can, for example, be modelled by applying a mixed variational principle to a micromorphic continuum. This has considerable consequences for the numerical implementation: the Euler–Lagrange equations describing the seemingly more intricate micromorphic continuum require only continuous approximations when implemented in a FEM code, while, in contrast, the Euler–Lagrange equations deduced for the gradient continuum require differentiability of the involved unknowns.
Automatic detection of previously-unseen application states for deployment environment testing and analysis

For large, complex software systems, it is typically impossible in terms of time and cost to reliably test the application in all possible execution states and configurations before releasing it into production. One proposed way of addressing this problem has been to continue testing and analysis of the application in the field, after it has been deployed. A practical limitation of many such automated approaches is the potentially high performance overhead incurred by the necessary instrumentation. However, it may be possible to reduce this overhead by selecting test cases and performing analysis only in previously-unseen application states, thus reducing the number of redundant tests and analyses that are run. Solutions for fault detection, model checking, security testing, and fault localization in deployed software may all benefit from a technique that ignores application states that have already been tested or explored. In this paper, we present a solution that ensures that deployment environment tests are only executed in states that the application has not previously encountered. In addition to discussing our implementation, we present the results of an empirical study that demonstrates its effectiveness, and explain how the new approach can be generalized to assist other automated testing and analysis techniques intended for the deployment environment.
N-terminal protein modification through a biomimetic transamination reaction.

An important challenge in the field of protein bioconjugation is the development of strategies that can modify a protein once at a single site. Although many bioconjugation reactions can functionalize specific amino acids in aqueous solution, most proteins display multiple copies of the targeted residue on their surface. This commonly results in product mixtures that present the new functionality in multiple locations on the protein surface. As it is one of the rarest amino acids, cysteine is the most commonly targeted residue when siteselective modification is required, but there remain many situations in which the modification of a unique copy of this residue is inconvenient or impossible. To address these limitations, several chemoselective techniques have been developed to target surface-accessible aromatic residues. To complement these methods further, we report herein a biomimetic transamination reaction that can modify the N terminus of proteins and peptides under mild conditions. This technique introduces a uniquely reactive ketone or aldehyde group in a single location, thus allowing further modification through oxime or hydrazone formation. This simple strategy does not require the use of site-directed mutagenesis, and therefore has the potential to introduce virtually any functional group on a wide range of protein substrates. The unique reactive properties of the N terminus have resulted in several strategies targeting this location to achieve site-selective protein modification. To a limited extent, the lower pKa value of N-terminal amino groups (relative to lysine side chains) can be used to direct acylation reactions to
Mechanical factors activate ß‐catenin‐dependent oncogene expression in APC1638N/+ mouse colon

ß‐catenin acts as a critical regulator of gastrointestinal homeostasis through its control of the Wnt signaling pathway, and genetic or epigenetic lesions which activate Wnt signaling are the primary feature of colon cancer. ß‐catenin is also a key element of mechanotranscription pathways, leading to upregulation of master developmental gene expression during Drosophila gastrulation, or regulating mammalian bone development and maintenance. Here we investigate the impact of mechanical stimulation on the initiation of colon cancer. Myc and Twist1, two oncogenes regulated through ß‐catenin, are expressed in response to transient compression in APC deficient (APC1638N/+) colon tissue explants, but not in wild‐type colon explants. Mechanical stimulation of APC1638N/+ tissue leads to the phosphorylation of ß‐catenin at tyrosine 654, the site of interaction with E‐cadherin, as well as to increased nuclear localization of ß‐catenin. The mechanical activation of Myc and Twist1 expression in APC1638N/+ colon can be prevented by blocking ß‐catenin phosphorylation using Src kinase inhibitors. Microenvironmental signals are known to cooperate with genetic lesions to promote the nuclear ß‐catenin accumulation which drives colon cancer. Here we demonstrate that when APC is limiting, mechanical strain, such as that associated with intestinal transit or tumor growth, can be interpreted by cells of preneoplastic colon tissue as a signal to initiate a ß‐catenin dependent transcriptional program characteristic of cancer.
COSMIC RAY ACCELERATION AT BLAST WAVES FROM TYPE Ia SUPERNOVAE

We have calculated the cosmic ray(CR) acceleration at young remnants from Type Ia supernovae expanding into a uniform interstellar medium(ISM). Adopting quasi-parallel magnetic fields, gasdynamic equations and the diffusion convection equation for the particle distribution function are solved in a comoving spherical grid which expands with the shock. Bohm-type diffusion due to self-excited waves, drift and dissipation of these waves in the precursor and thermal leakage injection were included. With magnetic fields amplified by the CR streaming instability, the particle energy can reach up to eV at young supernova remnants(SNRs) of several thousand years old. The fraction of the explosion energy transferred to the CR component asymptotes to 40-50 % by that time. For a typical SNR in a warm ISM, the accelerated CR energy spectrum should exhibit a concave curvature with the power-law slope flattening from 2 to 1.6 at TeV.
Retinal Blood Vessel Segmentation Using Line Operators and Support Vector Classification

In the framework of computer-aided diagnosis of eye diseases, retinal vessel segmentation based on line operators is proposed. A line detector, previously used in mammography, is applied to the green channel of the retinal image. It is based on the evaluation of the average grey level along lines of fixed length passing through the target pixel at different orientations. Two segmentation methods are considered. The first uses the basic line detector whose response is thresholded to obtain unsupervised pixel classification. As a further development, we employ two orthogonal line detectors along with the grey level of the target pixel to construct a feature vector for supervised classification using a support vector machine. The effectiveness of both methods is demonstrated through receiver operating characteristic analysis on two publicly available databases of color fundus images.
Low dose aspirin and cognitive function in the women's health study cognitive cohort

Objective To determine whether low dose aspirin protects women aged 65 or more against cognitive decline. Design Cohort study within both arms of the women's health study, a randomised, double blind, placebo controlled trial of low dose aspirin for the primary prevention of cardiovascular disease and cancer, 1992-5. Setting Women's health study, 1998-2004. Participants 6377 women aged 65 or more. Interventions Low dose aspirin (100 mg on alternate days) or placebo for a mean of 9.6 years. Main outcome measures Women had three cognitive assessments at two year intervals by telephone. The battery to assess cognition included five tests measuring general cognition, verbal memory, and category fluency. The primary prespecified outcome was a global score, averaging performance across all tests. The key secondary outcome was a verbal memory score, averaging performance on four measures of verbal memory. Results At the initial assessment (mean 5.6 years after randomisation) cognitive performance in the aspirin group was similar to that of the placebo group (mean difference in global score −0.01, 95% confidence interval −0.04 to 0.02). Mean decline in the global score from the first to the final cognitive assessment was also similar in the aspirin compared with placebo groups (mean difference 0.01, −0.02 to 0.04). The risk of substantial decline (in the worst 10th centile of decline) was also comparable between the groups (relative risk 0.92, 0.77 to 1.10). Findings were similar for verbal memory; however, a 20% lower risk was observed for decline in category fluency with aspirin (relative risk 0.80, 0.67 to 0.97). Conclusion Long term use of low dose aspirin does not provide overall benefits for cognition among generally healthy women aged 65 or more.
Cooperative Precoding with Limited Feedback for MIMO Interference Channels

Multi-antenna precoding effectively mitigates the interference in wireless networks. However, the resultant performance gains can be significantly compromised in practice if the precoder design fails to account for the inaccuracy in the channel state information (CSI) feedback. This paper addresses this issue by considering finite-rate CSI feedback from receivers to their interfering transmitters in the two-user multiple-input-multiple-output (MIMO) interference channel, called cooperative feedback, and proposing a systematic method for designing transceivers comprising linear precoders and equalizers. Specifically, each precoder/equalizer is decomposed into inner and outer components for nulling the cross-link interference and achieving array gain, respectively. The inner precoders/equalizers are further optimized to suppress the residual interference resulting from finite-rate cooperative feedback. Furthermore, the residual interference is regulated by additional scalar cooperative feedback signals that are designed to control transmission power using different criteria including fixed interference margin and maximum sum throughput. Finally, the required number of cooperative precoder feedback bits is derived for limiting the throughput loss due to precoder quantization.
Swedish Medical Nanoscience Center at Karolinska Institutet

Abstract The Swedish Medical Nanoscience Center is an integrative research hub located at Karolinska Institutet in Stockholm, Sweden. In this highly reputed medical research institute, our mission is to establish the area of nanomedicine as a means to advance this new research area to meet the demands of future innovative health care solutions. Using interdisciplinary basic research, often referred to as ‘curiosity-driven’ research, as our driving force, we promote the integration of cutting-edge nanotechnology and biomedical research. As new concepts and technologies mature, focus of our projects is gradually shifted towards clinically relevant problems. Advancement of the area of nanomedicine requires engagement of a new breed of scientist with the enthusiasm, devotion and competence to communicate and work across many disciplines. Together, they help generate a highly multidisciplinary scientific environment, producing new knowledge that ultimately becomes the stepping-stone towards novel therapies for the benefit of the patient.