Miracle-dz/UniFAR-FTUs huggingface dataset:
Persistent inflammation promotes endocannabinoid release and presynaptic cannabinoid 1 receptor desensitization

Pain therapies targeting the cannabinoid system are increasing with expansion of cannabis legalization but adaptations in the endogenous cannabinoid system during inflammatory pain could limit their efficacy. Presynaptic inhibition of GABA release mediated by cannabinoid 1 receptor (CB1R) agonists in the ventrolateral periaqueductal gray (vlPAG) is markedly reduced in male and female Sprague Dawley rats after persistent inflammation induced by Complete Freund’s Adjuvant (CFA). Inflammation results in increased endocannabinoid (eCB) synthesis and desensitization of presynaptic CB1Rs that is reversed by a GRK2/3 inhibitor, Compound 101. Despite CB1R desensitization, eCB activation of CB1Rs is maintained after inflammation. Depolarization-induced suppression of inhibition (DSI) in naïve animals is rapid and transient, but is prolonged in recordings after inflammation. Prolonged DSI is mediated by 2-arachidonoylglycerol (2-AG) indicating reduced monoacylglycerol lipase (MAGL) activity. These adaptations within the endogenous cannabinoid system have important implications for the development of future pain therapies targeting CB1Rs or MAGL.
A highly selective response to food in human visual cortex revealed by hypothesis-free voxel decomposition

Prior work has identified cortical regions selectively responsive to specific categories of visual stimuli. However, this hypothesis-driven work cannot reveal how prominent these category selectivities are in the overall functional organization of visual cortex, or what others might exist that scientists have not thought to look for. Further, standard voxel-wise tests cannot detect distinct neural selectivities that coexist within voxels. To overcome these limitations, we used data-driven voxel decomposition methods to identify the main components underlying fMRI responses to thousands of complex photographic images (Allen et al 2021). Our hypothesis-neutral analysis rediscovered components selective for faces, places, bodies, and words, validating our method and showing that these selectivities are dominant features of the ventral visual pathway. The analysis also revealed an unexpected component with a distinct anatomical distribution that responded highly selectively to images of food. Alternative accounts based on low to mid-level visual features like color, shape or texture failed to account for the food selectivity of this component. High-throughput testing and control experiments with matched stimuli on a highly accurate computational model of this component confirm its selectivity for food. We registered our methods and hypotheses before replicating them on held-out participants and in a novel dataset. These findings demonstrate the power of data-driven methods, and show that the dominant neural responses of the ventral visual pathway include not only selectivities for faces, scenes, bodies, and words, but also the visually heterogeneous category of food, thus constraining accounts of when and why functional specialization arises in the cortex.
Super-enhancers require a combination of classical enhancers and novel facilitator elements to drive high levels of gene expression

Super-enhancers (SEs) are a class of compound regulatory elements which control expression of key cell-identity genes. It remains unclear whether they are simply clusters of independent classical enhancers or whether SEs manifest emergent properties and should therefore be considered as a distinct class of element. Here, using synthetic biology and genome editing, we engineered the well characterised erythroid α-globin SE at the endogenous α-globin locus, removing all SE constituent elements in a mouse embryonic stem cell-line, to create a “blank canvas”. This has allowed us to re-build the SE through individual and combinatorial reinsertion of its five elements (R1, R2, R3, Rm, R4), to test the importance of each constituent’s sequence and position within the locus. Each re-inserted element independently creates a region of open chromatin and binds its normal repertoire of transcription factors; however, we found a high degree of functional interdependence between the five constituents. Surprisingly, the two strongest α-globin enhancers (R1 and R2) act sub-optimally both on their own and in combination, and although the other three elements (R3, Rm and R4) exhibit no discernible enhancer activity, they each exert a major positive effect in facilitating the activity of the classical enhancers (R1 and R2). This effect depends not simply on the sequence of each element but on their positions within the cluster. We propose that these “facilitators” are a novel form of regulatory element, important for ensuring the full activity of SEs, but distinct from conventional enhancer elements.
Queuine Salvaging in the Human Parasite Entamoeba histolytica

Queuosine (Q) is a naturally occurring modified nucleoside that occurs in the first position of transfer RNA anticodons such as Asp, Asn, His, and Tyr. As eukaryotes lack pathways to synthesize queuine, the Q nucleobase, they must obtain it from their diet or gut microbiota. Previously, we described the effects of queuine on the physiology of the eukaryotic parasite Entamoeba histolytica and characterized the enzyme EhTGT responsible for queuine incorporation into tRNA. At present, it is unknown how E. histolytica salvages Q from gut bacteria. We used liquid chromatography–mass spectrometry (LC–MS) and N-acryloyl-3-aminophenylboronic acid (APB) PAGE analysis and to demonstrate that E. histolytica trophozoites can salvage queuine from Q or E. coli K12 but not from the modified E. coli QueC strain, which cannot produce queuine. We then examined the role of EhDUF2419, a protein with homology to DNA glycosylase, as queuine salvage enzyme in E. histolytica. Trophozoites silenced for EhDUF2419 expression are impaired in their ability to form Q-tRNA from Q or from E. coli. We also observed that Q partially protects control trophozoites from oxidative stress (OS), but not siEhDUF2419 trophozoites. Overall, our data reveal that EhDUF2419 is central for the salvaging of queuine from bacteria and for the resistance of the parasite to OS.
Probing the biophysical constraints of SARS-CoV-2 spike N-terminal domain using deep mutational scanning

Increasing the expression level of the SARS-CoV-2 spike (S) protein has been critical for COVID-19 vaccine development. While previous efforts largely focused on engineering the receptor-binding domain (RBD) and the S2 subunit, the N-terminal domain (NTD) has been long overlooked due to the limited understanding of its biophysical constraints. In this study, the effects of thousands of NTD single mutations on S protein expression were quantified by deep mutational scanning. Our results revealed that in terms of S protein expression, the mutational tolerability of NTD residues was inversely correlated with their proximity to the RBD and S2. We also identified NTD mutations at the interdomain interface that increased S protein expression without altering its antigenicity. Overall, this study not only advances the understanding of the biophysical constraints of the NTD, but also provides invaluable insights into S-based immunogen design.
Soft robotic hands for compliant grasping

The thesis considers the problem of grasping for autonomous robots, with a focus on the design and construction of robotic hands and grippers. The approach we take is to fundamentally reconsider the basic motivation and goals for grasping that steer hand design. We consider grasping as the result of reliable and robust patterns of interaction between hand, object and environment which are mechanically opaque to the robot. This motivates the investigation of a new type of robotic hands, pneumatic soft hands. These hands enable the robot to collide with objects safely, maintain contact under disturbance, and provide many places of contact for a robust grasp. At the same time they intend to lower requirements on control and perception compared to fully actuated hands. Due to the fundamental change in perspective compared to the classical, mechanics-centric view in grasping, I believe we will ultimately have to reconsider all aspects of a robot system to use soft hands effectively. We call this alternative view the Soft Manipulation paradigm. In this thesis we propose a list of defining principles for Soft Manipulation and focus on the ramifications for hand hardware, but we also consider the adjacent domains of hand control and grasping strategies. Research on soft hands is complicated by the fact that the technology and body of knowledge for building soft hands only is emerging right now. The thesis contributes the groundwork for soft hand research by developing a coherent and comprehensive set of tools to rapidly prototype pneumatic soft hands. This toolkit is built around a versatile and easy to prototype actuator design named PneuFlex. The thesis will cover all aspects of prototyping such as designing mechanical properties, manufacturing actuators, assembling them into hands, and controlling them without interfering in their compliance. We also propose and validate a fast and stable dynamic simulation model for the simulation of pneumatic soft hands which for the first time makes interactive and automated design of soft hands feasible. The thesis also explores the properties and capabilities of pneumatic soft hands in a series of grasping experiments with the help of two artifacts, the RBO Hand 1 and RBO Hand 2. We investigate their shape adaptability, their grasp dexterity, and their suitability for implementing grasping strategies that exploit environment constraints to motion for robust execution. We will see that soft hands built with technology developed in the first part of the thesis provide a solid foundation for further research on Soft Manipulation.
A pituitary gene network linking vgll3 to regulators of sexual maturation in male Atlantic salmon

Age at maturity is a key life history trait and a significant contributor to life history strategy variation. The maturation process is complex and influenced by genetic and environmental factors alike, but specific causes of variation in maturation timing remain elusive. In many species, the increase in the regulatory gonadotropin-releasing hormone 1 (GnRH1) marks the onset of puberty. Atlantic salmon, however, lack the gene encoding GnRH1, suggesting other regulatory factors are involved in the maturation process. Earlier research in Atlantic salmon has found a strong association between alternative alleles of vgll3 and maturation timing, making vgll3 a candidate reproductive axis gene regulator. Recently we reported strong induction of gonadotropin encoding genes (fshb and lhb) in the pituitary of male Atlantic salmon homozygous for the vgll3 allele linked with the early maturation allele (E). The induction of gonadotropins was accompanied by increased expression of their direct upstream regulators, c-jun and sf1 (nr5a1b) in the pituitary. In mammals, the transcriptional activation of c-jun and sf1 is also required for induction of fshb and lhb, however, GnRH1 is responsible for increased transcriptional activity of c-jun and sf1. The absence of gnrh1 in salmon raises the possibility of the involvement of other regulators upstream of these factors. In this study, we investigated such a possibility through a stepwise approach for identifying a gene regulatory network (GRN) containing c-jun and sf1 and using the zebrafish coexpression database and transcription factor motif enrichment analysis. We found a GRN containing c-jun with predicted upstream regulators, e2f1, egr1, foxj1 and klf4, which are also differentially expressed in the pituitary. Finally, we suggest a model for transcriptional regulation of c-jun and sf1in the absence of gnrh1 in the pituitary, which may have broader implications across vertebrates.
Simultaneous multifunctional transcriptome engineering by CRISPR RNA scaffold

RNA processing and metabolism are subjected to precise regulation in the cell to ensure integrity and functions of RNA. Though targeted RNA engineering has become feasible with the discovery and engineering of the CRISPR-Cas13 system, simultaneous modulation of different RNA processing steps remains unavailable. In addition, off-target events resulting from effectors fused with dCas13 limit its application. Here we developed a novel platform, Combinatorial RNA Engineering via Scaffold Tagged gRNA (CREST), which can simultaneously execute multiple RNA modulation functions on different RNA targets. In CREST, RNA scaffolds are appended to the 3’ end of Cas13 gRNA and their cognate RNA binding proteins are fused with enzymatic domains for manipulation. We show that CREST is capable of simultaneously manipulating RNA alternative splicing and A-to-G or C-to-U base editing. Furthermore, by fusing two split fragments of the deaminase domain of ADAR2 to dCas13 and PUFc respectively, we reconstituted its enzyme activity at target sites. This split design can reduce more than 90% of off-target events otherwise induced by a full-length effector. The flexibility of the CREST framework will enrich the transcriptome engineering toolbox for the study of RNA biology and the development of RNA-focused therapeutics.
Improving Operator Recognition and Prediction of Emergent Swarm Behaviors

Robot swarms are typically defined as large teams of coordinating robots that interact with each other on a local scale. The control laws that dictate these interactions are often designed to produce emergent global behaviors useful for robot teams, such as aggregating at a single location or moving between locations as a group. These behaviors are called emergent because they arise from the local rules governing each robot as they interact with neighbors and the environment. No single robot is aware of the global behavior yet they all take part in it, which allows for a robustness that is difficult to achieve with explicitly-defined global plans. Now that hardware and algorithms for swarms have progressed enough to allow for their use outside the laboratory, new research is focused on how operators can control them. Recent work has introduced new paradigms for imparting an operator's intent on the swarm, yet little work has focused on how to better visualize the swarm to improve operator prediction and control of swarm states. The goal of this dissertation is to investigate how to present the limited data from a swarm to an operator so as to maximize their understanding of the current behavior and swarm state in general. This dissertation develops--through user studies--new methods of displaying the state of a swarm that improve a user's ability to recognize, predict, and control emergent behaviors. The general conclusion is that how summary information about the swarm is displayed has a significant impact on the ability of users to interact with the swarm, and that future work should focus on the properties unique to swarms when developing visualizations for human-swarm interaction tasks.
Studying the Inﬂuence of Mica Particle Size on the Properties of Epoxy Acrylate/Mica Composite Coatings through Reducing Mica Particle Size by the Ball-Milled Method

: In this work, a series of epoxy acrylate (EA)/mica composite coatings were synthesized through introducing mica powders of different particle size into epoxy acrylate coatings and using an ultraviolet (UV) curing technique to investigate the inﬂuence of mica particle size on the coatings. Mica powders of different particle sizes were obtained by ball-milling for 4, 8, 12, 16, and 20 h with a planetary high-energy ball mill. The particle size and morphologies of ball-milled mica powders were characterized by laser particle size analyzer and scanning electron microscopy (SEM). The results indicated that planetary ball-milling reduced the particle size of mica powders effectively. Mica powders that were un-ball-milled and ball-milled were added into the epoxy acrylate matrix by a blending method to synthesize the organic-inorganic UV curable coatings. The optical photographs of the coatings showed greater stability of liquid mixtures with smaller particle size ﬁllers. The chemical structures of EA/mica composite coatings were investigated by Fourier transform infrared spectroscopy (FTIR), and the conversion rate of C=C bonds was calculated. The results indicated that the C=C conversion of coatings with mica powders of smaller particle sizes was higher. Tests of mechanical properties and tests using electrochemical impedance spectroscopy (EIS) showed that pencil hardness, impact resistance, and coating resistance were improved due to the reduction of mica powders particle size.
Small-angle X-ray Scattering Tensor Tomography: Model of 3D Reciprocal-Space Map, Reconstruction Algorithm, and Angular Sampling Requirements

Small-angle X-ray scattering tensor tomography, which allows reconstruction of the local 3D reciprocal-space map within a 3D sample as introduced by Liebi et al. (2015), is described in more detail with regard to the mathematical framework and the optimization algorithm. For the case of trabecular bone samples from vertebra it is shown that the model of 3D reciprocal-space map using spherical harmonics can adequately describe the measured data. The method enables the determination of nanostructure orientation and degree of orientation as demonstated previously in a single momentum transfer q range. Here we show a reconstruction of the complete reciprocal-space map for the case of bone over extended ranges of q . In addition, it is shown that uniform angular sampling and advanced regularization strategies help to reduce the amount of data required. In this manuscript we present a detailed description of the algorithm as well as a validation study to conﬁrm the suitability of spherical harmonic coeﬃcients to represent the 3D reciprocal-space map of trabecular bone where the features of the mineralized collagen ﬁbrils can be recovered. In order to reduce the number of coeﬃcients that need to be optimized we provide for each voxel a parametrization of the spherical harmonic zenith direction, which provides directly the orientation of the main symmetry axis of the nanostructure in 3D and subsequently allows us to impose reciprocal-space symmetry constraints. Regularization strategies for both the coeﬃcients and the orientation are introduced and described in detail. An important consideration is the distribution of projection angles for the measurements. By selectively removing angles the eﬀect on the reconstruction is shown, which conﬁrms that a uniform distribution of sample orientations is of signiﬁcant beneﬁt for the reconstruction quality. provides a technique that can probe 3D nanostructure information in relatively large volumes, oﬀering the unique chance to correlate spatial nanoscale features over several millimeters, i.e. separated over ﬁve or six orders of magnitude. The technique is applicable to a wide range of specimens in biology and materials science and also scalable. While the original demonstration was with 20 micron voxel size, by using microfocusing optics and improved scanning hardware the current demonstrated the technique to a spatial resolution of 5 microns. optics hardware the resolution can be
A Review of the Concept of ISO Standard 9000 Family

---In order to live in this period of customer oriented business every industry is endeavoring to slake the subsisting customers and additionally magnetize initial customers. One of the policies used is to maintain a quality standard of the products exceeding the client’s prospect. The software industry is no exclusion to identically tantamount. It is necessary for organizations to set up, manage and promote their quality control system and quality assurance systems and their integral standard operating functions and other quality documents to provide high-quality products and accommodations to plenarily gratify customer requirements and prospects. Quality control and quality assurance systems together form quality schemes. Quality management consists of both quality control as well as quality assurance. Quality control is engrossed on consummating quality requisites, whereas quality assurance is fixated on providing confidence that quality requisites are consummated.
Effect of linear feedback control on the optimal transient growth in particle-laden channel flow

The optimal transient growth process in a particle-laden channel flow is studied under the influence of the linear feedback control. The equilibrium Eulerian approach with the assumption that the particles are small and spherical is adopted. The effect of initial distribution of particles on the optimal transient growth of perturbations is discussed. The LQG control of the particle-laden flow system is considered and compared with the no control cases.
Smart Shopping Cart Learning Agents Modeling And Evaluation

—The paper describes the design, implementation and user evaluation of utility and goal-based intelligent learning agents for smart shopping cart. In keeping user’s shopping list, they guide visitors through the shops and the goods in the shopping center or according to new promotions in the shops, respectively. It is envisaged that concrete implementation of the shopping agents will be running on each shopping cart in the shopping centers. The k-d decision tree and reinforcement-learning algorithm are used for agents learning. The task environment is partially observable, cooperative, deterministic, and a multi - agent environment, with some stochastic and uncertainty elements. It incorporates text-to-speech and speech recognizing technology, Bluetooth low energy technology, holographic technology, picture exchange communication system. Machine learning techniques are used for agents modeling. This kind of intelligent system enables people with different communication capabilities to navigate in large buildings and in particular to shop in the large shopping centers and maximize user comfort. Some initial user opinions of the shopping cart agents are presented.
University of Birmingham Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese

Genome-wide association studies (GWAS) identified many common type 2 diabetes-associated variants, mostly found at the intronic or intergenic regions. Recent advancement of exome array genotyping platforms have opened up a novel means for detecting the associations of low-frequency or rare coding variants with type 2 diabetes. We conducted an exome-chip association analysis to identify additional type 2 diabetes susceptibility variants in the Chinese population. pathogenesis of type 2 diabetes. Our findings are suggestive of PAX4 being a possible effector gene of the 7q32 locus previously identified from GWAS amongst Asians. Exome-chip which interrogated 77,468 polymorphic SNPs, we identified the association of an Asian-specific coding variant in PAX4 and replicated the associations of some known type 2 diabetes-susceptibility loci. We also detected a few possible candidates which showed potential functional relevance in the pathogenesis of type 2 diabetes, such as TTBK2, FGFR1 and CSN1S1 .