Miracle-dz/UniFAR-FTUs huggingface dataset:
Invariant discovery and refinement plans for formal modelling in Event-B

The continuous growth of complex systems makes the development of correct software increasingly challenging. In order to address this challenge, formal methods offer rigorous mathematical techniques to model and verify the correctness of systems. Refinement is one of these techniques. By allowing a developer to incrementally introduce design details, refinement provides a powerful mechanism for mastering the complexities that arise when formally modelling systems. Here the focus is on a posit-and-prove style of refinement, where a design is developed as a series of abstract models introduced via refinement steps. Each refinement step generates proof obligations which must be discharged in order to verify its correctness – typically requiring a user to understand the relationship between modelling and reasoning. This thesis focuses on techniques to aid refinement-based formal modelling, specifically, when a user requires guidance in order to overcome a failed refinement step. An integrated approach has been followed: combining the complementary strengths of bottomup theory formation, in which theories about domains are built based on basic background information; and top-down planning, in which meta-level reasoning is used to guide the search for correct models. On the theory formation perspective, we developed a technique for the automatic discovery of invariants. Refinement requires the definition of properties, called invariants, which relate to the design. Formulating correct and meaningful invariants can be tedious and a challenging task. A heuristic approach to the automatic discovery of invariants has been developed building upon simulation, proof-failure analysis and automated theory formation. This approach exploits the close interplay between modelling and reasoning in order to provide systematic guidance in tailoring the search for invariants for a given model. On the planning perspective, we propose a new technique called refinement plans. Refinement plans provide a basis for automatically generating modelling guidance when a step fails but is close to a known pattern of refinement. This technique combines both modelling and reasoning knowledge, and, contrary to traditional pattern techniques, allow the analysis of failure and partial matching. Moreover, when the guidance is only partially instantiated, and it is suitable, refinement plans provide specialised knowledge to further tailor the theory formation process in an attempt to fully instantiate the guidance. We also report on a series of experiments undertaken in order to evaluate the approaches and on the implementation of both techniques into prototype tools. We believe the techniques presented here allow the developer to focus on design decisions rather than on analysing low-level proof failures. To the memory of my father, Guillermo Llano, and my Grandma, Yayita. You will always be in my heart.
Efficient Domain Adaptation for Endoscopic Visual Odometry

Visual odometry plays a crucial role in endoscopic imaging, yet the scarcity of realistic images with ground truth poses poses a significant challenge. Therefore, domain adaptation offers a promising approach to bridge the pre-operative planning domain with the intra-operative real domain for learning odometry information. However, existing methodologies suffer from inefficiencies in the training time. In this work, an efficient neural style transfer framework for endoscopic visual odometry is proposed, which compresses the time from pre-operative planning to testing phase to less than five minutes. For efficient traing, this work focuses on training modules with only a limited number of real images and we exploit pre-operative prior information to dramatically reduce training duration. Moreover, during the testing phase, we propose a novel Test Time Adaptation (TTA) method to mitigate the gap in lighting conditions between training and testing datasets. Experimental evaluations conducted on two public endoscope datasets showcase that our method achieves state-of-the-art accuracy in visual odometry tasks while boasting the fastest training speeds. These results demonstrate significant promise for intra-operative surgery applications.
A Novel Plant Vacuolar Na+/H+ Antiporter Gene Evolved by DNA Shuffling Confers Improved Salt Tolerance in Yeast*

Plant vacuolar Na+/H+ antiporters play important roles in maintaining cellular ion homeostasis and mediating the transport of Na+ out of the cytosol and into the vacuole. Vacuolar antiporters have been shown to play significant roles in salt tolerance; however the relatively low Vmax of the Na+/H+ exchange of the Na+/H+ antiporters identified could limit its application in the molecular breeding of salt tolerant crops. In this study, we applied DNA shuffling methodology to generate and recombine the mutations of Arabidopsis thaliana vacuolar Na+/H+ antiporter gene AtNHX1. Screening using a large scale yeast complementation system identified AtNHXS1, a novel Na+/H+ antiporter. Expression of AtNHXS1 in yeast showed that the antiporter localized to the vacuolar membrane and that its expression improved the tolerance of yeast to NaCl, KCl, LiCl, and hygromycin B. Measurements of the ion transport activity across the intact yeast vacuole demonstrated that the AtNHXS1 protein showed higher Na+/H+ exchange activity and a slightly improved K+/H+ exchange activity.
MicroRNAs as biomarkers of hepatotoxicity in a randomized placebo-controlled study of simvastatin and ubiquinol supplementation

Statins are potent cholesterol-lowering drugs and are generally well tolerated. Hepatotoxicity is a rare but serious adverse effect of statins; however, its mechanisms are not clear. Coenzyme Q10 deficiency has been suggested, and supplementation of reduced coenzyme Q10 (ubiquinol) has been shown to have hepatoprotective effects. MicroRNAs (miRNAs) are small nucleotides that have been shown to be up-regulated in drug-induced liver injury. We hypothesized that circulating miRNAs may be differentially regulated after simvastatin treatment and by comparing with that of simvastatin and ubiquinol supplementation could potentially uncover signatory miRNA profile for simvastatin-induced liver injury. In this double-blind, prospective, randomized-controlled trial, miRNA profiles and liver enzymes were compared between simvastatin-treated patients, with and without ubiquinol supplementation, over 12 weeks compared to baseline. miRNA expression was further validated in HepG2 liver cell lines by real-time PCR. Changes in miR-192, miR-146a, miR-148a, miR-15a, and miR-21 were positively correlated (p<0.05) with alanine aminotransferase in simvastatin-only treated patients. In ubiquinol supplementation group, alanine aminotransferase and alkaline phosphatase were significantly down-regulated after 12 weeks and changes in miR-15a, miR-21 and miR-33a were negatively correlated with alkaline phosphatase (p < 0.05). Bioinformatics analyses predicted that miRNA regulation in simvastatin group was related to reduce proliferation and adenosine triphosphate-binding cassette transporters. Ubiquinol supplementation additionally regulated miRNAs that inhibit apoptotic and inflammatory pathways, suggesting potential hepatoprotective effects. Our results suggest that 20 mg/day of simvastatin does not have significant risk of hepatotoxicity and ubiquinol supplementation may, at the miRNA level, provide potential beneficial changes to reduce the effects of coenzyme Q10 deficiency in the liver.
The diagnostic status of first-rank symptoms.

OBJECTIVE In the International Statistical Classification of Diseases, Tenth Revision(ICD-10) and Diagnostic and Statistical Manual of Mental Disorder, Third and Fourth Edition(DSM-III-IV), the presence of one of Schneider "first-rank symptoms" (FRS) is symptomatically sufficient for the schizophrenia diagnosis. Yet, it has been claimed that FRS may also be found in the nonschizophrenic conditions, and therefore, they are not specific or diagnostic for schizophrenia. This review was made to clarify the issue of diagnostic specificity. METHODS (1) A critical review of FRS studies published in English between 1970 and 2005. (2) A highlight of the 5 most frequently cited studies identified in the Web of Science. (3) Theoretical implications of the epistemological issues of FRS. RESULTS The reviewed studies do not allow for either a reconfirmation or a rejection of Schneider's claims about FRS. The sources of disagreement between the studies are (1) including or excluding acute patients with potential degradation of consciousness; (2) assessing or not the phenomenological context; (3) assessing patients in different stages of their illness evolution; and (4) differential emphasis on mood symptoms and history of psychiatric symptoms. CONCLUSION Both DSM-IV and ICD-10 emphasize FRS to a degree that is not supported by the empirical evidence. Until the status of FRS is clarified in depth, we suggest that the FRS, as these are currently defined, should be de-emphasized in the next revisions of our diagnostic systems. Future studies aiming at validation of FRS as diagnostic features need to apply a phenomenological perspective and include a homogenous group of patients across a wide spectrum of diagnoses.
Phasic Diversity Optimization for Population-Based Reinforcement Learning

Reviewing the previous work of diversity Rein-forcement Learning,diversity is often obtained via an augmented loss function,which requires a balance between reward and diversity.Generally,diversity optimization algorithms use Multi-armed Bandits algorithms to select the coefficient in the pre-defined space. However, the dynamic distribution of reward signals for MABs or the conflict between quality and diversity limits the performance of these methods. We introduce the Phasic Diversity Optimization (PDO) algorithm, a Population-Based Training framework that separates reward and diversity training into distinct phases instead of optimizing a multi-objective function. In the auxiliary phase, agents with poor performance diversified via determinants will not replace the better agents in the archive. The decoupling of reward and diversity allows us to use an aggressive diversity optimization in the auxiliary phase without performance degradation. Furthermore, we construct a dogfight scenario for aerial agents to demonstrate the practicality of the PDO algorithm. We introduce two implementations of PDO archive and conduct tests in the newly proposed adversarial dogfight and MuJoCo simulations. The results show that our proposed algorithm achieves better performance than baselines.
Are Galaxies Optically Thin to Their Own Lyman-Continuum Radiation? II. NGC 6822

Halpha and UBV photometry of NGC 6822 are used to study the distribution of OB stars and HII regions in the galaxy and to determine whether individual regions of the galaxy are in a state of ionization balance. Four distinct components of the Halpha emission (bright, halo, diffuse and field) differentiated by their surface brightnesses are identified. We find that approximately 1/2 of all OB stars in NGC 6822 are located in the field while only 1/4 are found in the combined bright and halo regions, suggesting that OB stars spend roughly 3/4 of their lifetimes outside ``classical'' H II regions. Comparing the observed Halpha emission with that predicted from stellar ionizing flux models, we find that although the bright, halo and diffuse regions are probably in ionization balance, the field region is producing at least 6 times as much ionizing flux as is observed. The ionization balance results in NGC 6822 suggest that star formation rates obtained from Halpha luminosities must underestimate the true star formation rate in this galaxy by about 50%. Comparing our results for NGC 6822 with previous results for the spiral galaxy M33, we find that the inner kiloparsec of M33 is in a more serious state of ionization imbalance, perhaps due to its higher surface density of blue stars.
DNA-dependent Protein Kinase Interacts with Antigen Receptor Response Element Binding Proteins NF90 and NF45*

The DNA-dependent protein kinase (DNA-PK) is composed of a large catalytic subunit of approximately 470 kDa (DNA-PKcs) and the DNA-binding protein, Ku. Absence of DNA-PK activity confers sensitivity to x-rays and defects in both DNA double-strand break repair and V(D)J recombination. However, the precise function of DNA-PK in DNA double-strand break repair is not known. Here we show, using electrophoretic mobility shift assays, that polypeptides in a fraction purified from human cells interact with DNA-PK and stabilize the formation of a complex containing DNA-PKcs-Ku and DNA. Five polypeptides in this fraction have been identified by amino-terminal sequence analysis and/or immunoblotting. These proteins are NF90 and NF45, which are the 90- and 45-kDa subunits of a protein known to bind specifically to the antigen receptor response element of the interleukin 2 promoter, and the α, β, and γ subunits of eukaryotic translation initiation factor eIF-2. We also show that NF90, NF45, and eIF-2β are substrates for DNA-PK in vitro. In addition, recombinant NF90 promotes formation of a complex between DNA-PKcs, Ku, and DNA, and antibodies to recombinant NF90 or recombinant NF45 immunoprecipitate DNA-PKcs in vitro. Together, our data suggest that NF90, in complex with NF45, interacts with DNA-PKcs and Ku on DNA and that NF90 and NF45 may be important for the function of DNA-PK.
Controlled Study of 50-Hz Repetitive Transcranial Magnetic Stimulation for the Treatment of Parkinson Disease

Objective. To investigate the safety and efficacy of 50-Hz repetitive transcranial magnetic stimulation (rTMS) in the treatment of motor symptoms in Parkinson disease (PD). Background. Progression of PD is characterized by the emergence of motor deficits that gradually respond less to dopaminergic therapy. rTMS has shown promising results in improving gait, a major cause of disability, and may provide a therapeutic alternative. Prior controlled studies suggest that an increase in stimulation frequency might enhance therapeutic efficacy. Methods. In this randomized, double blind, sham-controlled study, the authors investigated the safety and efficacy of 50-Hz rTMS of the motor cortices in 8 sessions over 2 weeks. Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, Unified Parkinson’s Disease Rating Scale (UPDRS), and additional clinical, neurophysiological, and neuropsychological parameters. In addition, the safety of 50-Hz rTMS was tested with electromyography-electroencephalogram (EMG-EEG) monitoring during and after stimulation. Results. The authors investigated 26 patients with mild to moderate PD: 13 received 50-Hz rTMS and 13 sham stimulation. The 50-Hz rTMS did not improve gait, bradykinesia, and global and motor UPDRS, but there appeared a short-lived “on”-state improvement in activities of daily living (UPDRS II). The 50-Hz rTMS lengthened the cortical silent period, but other neurophysiological and neuropsychological measures remained unchanged. EMG/EEG recorded no pathological increase of cortical excitability or epileptic activity. There were no adverse effects. Conclusion. It appears that 50-Hz rTMS of the motor cortices is safe, but it fails to improve motor performance and functional status in PD. Prolonged stimulation or other techniques with rTMS might be more efficacious but need to be established in future research.
Characterization of the Transport, Metabolism, and Pharmacokinetics of the Dopamine D3 Receptor-Selective Fluorenyl- and 2-Pyridylphenyl Amides Developed for Treatment of Psychostimulant Abuse

The recent discovery of novel high-affinity and selective dopamine D3 receptor (DA D3R) antagonists and partial agonists has provided tools with which to further elucidate the role DA D3R plays in substance abuse. The present study was conducted to evaluate the transport, metabolism, pharmacokinetics, and brain uptake of the DA D3R-selective fluorenyl amides, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide] fumarate) and JJC 4-077 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-9H-fluorene-2-carboxamide hydrochloride], and the 2-pyridylphenyl amides, CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridine-2-yl)benzamide hydrochloride] and PG 01037 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-(pyridine-2-yl)benzamide hydrochloride], all of which have been studied in animal models of psychostimulant abuse. Additional screening with a panel of human and rat Supersomes was performed for NGB 2904 and PG 01037. Drug-stimulated ATPase activation assays and bidirectional transport and efflux assays were used to test for substrate specificity of NGB 2904 and PG 01037 for human and rat efflux transporters. All compounds exhibited moderate elimination half-lives, ranging from 1.49 to 3.27 h, and large volumes of distribution (5.95–14.19 l/kg). The brain-to-plasma ratios ranged from 2.93 to 11.81 and were higher than those previously reported for cocaine. Brain exposure levels of NGB 2904 and PG 01037 were significantly reduced after intraperitoneal administration compared with intravenous administration. The metabolism of these compounds was mediated primarily by CYP3A subfamilies. PG 01037 was a P-glycoprotein-transported substrate. Higher doses of these compounds are often required for in vivo action, suggesting decreased bioavailability via extravascular administration that may be attributed to high drug efflux and hepatic metabolism. These studies provide important preclinical information for optimization of next-generation D3R selective agents for the treatment of drug addiction.
A 28 Gb/s 1.6 pJ/b PAM-4 Transmitter Using Fractionally Spaced 3-Tap FFE and $G_{m}$ -Regulated Resistive-Feedback Driver

We presents an energy-efficient PAM-4 transmitter that provides a controlled output impedance, scalable output voltage swing, and fractionally spaced feed-forward equalization (FFE). By using a resistive-feedback output driver, the proposed PAM-4 transmitter can reduce the power dissipation in the pre-driver stages compared with conventional transmitters. It also offers a more straightforward implementation of a 3-tap FFE owing to the simple current-summing structure of the pre-driver. In addition, the output impedance of the proposed output driver is controlled by regulating the ${G} _{\boldsymbol m}$ of the driver cell, which results in good signal integrity for high-speed operation without the use of peaking inductors. A prototype chip is fabricated in 28-nm CMOS technology and occupies an active area of 0.048 mm2. It achieves a data rate of 28 Gb/s, exhibiting the state-of-the-art energy efficiency of 1.59 pJ/b for the differential output swing of 207 mV.
A Metamodel of Central Inferences in Empirical Research

The purpose of the present paper is to emphasise the importance of inferences in an empirical study and to demonstrate how the inferences depend on a wider context. For that purpose a metamodel of central inferences is proposed, where each inference is characterised according to three dimensions: relevance, legitimacy, and validity. The relevance of an inference is a function of the research problem and general aim of the study, as well as of the philosophy of science; its legitimacy is given by the philosophy of science, whereas its validity is determined by the empirical methods and data within the study as well as by knowledge outside the study. Moreover, the metamodel includes combinations of the relevant inferences, together with the validities of such combinations, as answers to the research problem. The metamodel is meant to be an appropriate frame for both quantitative and qualitative research.
Neural Representation of Reward Probability: Evidence from the Illusion of Control

To support reward-based decision-making, the brain must encode potential outcomes both in terms of their incentive value and their probability of occurrence. Recent research has made it clear that the brain bears multiple representations of reward magnitude, meaning that a single choice option may be represented differently—and even inconsistently—in different brain areas. There are some hints that the same may be true for reward probability. Preliminary evidence hints that, even as systematic distortions of probability are expressed in behavior, these may not always be uniformly reflected at the neural level: Some neural representations of probability may be immune from such distortions. This study provides new evidence consistent with this possibility. Participants in a behavioral experiment displayed a classic “illusion of control,” providing higher estimates of reward probability for gambles they had chosen than for identical gambles that were imposed on them. However, an fMRI study of the same task revealed that neural prediction error signals, arising when gamble outcomes were revealed, were unaffected by the illusion of control. The resulting behavioral–neural dissociation reinforces the case for multiple, inconsistent internal representations of reward probability, while also prompting a reinterpretation of the illusion of control effect itself.
Accuracy of the Neuropad Test for the Diagnosis of Distal Symmetric Polyneuropathy in Type 2 Diabetes

OBJECTIVE To estimate the accuracy of Neuropad for the diagnosis and staging of distal symmetric polyneuropathy (DPN) across different stages of neuropathy, using multiple-level likelihood ratios (LRs) to interpret the time necessary to complete the color change of the test. RESEARCH DESIGN AND METHODS We conducted a cross-sectional, cohort-type diagnostic accuracy study in 251 consecutive adult type 2 diabetic patients with no peripheral arterial disease or other potential causes of neuropathy, who were recruited between January 2005 and December 2008 from the diabetes outpatient clinics in Alexandroupolis Hospital, Greece. Patients were tested for DPN by means of the neuropathy disability score (NDS) and Neuropad. Multiple-level LRs for time to complete color change were calculated across different stages of neuropathy. RESULTS The areas under the curve for the diagnosis of any (NDS of ≥3), at least moderate (NDS of ≥6), or severe (NDS of ≥9) DPN were 0.91, 0.96, and 0.97, respectively. The calculation of multiple-level LRs showed that time to complete color change <360 s suggested the absence of neuropathy. Values between 360 and 1,000 s were indicative of mild neuropathy. Finally, values between 1,000 and 1,200 or >1,200 s were strongly suggestive of moderate or severe DPN, respectively. CONCLUSIONS Neuropad could be used as a triage test for the diagnosis and staging of DPN in patients with type 2 diabetes, prompting referral to specialized care setting.