Miracle-dz/UniFAR-FTUs huggingface dataset:
RNA-RNA and RNA-protein interactions in coronavirus replication and transcription

Coronavirus (CoV) RNA synthesis includes the replication of the viral genome, and the transcription of sgRNAs by a discontinuous mechanism. Both processes are regulated by RNA sequences such as the 5’ and 3’ untranslated regions (UTRs), and the transcription regulating sequences (TRSs) of the leader (TRS-L) and those preceding each gene (TRS-Bs). These distant RNA regulatory sequences interact with each other directly and probably through protein-RNA and protein-protein interactions involving viral and cellular proteins.1 By analogy to other plus-stranded RNA viruses, such as polioviruses, in which translation and replication switch involves a cellular factor (PCBP) and a viral protein (3CD),2 it is conceivable that in CoVs the switch between replication and transcription is also associated with the binding of proteins that are specifically recruited by the replication or transcription complexes. Complexes between RNA motifs such as TRS-L and the TRS-Bs located along the CoV genome are probably formed previously to the transcription start, and most likely promote template-switch of the nascent minus RNA to the TRS-L region.3 Many cellular proteins interacting with regulatory CoV RNA sequences4 are members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of RNA-binding proteins, involved in mRNA processing and transport, which shuttle between the nucleus and the cytoplasm. In the context of CoV RNA synthesis, these cellular ribonucleoproteins might also participate in RNA-protein complexes to bring into physical proximity TRS-L and distant TRS-B, as proposed for CoV discontinuous transcription.5-7 In this review, we summarize RNA-RNA and RNA-protein interactions that represent modest examples of complex quaternary RNA-protein structures required for the fine-tuning of virus replication. Design of chemically defined replication and transcription systems will help to clarify the nature and activity of these structures.
Comparative immunochemistry of lipopolysaccharides from typable and polyagglutinable Pseudomonas aeruginosa strains isolated from patients with cystic fibrosis

Lipopolysaccharide (LPS) was extracted and purified from three Pseudomonas aeruginosa strains isolated from the infected lungs of patients with cystic fibrosis. Two of the strains could be typed by O-specific antibody (O:3 and O:9), and the third was polyagglutinable (O:3/9). The separated LPS was characterized by chemical and serological methods. The main neutral sugar constituents (glucose, rhamnose, and heptose) were found in various proportions in the three strains, whereas the amounts of glucosamine, galactosamine, ketodeoxyoctonate, and phosphate were more constant. Ester-bound C12, C16, 3-OH-C10, and 2-OH-C12, together with amide-bound 3-OH-C12, fatty acids were present in equimolar proportions in all three strains. Considerable amounts of LPS were liberated in the culture supernatant of the O:3 bacteria but not in those from the other two strains. This free LPS was shown to be immunologically identical to the cell-bound LPS and the extracted LPS. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis, O:3 and O:9 LPS showed a ladder pattern characteristic of smooth LPS, while O:3/9 LPS appeared rough. Rabbit antisera used for O-typing were found by enzyme-linked immunosorbent assay to contain anti-LPS antibodies that reacted strongly with homologous LPS, moderately with O:3/9 LPS, and slightly with heterologous LPS. Immunoblotting showed that common antigenic determinants in the core-lipid A part were involved in the observed cross-reaction. The polyagglutinability of P. aeruginosa may be explained by the antibodies to these common determinants that arose from the partial absence of O polysaccharides.
Gene mapping by haplotype pattern mining

Genetic markers are being increasingly utilized in gene mapping. The discovery of associations between markers and patient phenotypes - such as a disease status - enables the identification of potential disease gene loci. The rationale is that, in diseases with a reasonable genetic contribution, diseased individuals are more likely to have associated marker alleles near the disease susceptibility gene than control individuals. We describe a new gene mapping method-haplotype pattern mining (HPM) - that is based on discovering recurrent marker patterns. We define a class of useful haplotype patterns in genetic case-control data, give an algorithm for finding disease-associated haplotypes, and show how to use them to identify disease susceptibility loci. Experimental studies show that the method has good localization power in data sets with large degrees of phenocopies and with lots of missing and erroneous data. We also demonstrate how the method can be used to discover several genes simultaneously.
Inference of Evolutionary Forces Acting on Human Biological Pathways

Because natural selection is likely to act on multiple genes underlying a given phenotypic trait, we study here the potential effect of ongoing and past selection on the genetic diversity of human biological pathways. We first show that genes included in gene sets are generally under stronger selective constraints than other genes and that their evolutionary response is correlated. We then introduce a new procedure to detect selection at the pathway level based on a decomposition of the classical McDonald-Kreitman test extended to multiple genes. This new test, called 2DNS, detects outlier gene sets and takes into account past demographic effects as well as evolutionary constraints specific to gene sets. Selective forces acting on gene sets can be easily identified by a mere visual inspection of the position of the gene sets relative to their 2D null distribution. We thus find several outlier gene sets that show signals of positive, balancing, or purifying selection, but also others showing an ancient relaxation of selective constraints. The principle of the 2DNS test can also be applied to other genomic contrasts. For instance, the comparison of patterns of polymorphisms private to African and non-African populations reveals that most pathways show a higher proportion of non-synonymous mutations in non-Africans than in Africans, potentially due to different demographic histories and selective pressures.
When it comes to spintronics, there may be some room in the middle

Spintronic devices that utilize the spin degree of freedom of a charge carrier to store, process or transmit information, may be better performers than their traditional electronic counterparts if special properties of "spin" are exploited in the design. I review here the example of "single spin logic" which follows this principle. It can reduce power dissipation by several orders of magnitude and is the progenitor of today's spin based quantum logic gates. These devices are far easier to realize than "quantum computers", while much more likely to exhibit the advantages touted for spintronics than mere spin-based analogs of conventional transistors.
Current Status of Prospective Drug Utilization Review

BACKGROUND: The Omnibus Budget Reconciliation Act of 1990 offered the promise that prospective drug utilization review (pDUR) systems would improve the quality of drug prescribing and patient drug use. There is little evidence that this promise has been fulfilled. To the contrary, there is growing evidence that suboptimal use of drugs (in terms of preventable drug-related morbidity) is at least as costly as the prescription drugs themselves. Online computerized pDUR has been the subject of numerous critical examinations in the pharmacy and medical literature. Recent publications have sought to illustrate perceived shortcomings in the DUR systems currently in use. OBJECTIVES: We focus on the state of the art with regard to pDUR, what is known about its effectiveness, and how emerging technologies may change pDUR and consider the work that may be needed to establish its effectiveness. SUMMARY: A growing body of literature documents numerous problems and concerns with respect to the quality of DUR criteria, DUR alerts, and the response of health care professionals to these alerts. Problems with the current pDUR system can be grouped into those involving technical aspects (e.g., duplicate messaging from in-store and online systems, or message text limitations) and into those involving human aspects, specifically how pharmacists and other health care providers interpret and respond to potential drug therapy problem alerts generated by the electronic systems. CONCLUSIONS: DUR is a quality assurance system that holds promise as a tool that, if implemented effectively, could enhance appropriate drug use. We believe a more systematic approach to DUR is needed. Evaluation and management of public and private pDUR systems must link documentation of processes of care, such as pharmacists' cognitive services, patient interventions, etc. To address technical aspects, we strongly recommend (a) a national effort to validate DUR screen criteria relying upon evidence-based studies and (b) adoption of a minimal set of critical pDUR screen criteria by pharmacy service providers and third-party intermediaries, including pharmacy benefit managers. To address the human component of pDUR systems, we advocate (a) adoption of performance standards for pharmacists and (b) explicit remuneration for time spent identifying and responding to drug therapy problems.
Defaults and Normality in Causal Structures

A serious defect with the Halpern-Pearl (HP) definition of causality is repaired by combining a theory of causality with a theory of defaults. In addition, it is shown that (despite a claim to the contrary) a cause according to the HP condition need not be a single conjunct. A definition of causality motivated by Wright's NESS test is shown to always hold for a single conjunct. Moreover, conditions that hold for all the examples considered by HP are given that guarantee that causality according to (this version) of the NESS test is equivalent to the HP definition.
Increasing the Rigor of Case Study Evidence in Therapy Research

Over recent years, an increasing number of systematic case-based investigations of the process and outcomes of counseling and psychotherapy has been published. Nevertheless, case study knowledge continues to have a limited impact on therapy training, practice and policy. It is argued that improvement in the status of case study evidence requires further attention to ways of enhancing the rigor of case study reports. Strategies for strengthening the credibility of case study evidence are explored in relation to a range of methodological issues: the design and goals of case study research, quality criteria for evaluating the validity of case study findings, approaches to aggregating the conclusions of sets of cases, and the interpretation of case data. The paper concludes with a call for case study investigators to be active in asserting the value and relevance of this form of inquiry.
Electronic assessment: marking, monitoring and mediating learning

Electronic assessment can provide the opportunity to assist students to become more reflective learners. This is largely due to the immediacy of feedback that can be offered. This paper examines a number of recent developments, which exhibit innovation in electronic assessment together with specific reference to a suite of tools developed at the UK's Open University to support this process. It also raises the issue of what assessment practices should be automated and recommends the introduction of more formative computer-assisted assessment in higher education.
SIBRA: Scalable Internet Bandwidth Reservation Architecture

This paper proposes a Scalable Internet Bandwidth Reservation Architecture (SIBRA) as a new approach against DDoS attacks, which, until now, continue to be a menace on today's Internet. SIBRA provides scalable inter-domain resource allocations and botnet-size independence, an important property to realize why previous defense approaches are insufficient. Botnet-size independence enables two end hosts to set up communication regardless of the size of distributed botnets in any Autonomous System in the Internet. SIBRA thus ends the arms race between DDoS attackers and defenders. Furthermore, SIBRA is based on purely stateless operations for reservation renewal, flow monitoring, and policing, resulting in highly efficient router operation, which is demonstrated with a full implementation. Finally, SIBRA supports Dynamic Interdomain Leased Lines (DILLs), offering new business opportunities for ISPs.
Risk Factors for Poor Treatment Outcomes in Patients with MDR-TB and XDR-TB in China: Retrospective Multi-Center Investigation

Background The treatment of patients with MDR- and XDR-TB is usually more complex, toxic and costly and less effective than treatment of other forms of TB. However, there is little information available on risk factors for poor outcomes in patients with MDR- and XDR-TB in China. Methodology/Principal Findings We retrospectively analyzed the clinical records of HIV-negative TB Patients with culture-proven MDR- or XDR-TB who were registered from July 2006 to June 2011 at five large-scale Tuberculosis Specialized Hospitals in China. Among 1662 HIV-seronegative TB cases which were culture-positive for M. tuberculosis complex and had positive sputum-smear microscopy results, 965 cases (58.1%) were DR-TB, and 586 cases (35.3%) were classified as having MDR-TB, accounting for 60.7% of DR-TB. 169 cases (10.2%) were XDR-TB, accounting for 17.5% of DR-TB, 28.8% of MDR-TB. The MDR-TB patients were divided into XDR-TB group (n=169) and other MDR-TB group (non-XDR MDR-TB) (n=417). In total, 240 patients (40.95%) had treatment success, and 346 (59.05%) had poor treatment outcomes. The treatment success rate in other MDR-TB group was 52.2%, significantly higher than that in the XDR-TB group (13%, P<0.001). In multivariate logistic regression analysis, poor outcomes were associated with duration of previous anti-TB treatment of more than one year (OR, 0.077; 95% CI, 0.011-0.499, P<0.001), a BMI less than 18.5 kg/m2 (OR, 2.185; 95% CI, 1.372-3.478, P<0.001), XDR (OR, 13.368; 95% CI, 6.745-26.497, P<0.001), retreatment (OR, 0.171; 95% CI, 0.093-0.314, P<0.001), diabetes (OR, 0.305; 95% CI, 0.140-0.663, P=0.003), tumor (OR, 0.095; 95% CI, 0.011-0.795, P=0.03), decreased albumin (OR, 0.181; 95% CI, 0.118-0.295, P<0.001), cavitation (OR, 0.175; 95% CI, 0.108-0.286, P<0.001). Conclusions/Significance The patients with MDR-TB and XDR-TB have poor treatment outcomes in China.The presence of extensive drug resistance, low BMI, hypoalbuminemia, comorbidity, cavitary disease and previous anti-TB treatment are independent prognostic factors for poor outcome in patients with MDR-TB.
The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95

Fragile X syndrome (FXS) is a common inherited cause of mental retardation resulting from the absence of the fragile X mental retardation protein (FMRP). FMRP is thought to regulate the translation of target mRNAs, including its own transcript. Here we show that the levels of FMRP are rapidly up-regulated in primary cortical neurons in response to the type-I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydrophenylglycine. These changes require new protein synthesis but not transcription and are specific to mGluR activation. We also demonstrate that the mRNA for PSD-95, a scaffolding protein involved in synaptic plasticity, contains a highly conserved canonical binding site for FMRP within its 3′ UTR. Furthermore, PSD-95 is rapidly translated in response to S-3,5-dihydrophenylglycine. Finally, we show that these mGluR-dependent changes in PSD-95 expression are lost in neurons derived from FMRP knockout mice, a model of FXS. Taken together, these studies suggest that FMRP is required for mGluR-dependent translation of PSD-95 and provide insights into the pathophysiology of FXS.
Reaction of neuronal nitric-oxide synthase with 2,6-dichloroindolphenol and cytochrome c3+: influence of the electron acceptor and binding of Ca2+-activated calmodulin on the kinetic mechanism.

Binding of Ca(2+)-activated calmodulin (Ca(2+)-CaM) to neuronal nitric-oxide synthase (nNOS) increases the rate of 2,6-dichloroindolphenol (DCIP) reduction 2-3-fold and that of cytochrome c(3+) 10-20-fold. Parallel initial velocity patterns indicated that both substrates were reduced via two-half reactions in a ping-pong mechanism. Product and dead-end inhibition data with DCIP were consistent with an iso ping-pong bi-bi mechanism; however, product and dead-end inhibition studies with cytochrome c(3+) were consistent with the (two-site) ping-pong mechanism previously described for the NADPH-cytochrome P450 reductase-catalyzed reduction of cytochrome c(3+) [Sem, D. , and Kasper, C. (1994) Biochemistry 33, 12012--12021]. Dead-end inhibition by 2'-adenosine monophosphate (2'AMP) was competitive versus NADPH for both electron acceptors, although the value of the slope inhibition constant, K(is), was 25-30-fold greater with DCIP as the substrate than with cytochrome c(3+). The difference in the apparent affinity of 2'AMP is proposed to result from a rapidly equilibrating isomerization step that occurs in both mechanisms prior to the binding of NADPH. Thus, initial velocity, product, and dead-end inhibition data were consistent with a di-iso ping-pong bi-bi and an iso (two-site) ping-pong mechanism for the reduction of DCIP and cytochrome c(3+), respectively. The presence Ca(2+)-CaM did not alter the proposed kinetic mechanisms. The activated cofactor had a negligible effect on (k(cat)/K(m))(NADPH), while it increased (k(cat)/K(m))(DCIP) and (k(cat)/K(m))(cytc) 4.5- and 23-fold, respectively.
Prosodic effects of focus in Dutch declaratives

Seventeen speakers of Standard Dutch participated in a production experiment that investigated the effects of focus condition (broad, narrow, corrective focus) on the prosodic realization of nuclear accented words in declarative sentences. It was found that focus has an effect on the duration of onset and coda of the nuclear accented syllable as well as on the timing, scaling, and slope of f0 targets and movements. A significant effect exists mainly between broad focus accents on the one hand, and narrow and corrective focus accents on the other. The results are interpreted in terms of phonetic variation, but such that phonetic differences between these two conditions are to a large extent conventionalized.
Journal of Graph Algorithms and Applications a Healthy Critical Attitude: Revisiting the Results of a Graph Drawing Study

This paper reports on a series of three similar graph drawing empirical studies, and describes the results of investigating subtle variations on the experimental method. Its purpose is twofold: to report the results of the experiments, as well as to illustrate how easy it is to inadvertently make conclusions that may not stand up to scrutiny. While the results of the initial experiment were validated, instances of speculative conclusions and inherent bias were identified. This research highlights the importance of stating the limitations of any experiment, being clear about conclusions that are speculative, and not assuming that (even minor) experimental decisions will not affect the results.
Preliminary design examination of the ParalleX system from a software and hardware perspective

Exascale systems, expected to emerge by the end of the next decade, will require the exploitation of billion-way parallelism at multiple hierarchical levels in order to achieve the desired sustained performance. While traditional approaches to performance evaluation involve measurements of existing applications on the available platforms, such a methodology is obviously unsuitable for architectures still at the brainstorming stage. The prediction of the future machine performance is an important factor driving the design of both the execution hardware and software environment. A good way to start assessing the performance is to identify the factors challenging the scalability of parallel applications. We believe the root cause of these challenges is the incoherent coupling between the current enabling technologies, such as Non-Uniform Memory Access of present multicore nodes equipped with optional hardware accelerators and the decades older execution model, i.e., Communicating Sequential Processes (CSP). Supercomputing is in the midst of a much needed phase change and the High-Performance Computing community is slowly realizing the necessity for a new design dogma, as affirmed in the preliminary Exascale studies. In this paper, we present an overview of the ParalleX execution model and its complementary design efforts at the software and hardware levels, while including power draw of the system as the resource of utmost importance. Since the interplay of hardware and software environment is quickly becoming one of the dominant factors in the design of well integrated, energy efficient, large-scale systems, we also explore the implications of the ParalleX model on the organization of parallel computing architectures. We also present scaling and performance results for an adaptive mesh refinement application developed using a ParalleX-compliant runtime system implementation, HPX.
Results of the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial: A Behavioral Weight Loss Intervention in Overweight or Obese Breast Cancer Survivors.

PURPOSE Obesity increases risk for all-cause and breast cancer mortality and comorbidities in women who have been diagnosed and treated for breast cancer. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is the largest weight loss intervention trial among survivors of breast cancer to date. METHODS In this multicenter trial, 692 overweight/obese women who were, on average, 2 years since primary treatment for early-stage breast cancer were randomly assigned to either a group-based behavioral intervention, supplemented with telephone counseling and tailored newsletters, to support weight loss or a less intensive control intervention and observed for 2 years. Weight and blood pressure were measured at 6, 12, 18, and 24 months. Longitudinal mixed models were used to analyze change over time. RESULTS At 12 months, mean weight loss was 6.0% of initial weight in the intervention group and 1.5% in the control group (P<.001). At 24 months, mean weight loss in the intervention and control groups was 3.7% and 1.3%, respectively (P<.001). Favorable effects of the intervention on physical activity and blood pressure were observed. The weight loss intervention was more effective among women older than 55 years than among younger women. CONCLUSION A behavioral weight loss intervention can lead to clinically meaningful weight loss in overweight/obese survivors of breast cancer. These findings support the need to conduct additional studies to test methods that support sustained weight loss and to examine the potential benefit of intentional weight loss on breast cancer recurrence and survival.