Miracle-dz/UniFAR-FTUs huggingface dataset:
Reverse Conservation Analysis Reveals the Specificity Determining Residues of Cytochrome P450 Family 2 (CYP 2)

The concept of conservation of amino acids is widely used to identify important alignment positions of orthologs. The assumption is that important amino acid residues will be conserved in the protein family during the evolutionary process. For paralog alignment, on the other hand, the opposite concept can be used to identify residues that are responsible for specificity. Assuming that the function-specific or ligand-specific residue positions will have higher diversity since they are under evolutionary pressure to fit the target specificity, these function-specific or ligand-specific residues positions will have a lower degree of conservation than other positions in a highly conserved paralog alignment. This study assessed the ability of reverse conservation analysis to identify function-specific and ligand-specific residue positions in closely related paralog. Reverse conservation analysis of paralog alignments successfully identified all six previously reported substrate recognition sites (SRSs) in cytochrome P450 family 2 (CYP 2). Further analysis of each subfamily identified the specificity-determining residues (SDRs) that have been experimentally found. New potential SDRs were also predicted and await confirmation by further experiments or modeling calculations. This concept may be also applied to identify SDRs in other protein families.
Plagues in Animal Populations [Abridged]

carcases, together with the identification and slaughter of infected flocks, were successful and outbreaks fell from a peak of 2,222 in 1947 to 172 in 1950, and none has been recorded since 1953. Meanwhile infection with less lethal strains had been recorded in 1948 and 55 outbreaks due to one of these occurred in East Anglia in 1950. In these outbreaks mortality was low though morbidity was high, the clinical picture presenting a disease with more marked respiratory symptoms. From 1951 to 1963 epidemics in various parts of the country were controlled and the majority of counties were maintained free of infection apart from minor outbreaks which were quickly over. Wales and Scotland remained virtually free of the disease. Only in Lancashire and East Anglia did incidence remain high and even in these areas with a very high density of stock the policy of eradication was successful in eliminating infection for long periods (Callender 1958). The importance of the poultry slaughtering industry in the epidemiology of the disease in this period must be stressed, and attention drawn to the fact that the movement of soiled crates, vehicles and personnel associated with the collection of birds for slaughter repeatedly seeded infection into clean flocks over the whole of England. With the development since 1959 of large broiler flocks and intensive units the eradication policy has become more and more costly to enforce. The number of outbreaks climbed to over 3,000 in 1962 and the total compensation figure over the years has amounted to about £20 million. In 1962 the Government accepted the main recommendation of a Departmental Committee (Committee on Fowl Pest Policy 1962) and in April 1963 the policy of eradication by slaughter was changed to one of control by the use of inactivated vaccines. Since then 400 million doses of vaccine have been distributed and moderate success can be claimed for the new policy (Loxam 1964, unpublished report). Large areas of East Anglia, where an 80% vaccinationcoverhas been attained, have remained virtually free of infection. The main epidemiological change has been a decrease in the dissemination of the disease by intensive units. When disease occurs in vaccinated birds in these units the multiplication of virus is so limited that massive spread is no longer seen.
Automatic operator configuration in the synthesis of pipelined architectures

An algorithm is presented for automating the choice of operator configurations while synthesizing a pipelined design. The chosen configuration set must meet the design constraints of the pipeline (number of stages and stage time) while minimizing the total cost(s) (e.g., area, power) of the design. The configuration algorithm is first used with heuristics to make initial operator choices for insertion of stage latches and then to choose optimally configurations within each stage. The new algorithm allows the designer to specify the number of stages in the pipeline as well as the clocking frequency of each stage. It also permits the use of totally arbitrary timing functions-that is, an implementation may produce different output times if the ready times of its various inputs are rearranged. <<ETX>>
Requirement of Rho‐family GTPases in the invasion of Type 1‐piliated uropathogenic Escherichia coli

Bladder infections caused by uropathogenic Esche‐richia coli (UPEC) depends on the ability of E. coli to express type 1 pili. The adhesive component of the pilus, FimH, mediates the invasion of E. coli into the bladder epithelium, a mechanism that facilitates the survival and persistence of E. coli in the bladder. The invasion mechanism requires actin polymerization, focal adhesion kinase phosphorylation and PI 3‐kinase activation as well as the formation of FAK/PI 3‐kinase and downstream vinculin/α‐actinin complexes. In this study, we report a role for Rho‐GTPase family members, namely RhoA, Cdc42 and Rac1, in the invasion process. Internalization of type 1‐piliated E. coli (fimH+) and FimH‐coated micro‐spheres was inhibited by compactin, a pan‐Rho‐GTPase inhibitor and dominant negative isoforms of Rac1 and Cdc42. Expression of active Rac1 induced an internalization of E. coli that was insensitive to wortmannin and genistein. Expression of constitutively active Cdc42 induced the formation of FAK/PI 3‐kinase and vinculin/α‐actinin complexes whereas active Rac1 induced only a vinculin/α‐actinin complex. Taken together, these data suggest that FimH‐mediated invasion is dependent on GTP‐binding protein activity that involves Cdc42 and PI 3‐kinase activation probably upstream of Rac1.
An Evaluation of Microkernel-Based Virtualization for Embedded Real-Time Systems

Devices for the mobile market have to satisfy a set of challenging constraints. In addition to the classical power, reliability and cost constraints, modern devices often have to be open to third party applications and at the same time provide a closed and secure environment for system functionality. In current systems, this antagonism is solved by maintaining a physical separation of subsystems with contrary constraints. Virtualization technology is a promising solution to safely merge conflicting subsystems on a single processor which leads to huge cost benefits and higher flexibility. Microkernel based hyper visors are an attractive choice for virtualization, due to their reliability and robustness. However, the involvement of real-time constraints remains a challenging factor. In this paper, we investigate how the security and isolation features of the L4/Fiasco microkernel impact real-time applications by comparing thread switching times and interrupt latencies to those of a conventional Real-time Operating System (RTOS). In addition, we demonstrate that microkernel based systems require significantly more cache resources than traditional systems. Finally, we investigate the performance loss caused by cache and TLB interference imposed by an application subsystem which runs in parallel to the real-time subsystem.
LAS CONDUCTAS QUE ALTERAN LA CONVIVENCIA EN LAS CLASES DE EDUCACIÓN FÍSICA

El objetivo de este articulo es identificar y comparar la percepcion de las conductas que alteran la convivencia en las clases de educacion fisica entre alumnado y profesorado de la provincia de Toledo. Para ello 86 docentes y 447 discentes de educacion secundaria obligatoria participaron en el estudio y completaron la adaptacion espanola de un instrumento que describe 59 conductas inadecuadas que pueden surgir en las clases, desde las mas leves hasta las mas graves. Los resultados sugieren que existe desacuerdo entre la percepcion de alumnado y profesorado en cuanto a la frecuencia con la que se identifican las conductas de indisciplina en el transcurso de las clases. Los descriptivos revelan tambien que las conductas disruptivas, presiden el ambiente de aprendizaje en las clases, y las conductas de indisciplina leves y moderadas se perciben como las que se producen con mas frecuencia en las sesiones
Adjunctive effects of systemic amoxicillin and metronidazole with scaling and root planing: a randomized, placebo controlled clinical trial.

AIMS The objective of this study was to investigate the effect of the systemic administration of metronidazole and amoxicillin as an adjunct to initial periodontal therapy in patients with moderate to severe chronic periodontitis. METHODS AND MATERIALS This randomized, double blind, placebo controlled parallel study involved 50 adult patients with untreated periodontitis who were randomly assigned to receive either a full-mouth scaling and root planing along with systemic metronidazole and amoxicillin (T group) or scaling and root planing with a placebo (P group). Clinical measurements including probing depth (PD), clinical attachment levels (CAL), Plaque Index (PI), and Bleeding Index (BI) were recorded at baseline and six to eight weeks after therapy. The deepest pocket was selected and samples for microbiological testing were taken. Patients received coded study medications of either 500 mg amoxicillin in combination with 250 mg metronidazole or an identical placebo every eight hours for seven days following scaling and root planing. RESULTS There was a significant change in PD (P=0.0001), CAL (P=0.00001), PI (P<0.05), and BI (P<0.05) in the T group compared to the placebo group after therapy. Parallel to the clinical changes, treatment significantly reduced the number of Actinobacillus actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), and P. intermedia (Pi) compared with baseline in the T group (P=0.003, 0.021 and 0.0001, respectively). However, in the P group only the Pi colony count was reduced significantly (P=0.0001). After therapy, there was a significant difference between the T and P groups in the number of patients negative for Aa, Pg, and Pi (Pv = 0.033). CONCLUSIONS The significant differences between treatment and placebo groups are in line with other studies and support the considerable adjunctive benefits of the combination of amoxicillin and metronidazole in the treatment of chronic periodontitis.
Use of a Covered Stent Modification to Produce a Transcatheter Valve: Laboratory and Animal Testing

Stent-based transcatheter valves continue to require large sheaths inappropriate for deployment in children. Low-profile covered stent valves (CSVs) were constructed by removing triangular sections from two sides of partially expanded Palmaz P308 stents before covering the stents with 0.1 mm polytetrafluoroethylene. Valves were carefully crimped onto balloon catheters and deployed in a pulsatile flow loop. With fixed afterload and pump output, flow, degree of stenosis, effect on pulse pressure, and ease of deployment were determined for each valve. In vivo transcatheter feasibility studies were then performed by disabling the aortic valve of two 25-kg pigs, and deploying transcatheter CSVs into their descending aorta. All transcatheter valves deployed consistently via sheaths three French sizes larger than the recommended sheath for their balloon and none created significant obstruction. With the bicuspid and supravalvar CSVs, the flow was 64% and 79% (respectively) of a commercially available valve. Angiograms revealed excellent acute CSV function after deployment with only mild regurgitation and without significant obstruction to systolic flow. Although long-term testing is required, a modified CSV design may have utility in low-profile pediatric transcatheter valve replacement.
Sequoia: Programming the Memory Hierarchy

We present Sequoia, a programming language designed to facilitate the development of memory hierarchy aware parallel programs that remain portable across modern machines featuring different memory hierarchy configurations. Sequoia abstractly exposes hierarchical memory in the programming model and provides language mechanisms to describe communication vertically through the machine and to localize computation to particular memory locations within it. We have implemented a complete programming system, including a compiler and runtime systems for cell processor-based blade systems and distributed memory clusters, and demonstrate efficient performance running Sequoia programs on both of these platforms
Biophysical Aspects of Resource Acquisition and Competition in Algal Mixotrophs

Mixotrophic organisms combine autotrophic and heterotrophic nutrition and are abundant in both freshwater and marine environments. Recent observations indicate that mixotrophs constitute a large fraction of the biomass, bacterivory, and primary production in oligotrophic environments. While mixotrophy allows greater flexibility in terms of resource acquisition, any advantage must be traded off against an associated increase in metabolic costs, which appear to make mixotrophs uncompetitive relative to obligate autotrophs and heterotrophs. Using an idealized model of cell physiology and community competition, we identify one mechanism by which mixotrophs can effectively outcompete specialists for nutrient elements. At low resource concentrations, when the uptake of nutrients is limited by diffusion toward the cell, the investment in cell membrane transporters can be minimized. In this situation, mixotrophs can acquire limiting elements in both organic and inorganic forms, outcompeting their specialist competitors that can utilize only one of these forms. This advantage can be enough to offset as much as a twofold increase in additional metabolic costs incurred by mixotrophs. This mechanism is particularly relevant for the maintenance of mixotrophic populations and productivity in the highly oligotrophic subtropical oceans.
The Nonstationary Dynamics of Fitness Distributions: Asexual Model with Epistasis and Standing Variation

Various models describe asexual evolution by mutation, selection, and drift. Some focus directly on fitness, typically modeling drift but ignoring or simplifying both epistasis and the distribution of mutation effects (traveling wave models). Others follow the dynamics of quantitative traits determining fitness (Fisher’s geometric model), imposing a complex but fixed form of mutation effects and epistasis, and often ignoring drift. In all cases, predictions are typically obtained in high or low mutation rate limits and for long-term stationary regimes, thus losing information on transient behaviors and the effect of initial conditions. Here, we connect fitness-based and trait-based models into a single framework, and seek explicit solutions even away from stationarity. The expected fitness distribution is followed over time via its cumulant generating function, using a deterministic approximation that neglects drift. In several cases, explicit trajectories for the full fitness distribution are obtained for arbitrary mutation rates and standing variance. For nonepistatic mutations, especially with beneficial mutations, this approximation fails over the long term but captures the early dynamics, thus complementing stationary stochastic predictions. The approximation also handles several diminishing returns epistasis models (e.g., with an optimal genotype); it can be applied at and away from equilibrium. General results arise at equilibrium, where fitness distributions display a “phase transition” with mutation rate. Beyond this phase transition, in Fisher’s geometric model, the full trajectory of fitness and trait distributions takes a simple form; robust to the details of the mutant phenotype distribution. Analytical arguments are explored regarding why and when the deterministic approximation applies.
An intrinsic value system for developing multiple invariant representations with incremental slowness learning

Curiosity Driven Modular Incremental Slow Feature Analysis (CD-MISFA;) is a recently introduced model of intrinsically-motivated invariance learning. Artificial curiosity enables the orderly formation of multiple stable sensory representations to simplify the agent's complex sensory input. We discuss computational properties of the CD-MISFA model itself as well as neurophysiological analogs fulfilling similar functional roles. CD-MISFA combines 1. unsupervised representation learning through the slowness principle, 2. generation of an intrinsic reward signal through learning progress of the developing features, and 3. balancing of exploration and exploitation to maximize learning progress and quickly learn multiple feature sets for perceptual simplification. Experimental results on synthetic observations and on the iCub robot show that the intrinsic value system is essential for representation learning. Representations are typically explored and learned in order from least to most costly, as predicted by the theory of curiosity.
Diversity of bacterial type II toxin–antitoxin systems: a comprehensive search and functional analysis of novel families

Type II toxin–antitoxin (TA) systems are generally composed of two genes organized in an operon, encoding a labile antitoxin and a stable toxin. They were first discovered on plasmids where they contribute to plasmid stability by a phenomenon denoted as ‘addiction’, and subsequently in bacterial chromosomes. To discover novel families of antitoxins and toxins, we developed a bioinformatics approach based on the ‘guilt by association’ principle. Extensive experimental validation in Escherichia coli of predicted antitoxins and toxins increased significantly the number of validated systems and defined novel toxin and antitoxin families. Our data suggest that toxin families as well as antitoxin families originate from distinct ancestors that were assembled multiple times during evolution. Toxin and antitoxin families found on plasmids tend to be promiscuous and widespread, indicating that TA systems move through horizontal gene transfer. We propose that due to their addictive properties, TA systems are likely to be maintained in chromosomes even though they do not necessarily confer an advantage to their bacterial hosts. Therefore, addiction might play a major role in the evolutionary success of TA systems both on mobile genetic elements and in bacterial chromosomes.
Fiber-modified adenovirus-mediated suicide gene therapy can efficiently eliminate bladder cancer cells in vitro and in vivo

Adenovirus-mediated gene therapy is a promising strategy for bladder cancer treatment. However, the loss of the coxsackie and adenovirus receptor (CAR) in bladder cancer cells decreases the infection efficiency of the therapeutic adenovirus. In this study, we constructed an Arg-Gly-Asp (RGD)-modified adenovirus, RGDAd-UPII-TK, that carries a suicide gene called HSV-TK that is driven by a human UPII promoter. Then, we tested the bladder cancer specificity of the UPII promotor and the expression of the HSV-TK protein. Additionally, we observed a potent cytotoxic effects of RGDAd-UPII-TK and ganciclovir (GCV) on bladder cancer as demonstrated by reduced cell survival and morphology changes in vitro. Furthermore, we confirmed that RGDAd-UPII-TK in combination with a GCV injection could significantly reduce the established T24 tumor growth and increase apoptosis in vivo. Altogether, our results indicated that the recombinant adenovirus RGDAd-UPII-TK could target bladder cancer through valid gene therapy.
MANAGEMENT OF HIV CARE IN HARD-TO-REACH PATIENT POPULATIONS * —

People who inject drugs face stigmatization by society in general, and also by healthcare workers. This creates incentives for individuals with addiction to conceal their drug use, which can interfere with optimal medical care. There are several common misconceptions about individuals who use injection drugs, including the belief that they do not care about their health. The reality is that substance use is a complex disorder that includes biological, behavioral, and social aspects. Drug users are concerned about their health. There are several opportunities to connect patients with HIV infection and substance use problems to medical care, including community outreach programs, addiction treatment centers, and counseling-testingreferral sites. One of the most important points of contact with healthcare for many of these individuals is in the correctional system. In Rhode Island, where there is routine testing of almost all prisoners upon incarceration, approximately 33% of all people in the state with HIV have been identified during incarceration. Most states do not routinely test their incarcerated populations for HIV. Specialized programs to enhance HIV care in individuals who have recently been released from prison have been shown to retain a large proportion of patients in medical care for more than 1 year after prison discharge. Many clinicians assume that HIV-infected patients with addiction are poor candidates for antiretroviral therapy. These individuals are thought to be unlikely to adhere to treatment and to be at high risk for the development of drug-resistant HIV strains. However, there is evidence that there is little or no difference between injection drug users and nonusers in the development of drug-resistant HIV. A modified directly observed therapy approach, adapted from the directly observed therapy paradigm of tuberculosis treatment, may help to improve plasma viral load, CD4 cell counts, and other clinical outcomes in some difficult-to-reach patients with HIV infection and substance use disorders. (Adv Stud Med. 2006;6(3A):S123-S129)
The structure of cyclin H: common mode of kinase activation and specific features

The crystal structure of human cyclin H refined at 2.6 Å resolution is compared with that of cyclin A. The core of the molecule consists of two repeats containing five helices each and forming the canonical cyclin fold also observed in TFIIB. One hundred and thirty‐two out of the 217 Cα atoms from the cyclin fold can be superposed with a root‐mean‐square difference of 1.8 Å. The structural homology is even higher for the residues at the interface with the kinase, which is of functional significance, as shown by our observation that cyclin H binds to cyclin‐dependent kinase 2 (cdk2) and that cyclin A is able to activate cdk7 in the presence of MAT1. Based on this superposition, a new signature sequence for cyclins was found. The specificity of the cyclin H molecule is provided mainly by two long helices which extend the cyclin fold at its N‐ and C‐termini and pack together against the first repeat on the side opposite to the kinase. Deletion mutants show that the terminal helices are required for a functionally active cyclin H.