Miracle-dz/UniFAR-FTUs huggingface dataset:
Modeling a Ryanodine Receptor N-terminal Domain Connecting the Central Vestibule and the Corner Clamp Region*

Background: High resolution structural information only covers 15% of the full-length sequence of RyR. Results: Pseudo-atomic structures are generated for RyR1 fragments 850–1,056 and RyR2 861–1,067, docked into cryo-EM maps, and supported by FRET experiments. Conclusion: The binding interface between RyR and FKBP consists of electrostatic contacts and contains mutations. Significance: The fragments docked into a domain that forms an intersubunit interaction with a phosphorylation domain. Ryanodine receptors (RyRs) form a class of intracellular calcium release channels in various excitable tissues and cells such as muscles and neurons. They are the major cellular mediators of the release of calcium ions from the sarcoplasmic reticulum, an essential step in muscle excitation-contraction coupling. Several crystal structures of skeletal muscle RyR1 peptide fragments have been solved, but these cover less than 15% of the full-length RyR1 sequence. In this study, by combining modeling techniques with sub-nanometer resolution cryo-electron microscopy (cryo-EM) maps, we obtained pseudo-atomic models for RyR fragments consisting of residues 850–1,056 in rabbit RyR1 or residues 861–1,067 in mouse RyR2. These fragments are docked into a domain that connects the central vestibule and corner clamp region of RyR, resulting in a good match of the secondary structure elements in the cryo-EM map and the pseudo-atomic models, which is also consistent with our previous mappings of GFP insertions by cryo-EM and with FRET measurements involving RyR and FK506-binding protein (FKBP). A combined model of the RyR fragment and FKBP docked into the cryo-EM map suggests that the fragment is positioned adjacent to the FKBP-binding site. Its predicted binding interface with FKBP consists primarily of electrostatic contacts and contains several disease-associated mutations. A dynamic interaction between the fragment and an RyR phosphorylation domain, characterized by FRET experiments, also supports the structural predictions of the pseudo-atomic models.
Sequence Analysis of Porcine Endogenous Retrovirus Long Terminal Repeats and Identification of Transcriptional Regulatory Regions

ABSTRACT Porcine cells express endogenous retroviruses, some of which are infectious for human cells. To better understand the replication of these porcine endogenous retroviruses (PERVs) in cells of different types and animal species, we have performed studies of the long terminal repeat (LTR) region of known gammaretroviral isolates of PERV. Nucleotide sequence determination of the LTRs of PERV-NIH, PERV-C, PERV-A, and PERV-B revealed that the PERV-A and PERV-B LTRs are identical, whereas the PERV-NIH and PERV-C LTRs have significant sequence differences in the U3 region between each other and with the LTRs of PERV-A and PERV-B. Sequence analysis revealed a similar organization of basal promoter elements compared with other gammaretroviruses, including the presence of enhancer-like repeat elements. The sequences of the PERV-NIH and PERV-C repeat element are similar to that of the PERV-A and PERV-B element with some differences in the organization of these repeats. The sequence of the PERV enhancer-like repeat elements differs significantly from those of other known gammaretroviral enhancers. The transcriptional activities of the PERV-A, PERV-B, and PERV-C LTRs relative to each other were similar in different cell types of different animal species as determined by transient expression assays. On the other hand, the PERV-NIH LTR was considerably weaker in these cell types. The transcriptional activity of all PERV LTRs was considerably lower in porcine ST-IOWA cells than in cell lines from other species. Deletion mutant analysis of the LTR of a PERV-NIH isolate identified regions that transactivate or repress transcription depending on the cell type.
Relationship between In Vitro Human Immunodeficiency Virus Type 1 Replication Rate and Virus Load in Plasma

ABSTRACT Although plasma human immunodeficiency virus type 1 (HIV-1) RNA concentration is a major determinant of the rate of HIV-1 disease progression, the reasons for variability in plasma virus loads among infected individuals are not fully understood. We conducted investigations with 15 HIV-1-infected individuals who were not receiving antiretroviral therapy to evaluate the hypothesis that HIV-1 replication rate in vitro is a significant determinant of plasma virus load. Virus could not be isolated from one subject. Two subjects were excluded because they had features previously associated with distinct plasma virus loads and altered rates of disease progression; one harbored a syncytium-inducing virus and the second was heterozygous for a 32-bp deletion from the CCR5 gene. HIV-1 replication rates were determined by culturing autologous virus isolates in phytohemagglutinin-treated peripheral blood mononuclear cells (PBMC) and determining the rate of p24 antigen production during the logarithmic phase of viral replication. The contribution of HIV-1 reverse transcriptase (RT) and protease (PR) alleles to replication capacity was assessed using recombinant viruses in a single-cycle infection assay. HIV-1 replication rates ranged from 0.15 to 0.76 log10 pg/ml/day and were reproducible within the same donor PBMC (coefficient of variation ± 4%). RT-PR replication capacity ranged from 14 to 95% of that of control virus and was linearly related to replication rate (r2 = 0.53; P = 0.007). Plasma HIV-1 RNA concentration was linearly related to replication rate (r2 = 0.71; P < 0.001) and RT-PR replication capacity (r2 = 0.44; P = 0.019). These data suggest that different RT-PR alleles are important determinants of HIV-1 replication rates and that HIV-1 replication rate explains much of the variability in plasma virus load in chronic HIV-1 infection.
Gene Expression Signatures of Seven Individual Human Embryonic Stem Cell Lines

Identification of molecular components that define a pluripotent human embryonic stem cell (hESC) provides the basis for understanding the molecular mechanisms regulating the maintenance of pluripotency and induction of differentiation. We compared the gene expression profiles of seven genetically independent hESC lines with those of nonlineage‐differentiated cells derived from each line. A total of 8,464 transcripts were expressed in all hESC lines. More than 45% of them have no yet‐known biological function, which indicates that a high number of unknown factors contribute to hESC pluripotency. Among these 8,464 transcripts, 280 genes were specific for hESCs and 219 genes were more than twofold differentially expressed in all hESC lines compared with nonlineage‐differentiated cells. They represent genes implicated in the maintenance of pluripotency and those involved in early differentiation. The chromosomal distribution of these hESC‐enriched genes showed over‐representation in chromosome 19 and under‐representation in chromosome 18. Although the overall gene expression profiles of the seven hESC lines were markedly similar, each line also had a subset of differentially expressed genes reflecting their genetic variation and possibly preferential differentiation potential. Limited overlap between gene expression profiles illustrates the importance of cross‐validation of results between different ESC lines.
Modafinil affects mood, but not cognitive function, in healthy young volunteers

Modafinil is a selective wakefulness‐promoting agent with beneficial effects in narcolepsy and conditions of sleep deprivation. In a double‐blind study we examined its effects in 30 healthy, non sleep‐deprived students (19 men and 11 women, aged 19–23 years), who were randomly allocated to placebo, 100 or 200 mg modafinil and 3 h later completed 100 mm visual analogue scales relating to mood and bodily symptoms, before and after an extensive battery of cognitive tests (pen and paper and CANTAB). There were no significant differences between the three treatment groups on any of the cognitive tests used in this study. There was a significant post‐treatment change in the factor measuring ‘somatic anxiety’ and in individual ratings of ‘shaking’, ‘palpitations’, ‘dizziness’, ‘restlessness’, ‘muscular tension’, ‘physical tiredness’ and ‘irritability’, which was mainly due to significantly higher ratings of somatic anxiety in the 100 mg group compared with the other two groups. Further changes in mood were revealed after the stress of cognitive testing, with the 100 mg group showing greater increases in the ‘psychological anxiety’ and the ‘aggressive mood’ factors (as measured from the Bond and Lader scales). Copyright © 2002 John Wiley & Sons, Ltd.
Approach for a demand compliant choice of induction machines used in roller conveyors

The dimensioning of the drives of roller conveyors used in intralogistic facilities has to meet three main criteria, defined by minimum requirements on the dynamics, safety and durability considerations and the energy efficiency of the conveyor system. In order to investigate the influence of rated machine power of commonly used induction machines on these dimensioning criteria, a study on the most common transient mechanical incidents and most dangerous electrical failures was performed, using an analytical simulation model of the coupled system of the drive itself as well as the conveyer-system comprising the rollers, the drive-belt and the conveyed boxes.
Ovarian volume in pre- and perimenopausal women: a population-based study *

ObjectiveTo evaluate the relationship between ovarian volume and age, hormonal levels, obesity, and phase of menstrual cycle in pre- and perimenopausal women. DesignA study was carried out with 98 women from the general population who were not receiving drugs known to interfere with hormonal levels. Right and left ovary volume was measured by ultrasound. Blood samples were drawn for estradiol, follicle-stimulating hormone, and luteinizing hormone determinations. ResultsFourteen women were excluded because of the presence of ovarian cysts. Mean ovarian volume for pre- and perimenopausal women was 7.1 ± 3.1 cm3. There was no statistical difference in ovarian volume related to the phases of the menstrual cycle. Ovarian volume was significantly smaller in all age groups over 40 years compared with the 35-to-39 age group (P < 0.05). No association was observed between ovarian volume and body mass index. In turn, age (P = 0.013) and follicle-stimulating hormone levels (P = 0.002) showed a significant negative correlation, and luteinizing hormone showed a significant positive correlation with ovarian volume (P = 0.005). ConclusionsOvarian volume was smaller in pre- and perimenopausal women aged 40 years and older in relation with younger women. The current standard measurements of ovarian volume by transvaginal ultrasound should be reevaluated for pre- and perimenopausal women between 40 and 55 years of age.
Caesarean delivery and risk of stillbirth in subsequent pregnancy: a retrospective cohort study in an English population

Objective Two recent studies indicate an increased risk of stillbirth in the pregnancy that follows a pregnancy delivered by caesarean section. In this study, we report an analysis designed to test the hypothesis that delivery by caesarean section is a risk factor for explained or unexplained stillbirth in any subsequent pregnancy. We also report on the proportion of stillbirths in our study population, which may have been attributable to previous delivery by caesarean section.
Video Games for Entertainment and Education

While the morality of games and their ethical implications in an educational context have been questioned from the very beginning of game technology evolution (e.g., McLean, 1978), video games1 have become not only increasingly attractive for players of both genders (Burke, 2000), various ethnicities (Bickham et al., 2003), and ages (IDSA, 2003), but are also utilized more and more for educational purposes (see, for example, the annual serious games summit, http://www.seriousgamessummit.com/). Thus, studying the education potential for this new and controversial medium is of tremendous importance. Although comprehensive effect theories on the specific impact of video game playing are still missing, more than a decade of research provides us with an impressive body of literature demonstrating mostly negative, but also significant positive effects (see, for introduction, Mitchell & Savill-Smith, 2004). The majority of research has focused on the potential negative effects of video game playing; however, this is due to an abundance of studies on violent games and does not reflect the potential of video games as a medium. While Weber, Ritterfeld, and Kostygina (chap. 24) discuss the findings on violent video game playing, hostility, and aggression, Lee and Peng (chap. 22) as well as Lieberman (chap. 25) give a comprehensive overview on effect studies with an emphasis on learning, and Durkin (chap. 21) further elaborates the benefits of video game playing for adolescents. This chapter focuses on the potential of video game playing to facilitate developmental processes through the unique combination of interactive entertainment and learning, while at the same time taking a rather theoretical perspective. The term “developmental processes” refers to an understanding of media usage and effects in the context of human development. Human development is the result of continuous transactions between a person’s biological constitution and his or her physical, social, and media environment over the life span. According to this perspective, media usage is not random but already reflects the developmental processes of a user who is selecting some media or content over others, and processing it according to his or her developmental capacities, previous
Evidence of early subchondral bone changes in the meniscectomized guinea pig. A densitometric study using dual-energy X-ray absorptiometry subregional analysis.

OBJECTIVE Subchondral bone changes are thought to be an important aetiological element in the pathogenesis of osteoarthritis (OA). To confirm this hypothesis in the meniscectomized (MNX) guinea pig model, bone densitometry was performed in the subchondral bone of the distal femur. METHODS MNX and sham-operated (SH) guinea pigs were studied 1 and 3 months after partial meniscectomy at the medial side of the left knee. Bone mineral density was measured at the lateral (BMD-L) and medial (BMD-M) sides of the distal femur using dual-energy X-ray absorptiometry (DXA). BMD-M was then compared to the bone volume evaluated by histomorphometry at the medial epiphyseal part of the proximal tibia (BV-M). RESULTS One month after operation, in MNX animals left femur BMD-M was significantly lower than in the contralateral femur (-9%, P< 0.01) and than in the left femur of SH (-11%, P< 0.01). By contrast, 3 months after meniscectomy BMD-M was higher in the femur than in the contralateral femur (+4%, P< 0.05); BV-M tended to be higher on the left than on the right side (+4%, P< 0.06), and was significantly correlated with BMD-M at the 2 grouped time points: r=0.74 (P< 0.001). CONCLUSIONS These data emphasize the usefulness of DXA as a simple tool to assess subchondral bone changes at the OA-affected side of the femur and reveal typical variations of bone metabolism in the initiation of OA pathology in the MNX guinea pig: early bone loss at the subchondral level followed by increased bone density.
Bacterial Reductive Dissolution of Crystalline Fe(III) Oxide in Continuous-Flow Column Reactors

ABSTRACT Bacterial reductive dissolution of synthetic crystalline Fe(III) oxide-coated sand was studied in continuous-flow column reactors in comparison with parallel batch cultures. The cumulative amount of aqueous Fe(II) exported from the columns over a 6-month incubation period corresponded to (95.0 ± 3.7)% (n = 3) of their original Fe(III) content. Wet-chemical analysis revealed that only (6.5 ± 3.2)% of the initial Fe(III) content remained in the columns at the end of the experiment. The near-quantitative removal of Fe was visibly evidenced by extensive bleaching of color from the sand in the columns. In contrast to the column reactors, Fe(II) production quickly reached an asymptote in batch cultures, and only (13.0 ± 2.2)% (n = 3) of the Fe(III) oxide content was reduced. Sustained bacterial-cell growth occurred in the column reactors, leading to the production and export of a quantity of cells 100-fold greater than that added during inoculation. Indirect estimates of cell growth, based on the quantity of Fe(III) reduced, suggest that only an approximate doubling of initial cell abundance was likely to have occurred in the batch cultures. Our results indicate that removal of biogenic Fe(II) via aqueous-phase transport in the column reactors decreased the passivating influence of surface-bound Fe(II) on oxide reduction activity, thereby allowing a dramatic increase in the extent of Fe(III) oxide reduction and associated bacterial growth. These findings have important implications for understanding the fate of organic and inorganic contaminants whose geochemical behavior is linked to Fe(III) oxide reduction.
Current Understanding of Drug Disposition in Kidney Disease

Patients with chronic kidney disease (CKD) represent 13% of the American population. CKD has been shown to significantly alter drug disposition of nonrenally eliminated drugs. Indeed, modifications in the expression and function of intestinal and hepatic drug metabolism enzymes and uptake and efflux transporters have been reported. Uremic toxins, inflammatory cytokines, and parathyroid hormone have been implicated as causes. These changes can have an important clinical impact on drug disposition and lead to unintended toxicity if they are administered without dose adjustment in patients with impaired kidney function. This review summarizes recent preclinical and clinical studies and presents the current understanding of the effect of CKD on drug absorption, distribution, metabolism, and excretion.
Stratégies de chasse chez le manchot royal : prise alimentaire et optimisation du comportement de plongée

Les strategies de recherche alimentaire sont des comportements qui determinent la quantite d'energie qu'un individu peut extraire de son environnement et allouer a sa survie et a sa reproduction. L'evolution favorise donc les strategies d'approvisionnement optimales, c'est a dire celles qui maximisent la quantite d'energie extraite par rapport a l'energie investie par unite de temps. Chez les predateurs marins a respiration aerienne, l'optimisation consiste a ajuster le comportement respiratoire en surface afin de maximiser la proportion du temps qui peut etre passee a se nourrir en apnee. Pour tester les predictions d'optimalite en milieu naturel, il est necessaire de pouvoir quantifier d'une part la prise alimentaire et d'autre part la depense energetique. Avec le manchot royal comme modele, nous avons cherche a denombrer le nombre de proies capturees en utilisant simultanement plusieurs methodes, dont la mesure de l'angle d'ouverture du bec et un indice associe a la locomotion : l'acceleration dynamique. La mesure de l'ouverture du bec nous a fourni des informations detaillees sur le comportement de prise alimentaire, et deux types d'ouvertures attribuees aux tentatives et aux captures ont ete mis en evidence. L'acceleration dynamique s'est revelee etre un indice plus facile a obtenir, mais de qualite inferieure ne permettant pas de realiser un denombrement des ingestions. Par ailleurs, nous avons tente d'estimer la depense energetique des manchots en plongee par la mesure de l'acceleration dynamique et de la frequence cardiaque, mais des problemes techniques nous ont empeches d'y parvenir. L'etude du comportement de plongee selon le taux de rencontre avec des proies montre que, conformement aux predictions, les manchots royaux reduisent le temps passe en surface et le temps perdu en transit lorsque la ressource est plus abondante, afin d'augmenter la proportion du temps passe a chasser. Cependant, un veritable bilan ne peut etre etabli que si le gain et les depenses sont mesurees precisement. L'echelle temporelle a prendre en compte n'est peut-etre pas celle d'une plongee unique car la physiologie de la plongee et de la prise alimentaire impliquent des mecanismes complexes (echanges gazeux, thermoregulation, digestion) auxquels il n'est pas aise d'avoir acces.
Malarial hepatitis.

AIMS AND OBJECTIVE To study the clinical, biochemical and histopathological changes in the liver of patients of Plasmodium falciparum malaria with jaundice. MATERIAL AND METHOD This study was conducted on 50 PBF confirmed cases of Plasmodium falciparum malaria with jaundice. Detailed history, clinical examination, biochemical parameters for liver function test and blood for hepatitis B and C was done in all patients. Liver biopsy was done for detailed histopathological examination in all the 20 patients having serum bilirubin between 3 to 10 mg%. All patients were treated by IV/oral quinine using standard regimen. RESULTS Age of the patient was ranging from 15-45 years. All patients had jaundice, 70% had pallor, 56% had splenomegaly, 48% had hepatomegaly and 24% of cases had coma. Based on serum bilirubin level, the patients were categorized in group A (18 patients, serum bilirubin < 3 mg%), in group B (20 patients, serum bilirubin 3-10 mg%) and in group C (12 patients, serum bilirubin >10 mg%). Histopathological examination done in all the 20 patients of group B, showed evidence of swollen hepatocytes (100%), malarial pigment deposition (75%), inflammatory infiltrates (60%), congestion of hepatocyte (50%) alongwith centrizonal necrosis in 25% of cases. CONCLUSION The evidence of predominant conjugated hyperbilirubinemia, increased levels of AST and ALT along with evidence of hepatocellular necrosis in histopathological examination are strong evidence of gross hepatocytic dysfunction in patients of Plasmodium falciparum malaria with jaundice. Therefore the term malarial hepatitis should not be taken as a misnomer.
The Sustained Influence of an Error on Future Decision-Making

Post-error slowing (PES) is consistently observed in decision-making tasks after negative feedback. Yet, findings are inconclusive as to whether PES supports performance accuracy. We addressed the role of PES by employing drift diffusion modeling which enabled us to investigate latent processes of reaction times and accuracy on a large-scale dataset (>5,800 participants) of a visual search experiment with emotional face stimuli. In our experiment, post-error trials were characterized by both adaptive and non-adaptive decision processes. An adaptive increase in participants’ response threshold was sustained over several trials post-error. Contrarily, an initial decrease in evidence accumulation rate, followed by an increase on the subsequent trials, indicates a momentary distraction of task-relevant attention and resulted in an initial accuracy drop. Higher values of decision threshold and evidence accumulation on the post-error trial were associated with higher accuracy on subsequent trials which further gives credence to these parameters’ role in post-error adaptation. Finally, the evidence accumulation rate post-error decreased when the error trial presented angry faces, a finding suggesting that the post-error decision can be influenced by the error context. In conclusion, we demonstrate that error-related response adaptations are multi-component processes that change dynamically over several trials post-error.