Miracle-dz/UniFAR-FTUs huggingface dataset:
Loss of Folic Acid Exporter Function with Markedly Augmented Folate Accumulation in Lipophilic Antifolate-resistant Mammalian Cells*

We previously described a 1,000-fold pyrimethamine-resistant Chinese hamster ovary cell line (PyrR100) which retains parental dihydrofolate reductase activity and methotrexate (MTX) sensitivity. This study characterizes the basis for the 14-fold decrease in folic acid and leucovorin concentrations required for clonogenic growth of PyrR100 cells relative to parental AA8 cells. Under conditions in which folic acid reduction was blocked by trimetrexate, PyrR100 cells displayed relative to parental AA8 cells a: 1) 17- and 5-fold increase in the net transport of folic acid and MTX, respectively; 2) 23- and 5-fold decrease in the efflux rate constant for folic acid and MTX, respectively; and 3) 2-fold increase in folic acid influx with no significant change in MTX influx. The markedly increased net folic acid transport in PyrR100 cells could not be explained by cellular folic acid binding, mitochondrial sequestration, polyglutamylation, nor by a decreased membrane potential. The effect of energy deprivation on folic acid and MTX transport in both cell lines was quite different. Glucose and pyruvate deprivation nearly abolished the increase in net folic acid transport in PyrR100 cells. In contrast, energy deprivation increased net MTX transport in AA8 cells, whereas no change was seen with PyrR100 cells. Furthermore, while folic acid influx in PyrR100 and AA8 cells was markedly reduced with energy deprivation, MTX influx was not affected. Provision of glucose and pyruvate to energy-deprived cells resulted in a rapid onset of MTX efflux from parental AA8 cells but not from PyrR100 cells. Taken together these results indicate that the markedly enhanced net transport of folic acid and MTX in PyrR100 cells is largely due to the complete loss of exit pump activity. Furthermore, the energy source that sustains the augmented levels of folic acid appears linked to the influx process and is distinct from the energy source that sustains MTX gradients under these conditions. We conclude that the loss of folic acid efflux is an efficient means of augmenting cellular uptake of folate cofactors and subsequent survival on picomolar folate concentrations. This constitutes the first demonstration of the loss of folic acid exporter activity in mammalian cells as a response to lipophilic antifolate selective pressure.
Sex differences in fitness and selection for centric fusions between sex-chromosomes and autosomes.

A model of centric fusions between the X or Y chromosome and an autosome carrying a selected locus is studied. It is assumed that fusions are not associated with any fitness effects, and that all chromosomes disjoin regularly from their homologues. It is shown that a necessary condition for the fusion to be favoured is that there is a selectively maintained sex difference in allele frequencies at the selected locus. If this condition is satisfied, the initial rate of increase of a rare Y-autosome fusion is about three times that of an X-autosome fusion, with the same parameter values. Computer calculations of the final equilibrium states reached by populations containing such fusions were done.
Comparison of a Static with a Mobile Spacer in Total Knee Infection

Patients with infections of a total knee arthroplasty were stratified by medical status. Twenty-six knees in 26 patients treated with a static antibiotic-impregnated polymethylmethacrylate block spacer before 1995 were compared with 22 knees in 22 patients treated after 1995 with a mobile articulating spacer. Both groups were treated with 6 weeks of parenteral antibiotics and had reimplantation within 6 to 12 weeks after placement of the spacer. Followup for the patients who had block spacers was an average 7.5 years (range, 2.8–12.7 years), and followup for the patients with a mobile spacer was an average of 3.8 years (range, 2.6–6.4 years). Results showed that the patients with the mobile spacers had significantly better average range of motion at followup compared with patients who had block spacers (107.8° compared with 93.7°). The reinfection rate was the same between the two groups at 36 months, 7.6% (two of 26) for the patients with block spacers and 9% (two of 22) for the patients with mobile spacers. Extended followup available for the patients who had block spacers revealed a late reinfection rate of 23% (six of 26) with a new organism. There was no difference in the reinfection rate, with new or old organisms, in healthy hosts compared with patients with as many as two medical problems.
The quality of function of renal allografts is associated with donor age

The quality of renal allograft function was assessed by prospective measurement of creatinine clearance at 1 year (n=197) and at 3 years (n=115) after cadaveric renal transplantation in a cohort of 268 patients treated with triple therapy immunosuppression. Donor age (P<0.0012) and recipient age (P<0.01) were independently associated with creatinine clearance both at 1 and at 3 years. In patients with donor age above 50 years and recipient age above 45 years, the mean creatinine clearance was 32.7 (SD 10.4) ml/min (n=27). When the donor age was below 30 years and recipient age below 45 years, the mean creatinine clearance was 55.6 (SD 14.4) ml/min (n=47, P<0.001). However, in these patients there was no significant association between graft function and many of the factors known to influence graft survival, such as HLA matching, sensitisation of the recipient, and the occurrence of rejection. In conclusion, the quality of renal allograft function declined with increasing donor and recipient age in our patients, whilst immunological factors were not significantly associated with function in surviving grafts.
Metal Mixtures Modeling Evaluation project: 1. Background

Despite more than 5 decades of aquatic toxicity tests conducted with metal mixtures, there is still a need to understand how metals interact in mixtures and to predict their toxicity more accurately than what is currently done. The present study provides a background for understanding the terminology, regulatory framework, qualitative and quantitative concepts, experimental approaches, and visualization and data‐analysis methods for chemical mixtures, with an emphasis on bioavailability and metal–metal interactions in mixtures of waterborne metals. In addition, a Monte Carlo–type randomization statistical approach to test for nonadditive toxicity is presented, and an example with a binary‐metal toxicity data set demonstrates the challenge involved in inferring statistically significant nonadditive toxicity. This background sets the stage for the toxicity results, data analyses, and bioavailability models related to metal mixtures that are described in the remaining articles in this special section from the Metal Mixture Modeling Evaluation project and workshop. It is concluded that although qualitative terminology such as additive and nonadditive toxicity can be useful to convey general concepts, failure to expand beyond that limited perspective could impede progress in understanding and predicting metal mixture toxicity. Instead of focusing on whether a given metal mixture causes additive or nonadditive toxicity, effort should be directed to develop models that can accurately predict the toxicity of metal mixtures. Environ Toxicol Chem 2015;34:726–740. © 2014 SETAC
Depot risperidone in the outpatient management of bipolar disorder: a 2-year study of 10 patients

Nonadherence with pharmacotherapy occurs frequently in bipolar patients, and is a common cause of relapse. Depot formulations of first-generation antipsychotic medications have been shown to reduce manic relapses during maintenance therapy in bipolar patients, but appear to increase liability for depressive episodes. A depot formulation of risperidone has recently become commercially available, but to date there is little evidence regarding its efficacy or safety in bipolar patients. Ten outpatients with bipolar I or II disorder, with a predominantly depressive course of illness, were prescribed risperidone Consta as an adjunct to mood stabilizing and other medications in routine clinical practice, and were followed during 2 years of maintenance therapy. The number of mood episodes, including depressive episodes, decreased in all patients compared with an equivalent pretreatment period. No patient required hospitalization for a mood episode. The number and doses of concomitant medications was reduced in most patients risperidone Consta was well tolerated, with minimal to modest weight gain, absent or reduced extrapyramidal symptoms, and few other side effects. Clinicians may consider risperidone Consta as an option in patients with refractory bipolar illness, including those with a predominantly depressive course, and particularly in patients' nonadherence with prescribed medications.
Childhood Exposure to Caregiver Suicidal Behavior and Risk for Adult Suicide Attempts: Findings from a National Survey

The objective of this study was to investigate the association between exposure to caregiver suicidality and subsequent adult suicide attempt (SA). Data came from the National Epidemiologic Survey on Alcohol and Related Conditions Wave 2 (n = 34,653). Respondents were asked if they had a caregiver attempt or complete suicide during childhood. Logistic regression examined associations between SA and caregiver suicidality. Compared to individuals with no suicidality, risk for lifetime SA was higher for individuals that were exposed to a SA (15.6%, [OR] = 5.86, 95% [CI] = 4.57–7.51) and for those who experienced a death by suicide (6.1%, [OR] = 2.08, CI = 1.32–3.26]. Associations remained significant after controlling for demographics, Axis I and II disorders and childhood adversity. Individuals with exposure to suicidality are at increased odds for SA.
Factors related to the intended use of ERP systems

ERP systems have a strong effect on the business operation of large multinational corporations as well as on small and medium enterprises. When implementing these systems, it is very important how the users in the organization will accept them and what attitude they will take towards them. This paper integrates some of the propositions of the Expectation Confirmation Theory (ECT) and Technology Acceptance Model (TAM) to research the factors related to the intended use of the ERP system by students of Business Studies. It investigates the correlation of the perceived usefulness of the ERP system, perceived ease of using it, and computer anxiety in users to their satisfaction with the used ERP system. Additionally, the assumed positive correlation between students' satisfaction with the ERP system and their intention to use such systems in the future is justified and proved according to the EC theory. The research involved 180 third year students of the vocational program at the Faculty of Economics in Split, who may be potential users of the ERP system. During the winter semester of 2010/11, the respondents were using a concrete ERP system in the course called Information Systems. While attending the course, they got to know the basic functions of eight ERP modules. Although the research used an occasional pattern of respondents, it can be stated that the statistical significance of the obtained results points to the main factors related to the intended usage of ERP systems by business studies students as their prospective users.
Adaptation as a premise for perceptual-based multimedia communications

The vision of a new generation of network communication architectures, which deliver a Quality of Service based on intelligent decisions about the interactions that typically take place in a multimedia scenario, encourages researchers to look at novel ways of matching user-level requirements with parameters characterising underlying network performance. In this paper, we suggest an integrated architecture that makes use of the objective-technical information provided by the designer and the Quality of Perception metric for intelligent decision making in the construction of user-centred adaptable communication protocols. This approach, based on the Analytic Hierarchy Process, incorporates not only classical Quality of Service considerations, but indeed, user preferences as well, and opens the possibility for the suggested protocols to dynamically adapt based on a changing operating environment. Results show that the proposed approach does provide an enhanced user multimedia experience when compared with legacy communication protocols.
Activation of granulocytes by anti‐neutrophil cytoplasmic antibodies (ANCA): a FcγRII‐dependent process

ANCA have been demonstrated to induce the respiratory burst in primed neutrophils. In this study we have extended the investigations on neutrophil activation by ANCA directed against proteinase 3 (PR3). Myeloperoxidase (MPO) and lactoferrin (LF), and we have analysed the underlying mechanisms. All three ANCA antigens were expressed on the cell surface of primed neutrophils. Superoxide production assayed by both cytochrome c reduction and oxidation of dihydrorhodamine 123, was induced by heterologous polyclonal anti‐MPO and anti‐LF antibodies, and ANCA‐positive plasma samples. Induction of superoxide production was dose‐dependent. F(ab)2 fragments did not induce the respiratory burst. Blockade of Fc receptors by specific oAbs showed that anti‐FcγRII antibodies were able to turn off the ANCA‐induced respiratory burst, whereas anti‐FcγRII antibodies did not. Plasma samples that induced the respiratory bursl did not differ from samples that did not induce superoxide production with respect to ANCA titre, but had higher levels of the lgG3 subclass of ANCA. Levels of the other subclasses of ANCA were comparable between those samples. We conclude that ANCA‐induced activation of primed neutrophils is FcγRII‐dependent, and appears to be facilitated by antibodies of the IgG3 subclass.
Association between higher order visual processing abilities and a history of motor vehicle collision involvement by drivers ages 70 and over.

PURPOSE To examine in a population-based sample of 2000 drivers aged 70 years and older, the independent association between higher order visual processing impairment and motor vehicle collision (MVC) rate during the prior 5 years. METHODS Three higher order visual processing screening tests were administered since previous research found associations between impaired performance on these screens and MVC involvement. They included an estimate of visual processing speed under divided attention conditions (useful field of view [UFOV] subset 2); Trails B, a paper and pencil test of visual processing speed also involving problem solving, executive function, and working memory; and the visual closure subtest of the Motor Free Visual Perception Test (MVPT) examining the ability to recognize objects only partially visible. Potentially confounding variables were also assessed including demographics, general cognitive status, visual acuity, and contrast sensitivity. MVC involvement was determined by accident reports from the Alabama Department of Public Safety, and driving exposure was estimated from the Driving Habits Questionnaire. RESULTS MVC rates (for at fault and all MVCs) were significantly higher for those older drivers with impairments in any of the three visual processing screening tests. After adjustment for potentially confounding influences, the association between MVC rate and Trails B remained significant, whereas the association with MVPT and UFOV did not. CONCLUSIONS This population-based study of drivers aged 70 years and older suggests that a paper and pencil test assessing higher order visual processing skills is independently associated with a recent history of MVC involvement.
From Neurons to Neighborhoods: Old and New Challenges for Developmental and Behavioral Pediatrics

ABSTRACT. Rapidly advancing research in neurobiology and the behavioral and social sciences, coupled with dramatic changes in the social and economic circumstances under which families are raising young children, has created a highly dynamic context for early childhood policy, service delivery, and child rearing in the United States. A recent report from the National Research Council and the Institute of Medicine, From Neurons to Neighborhoods: The Science of Early Childhood Development, presents a critical analysis of that complex knowledge base and a set of recommendations designed to close the gap between what we know and what we do to promote the healthy development of young children. This article examines the report through the lens of Developmental & Behavioral pediatrics and highlights both exciting opportunities and sobering challenges.
Food, Culture, and Family: Exploring the Coordinated Management of Meaning Regarding Childhood Obesity

Increased rates of childhood obesity combined with more accessible information about the relationship between diet, physical activity and inactivity, and chronic diseases suggest the need for analyzing the complex process of receiving and transmitting messages related to child feeding practices. This study examined the perceptions of childhood obesity within 1 multiethnic community, the Commonwealth of the Northern Mariana Islands. In particular, through the use of focus groups, individuals indicated that sociocultural, familial, and official nutritional messages were most influential to their health care behaviors. The coordinated management of meaning (CMM) theory was used to gain insight into how individuals negotiate competing messages occurring at different levels of meaning. Given its focus on cultural influences (parallel to the concepts of archetypes), CMM proved especially relevant for understanding child feeding beliefs, values, attitudes, and practices in diverse ethnic populations. Implications for future health communication research that might draw from a CMM approach were identified, as well as pragmatic endeavors that focus on the development, implementation, and evaluation of culturally appropriate interventions in the prevention of childhood obesity.
Normal tension glaucoma: risk factors pertaining to a sick eye in a sick body

Normal tension glaucoma is a clinical condition, as- sociated with a pathologically excavated optic disc and characteristic glaucomatous visual field loss that represents a diagnostic and therapeutic challenge for ophthalmologists. Apart from intraocular pressure, the clinical course of the disease shares similarities with that of primary open angle glaucoma. Therefore, some authors have questioned whether normal tension glaucoma is artificially distinct from primary open angle glaucoma by intraocular pressure, or represents a subset of disease in which patients show different patterns of optic disc damage and quantity and quality of visual field loss, possibly as a result of different mechanisms of damage. The literature appears to support the hypothesis that nor- mal tension glaucoma and primary open angle glaucoma represent a continuum of open angle glaucomas, in which increased intraocular pressure is the predominant causative risk factor in primary open angle glaucoma, and factors in addition to intraocular pressure are important in normal tension glaucoma. This review will be published in 2 parts. Part 1 discusses the risk factors related to normal tension glaucoma. Part 2 will discuss a specific entity in normal tension glaucoma — disc hemorrhage. A Brief Report provides some approaches to the management of normal tension glaucoma.
A novel subset of B7-H3+CD14+HLA-DR−/low myeloid-derived suppressor cells are associated with progression of human NSCLC

Myeloid-derived suppressor cells (MDSC) potently inhibit antitumor immune responses, and thereby promoti tumor progression and metastasis. However, the nature of human tumor-infiltrating MDSC remains poorly characterized. Here, we find B7-H3 is exclusively expressed on a subset of intratumoral CD14+HLA-DR−/low MDSC but absent from adjacent normal lung tissues of patients with non-small cell lung carcinoma (NSCLC). Cytokine analysis revealed that B7-H3+CD14+HLA-DR−/low MDSC (B7-H3+MDSC) produced higher levels of IL-10 and TNFα but lower levels of IL-1β and IL-6 when compared with B7-H3−CD14+HLA-DR−/low myeloid-derived suppressor cells (B7-H3−MDSC). In a murine lung cancer model, B7-H3+MDSCs were found only in the tumor microenvironment and their frequencies increased during tumor progression. Clinical data analysis indicated that a higher frequency of B7-H3+MDSCs was associated with reduced recurrence-free survival in patients with NSCLC. Taken together, we identify a novel subset of MDSCs within the tumor microenvironment that fosters tumor progression.
A Specific Developmental Deficit in Obsessive-Compulsive Disorder: The Example of the Wolf Man

In this paper I suggest that the origins of the “contamination/cleaning” form of obsessive compulsive disorder (OCD) include a developmental history characterized by marked overprotectiveness allied with parental failure to respond to core aspects of the child's personal reality. The combined effect of these parental behaviors is likely to impede the establishment of a mature conception of the boundary between inner and outer worlds. The consequence of such a deficiency is the persistence of the magical form of thinking which is essential to the production of OCD. In addition, the individual is left with a disruption of personality development, the main features of which include timidity and falseness. The Wolf Man provides an example of both the characteristic development history in OCD and its consequences. Treatment based on this theoretical background may provide benefit not predicted by current psychoanalytic pessimism.