Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

ABSTRACT The Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (−)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (−)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility of eight clonal lines of P. falciparum derived from the 106/1 strain, each containing a unique pfcrt allele, to four Cinchona stereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of the Cinchona alkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC50 ratio of (−)/(+) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (−) and (+) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and other Cinchona alkaloids.
Ferritin Expression in Rat Hepatocytes and Kupffer Cells after Lead Nitrate Treatment

Lead nitrate induces hepatocyte proliferation and subsequent apoptosis in rat livers. Iron is a constituent of heme and is also required for cell proliferation. In this study, the expression of ferritin light-chain (FTL), the major iron storage protein, was investigated in rat livers after a single intravenous injection of lead nitrate. Western blotting and immunohistochemistry revealed that FTL was increased in hepatocytes around the central veins and strongly expressed in nonparenchymal cells. Some FTL-positive nonparenchymal cells were identified as Kupffer cells that were positive for CD68. FTL-positive Kupffer cells occupied about 60% of CD68-positive cells in the periportal and perivenous areas. The relationships between FTL expression and apoptosis induction or the engulfment of apoptotic cells were examined. TUNEL-positive cells were increased in the treatment group, and enhanced expression of milk fat globule EGF-like 8 was demonstrated in some Kupffer cells and hepatocytes, indicating enhanced apoptosis induction and phagocytosis of apoptotic cells. FTL-positive Kupffer cells were not detected without lead nitrate treatment or in rat livers treated with clofibrate, which induces hepatocyte proliferation but not apoptosis. These results suggest that FTL expression in Kupffer cells after lead treatment is dependent on phagocytosis of apoptotic cells.
Health locus of control, values, and weight reduction behavior.

This study, in a natural setting, attempted to predict health-related behavior on the basis of the personality construct locus of control. Thirty-six participants in a weight reduction program completed the Multidimensional Health Locus of Control Scale (MHLC) and a value scale that included the values of "health" and "physical appearance. " Subjects also were asked to determine their weight loss goal in pounds. Three months later their progress was assessed, and 22 of the subjects again completed the MHLC and value surveys. Consistent with the first hypothesis, those subjects who perceived their health status to be under the control of powerful others and valued health and/or physical appearance highly weighed in more frequently at the weight center than did the other subjects. Contrary to the second hypothesis, subjects did not become more "internal" as a result of successful weight loss. Subjects who valued physical appearance highly were found to have higher "external" control beliefs. Theoretical significance and practical applications of the findings are discussed.
Alfalfa Root Nodule Invasion Efficiency Is Dependent on Sinorhizobium melilotiPolysaccharides

ABSTRACT The soil bacterium Sinorhizobium meliloti is capable of entering into a nitrogen-fixing symbiosis with Medicago sativa (alfalfa). Particular low-molecular-weight forms of certain polysaccharides produced by S. meliloti are crucial for establishing this symbiosis. Alfalfa nodule invasion by S. meliloti can be mediated by any one of three symbiotically important polysaccharides: succinoglycan, EPS II, or K antigen (also referred to as KPS). Using green fluorescent protein-labeled S. meliloti cells, we have shown that there are significant differences in the details and efficiencies of nodule invasion mediated by these polysaccharides. Succinoglycan is highly efficient in mediating both infection thread initiation and extension. However, EPS II is significantly less efficient than succinoglycan at mediating both invasion steps, and K antigen is significantly less efficient than succinoglycan at mediating infection thread extension. In the case of EPS II-mediated symbioses, the reduction in invasion efficiency results in stunted host plant growth relative to plants inoculated with succinoglycan or K-antigen-producing strains. Additionally, EPS II- and K-antigen-mediated infection threads are 8 to 10 times more likely to have aberrant morphologies than those mediated by succinoglycan. These data have important implications for understanding how S. meliloti polysaccharides are functioning in the plant-bacterium interaction, and models are discussed.
Time-dependent changes in bone, placental, intestinal, and hepatic alkaline phosphatase activities in serum during human pregnancy.

To measure changes in bone alkaline phosphatase (EC 3.1.3.1) activity in serum as a function of duration of pregnancy, we adapted our existing alkaline phosphatase (ALP) isoenzyme assay (which has been used to measure bone, hepatic, and intestinal ALP activities in serum, in the absence of placental ALP) to allow quantification of individual ALP isoenzyme activities in the presence of placental ALP. The resulting CV for repeat measurements of bone ALP activity in artificial isoenzyme mixtures ranged from 23% for samples in which the bone isoenzyme represented 7% of total ALP activity to 11% for samples in which bone ALP accounted for 48% of total ALP activity. Values for repeat determinations of bone ALP activity in human serum samples (i.e., including samples obtained from pregnant women and from nonpregnant controls) varied by an average of 18%. We find, in initial applications of this method, that (a) the amount of bone ALP activity in serum is increased during pregnancy (P less than .001), and remains increased at six weeks postpartum, in non-lactating women (P less than .001), and (b) bone ALP activity at term was not significantly different in pregnant women with pre-eclampsia, diabetes, premature rupture of membranes, or premature labor, compared with normal pregnancies at term. Our data support the hypothesis that maternal bone formation may be increased during pregnancy.
RNF121 Inhibits Angiogenic Growth Factor Signaling by Restricting Cell Surface Expression of VEGFR‐2

Ligand stimulation promotes downregulation of RTKs, a mechanism by which RTKs, through the ubiquitination pathway are removed from the cell surface, causing a temporary termination of RTK signaling. The molecular mechanisms governing RTK trafficking and maturation in the endoplasmic reticulum (ER)/Golgi compartments are poorly understood. Vascular endothelial growth factor receptor‐2 (VEGFR‐2) is a prototypic RTK that plays a critical role in physiologic and pathologic angiogenesis. Here we demonstrate that Ring Finger Protein 121 (RNF121), an ER ubiquitin E3 ligase, is expressed in endothelial cells and regulates maturation of VEGFR‐2. RNF121 recognizes newly synthesized VEGFR‐2 in the ER and controls its trafficking and maturation. Over‐expression of RNF121 promoted ubiquitination of VEGFR‐2, inhibited its maturation and resulted a significantly reduced VEGFR‐2 presence at the cell surface. Conversely, the shRNA‐mediated knockdown of RNF121 in primary endothelial cells reduced VEGFR‐2 ubiquitination and increased its cell surface level. The RING Finger domain of RNF121 is required for its activity toward VEGFR‐2, as its deletion significantly reduced the effect of RNF121 on VEGFR‐2. Additionally, RNF121 inhibited VEGF‐induced endothelial cell proliferation and angiogenesis. Taken together, these data identify RNF121 as a key determinant of angiogenic signaling that restricts VEGFR‐2 cell surface presence and its angiogenic signaling.
The Relationship between Training Satisfaction and the Readiness to Transfer Learning: The Mediating Role of Normative Commitment

Organizations are becoming increasingly demanding in regard to training cost rationalization and justification, and to the associated result achievement obligation. In practice, these pressures result in the introduction of more or less adequate efficiency indicators in relation to training programs. The goal of this study is to understand the relationship between training and training efficiency indicators at the individual level, using a mediation model. This study proposes a three-factor mediation model estimated using a databank of 578 cases. The results first show a positive relation between training satisfaction and normative commitment. Normative commitment has a positive effect on readiness to transfer learning and a negative effect on absenteeism. Theoretical and practical implications are discussed in light of these findings.
Glucocorticoid sensitivity in inflammatory bowel disease

Abstract Glucocorticoid therapy is used in the treatment of moderate to severe inflammatory bowel disease (IBD). However, IBD patients display varying degrees of glucocorticoid sensitivity: some respond rapidly to the given treatment, whereas others show no response, or develop steroid therapy-related side-effects. At present, we cannot foresee whether the patient will benefit from the administered glucocorticoids or not. During the past 10 years, numerous attempts have been made to provide the means to identify and predict steroid therapy-sensitive patients in advance. This would be vital to avoid unnecessary glucocorticoid exposure in patients that do not respond to treatment with steroids. Here we provide a concise review of recent developments regarding the molecular basis of glucocorticoid sensitivity in IBD patients and the methods employed to assess it.
Multilevel mixed effects parametric survival models using adaptive Gauss-Hermite quadrature with application to recurrent events and IPD meta-analysis

Multilevel mixed effects survival models are used in the analysis of clustered survival data, such as repeated events, multi-centre clinical trials, and Individual Participant Data (IPD) meta-analyses, to investigate heterogeneity in baseline risk and covariate effects. In this paper we extend parametric frailty models including the exponential, Weibull, and Gompertz proportional hazards models, and the log logistic, log normal and generalised gamma accelerated failure time models, to allow any number of normally distributed random effects. Furthermore, we extend the flexible parametric survival model of Royston and Parmar, modelled on the log cumulative hazard scale using restricted cubic splines, to include random effects, whilst also allowing for non-proportional hazards (timedependent effects). Maximum likelihood is used to estimate the models utilising adaptive or non-adaptive Gauss-Hermite quadrature. The methods are evaluated through simulation studies representing clinically plausible scenarios of a multi-centre trial and IPD meta-analysis, showing good performance of the estimation method. The flexible parametric mixed effects model is illustrated using a dataset of patients with kidney disease and repeated times to infection, and an IPD metaanalysis of prognostic factor studies in patients with breast cancer. User-friendly Stata software is provided to implement the methods. Copyright c © 0000 John Wiley & Sons, Ltd.
Bladder cancer subtypes defined by genomic alterations

Bladder tumours comprise a heterogeneous group with respect to both histopathology and clinical behaviour. Although many features of bladder tumours have been studied, assessment of risk for recurrence and progression to invasive disease is not precise and response to specific therapies cannot be predicted accurately. It is anticipated that a thorough knowledge of the molecular alterations that are involved in the development and progression of bladder cancer will lead to greater predictive power and the application of novel individualized therapies. This review summarizes the current state of knowledge of genomic alterations found in transitional cell carcinoma and putative precursor lesions.
Mesoporous silica nanoparticles for reducing hemolytic activity towards mammalian red blood cells.

Recent reports on the design of silica-based nanomaterials, such as sol–gel, colloidal, and mesoporous silica nanoparticles (MSNs), have shown promising potential in utilizing these materials for controlled release, drug delivery, and other biotechnological applications. Several studies have demonstrated that the biocompatibility of these silica nanoparticles with a variety of cell types in vitro is fairly high. However, the low in vitro cytotoxicity offers no guarantee on the desired high biocompatibility in vivo. In fact, silica materials with amorphous particle morphology are known to cause the hemolysis of mammalian red blood cells (RBCs). This kind of hemolytic behavior raised serious bio-safety concerns regarding the application of amorphous silica for drug delivery involving intravenous administration and transport. Various explanations for the hemolytic effect have been proposed, including the generation of reactive oxygen species induced by the surface of silica, denaturation of membrane proteins through electrostatic interactions with silicate, and the high affinity of silicate for binding with the tetra-alkyl ammonium groups that are abundant in the membranes of RBCs. While the exact mechanism is still under investigation, most researchers agree that the hemolytic activity of silica is related to surface silanol groups. For example, a recent study by Murashov et al. demonstrated that the hemolytic activity of amorphous silica is proportional to the concentration of surface silanol groups of these solid materials. Given the fact that most, if not all, of the aforementioned silica nanoparticles with defined shapes and sizes also have abundant silanols on their surfaces, it is important to investigate the hemolytic properties of these materials with RBCs for potential intravenous applications. Herein, we describe an investigation of the hemolytic properties of a previously reported MSN material with mammalian
The Close AGN Reference Survey (CARS): What is causing Mrk 1018’s return to the shadows after 30 years?

We recently discovered that the active galactic nucleus (AGN) of Mrk 1018 has changed optical type again after 30 yr as a type 1 AGN. Here we combine Chandra, NuStar, Swift, Hubble Space Telescope and ground-based observations to explore the cause of this change. The 2–10 keV flux declines by a factor of ~8 between 2010 and 2016. We show with our X-ray observation that this is not caused by varying neutral hydrogen absorption along the line-of-sight up to the Compton-thick level. The optical-UV spectral energy distributions are well fit with a standard geometrically thin optically thick accretion disc model that seems to obey the expected L ~ T^4 relation. It confirms that a decline in accretion disc luminosity is the primary origin for the type change. We detect a new narrow-line absorber in Lyα blue-shifted by ~700 km s^(-1) with respect to the systemic velocity of the galaxy. This new Lyα absorber could be evidence for the onset of an outflow or a companion black hole with associated gas that could be related to the accretion rate change. However, the low column density of the absorber means that it is not the direct cause for Mrk 1018’s changing-look nature.
Infusion of intrathecal baclofen for generalized dystonia in cerebral palsy.

UNLABELLED Generalized dystonia occurs in 15 to 25% of persons with cerebral palsy (CP) and responds poorly to medical and surgical treatments. OBJECT After the authors observed a woman whose dystonic CP was dramatically improved by continuous infusion of intrathecal baclofen, they designed this pilot study to evaluate the effect of this treatment on a group of patients with dystonic CP. METHODS The authors assessed the short-term response to intrathecal baclofen infusion in 12 patients with dystonic CP. An intrathecal catheter was inserted percutaneously and connected to an external microinfusion pump. The infusion began at a rate of 100 microg/day and was increased by 50 microg every 12 hours until the dystonia abated, adverse effects occurred, or the dose reached 900 microg/day with no improvement. Two observers, one blinded and one not blinded to the patient's treatment status, viewed videotapes made before and after the infusions and graded the dystonia in eight body regions, using a 5-point scale. Overall and regional scores were compared by using Wilcoxon signed-rank tests. CONCLUSIONS Dystonia diminished in 10 of 12 patients whose average daily dose of intrathecal baclofen was 575 microg. Overall dystonia scores and scores for the extremities, trunk, and cervical regions were significantly better after infusion (p = 0.003). The two observers' scores were not significantly different. Programmable infusion pumps were subsequently implanted in eight patients for long-term therapy and improvement was sustained in six (p < 0.05). Intrathecal baclofen infusion is a promising treatment option for generalized dystonia associated with CP. The effects of intrathecal baclofen infusion on dystonia can be evaluated by using short-term continuous infusions.
Pulmonary Mechanics and the Work of Breathing in the Lizard, Gekko Gecko

Measurements of pulmonary mechanics made on anaesthetized specimens of the Tokay gecko Gekkogecko (Linne), indicate that both static and dynamic pulmonary mechanics are dominated by the mechanics of the body cavity and chest wall. The lungs are relatively large and compliant and offer little resistance to air flow at any of the ventilation frequencies (f) used in this study. The body wall is relatively stiff and becomes less compliant with increasing ventilation frequency and with increasing tidal volume (VT) at the higher frequencies. The vast majority of the work performed in breathing is used to overcome elastic forces in the chest wall resisting lung inflation. This work increases exponentially with increases in volume. As a consequence, in terms of total ventilation, the most economic breathing pattern is a high frequency, low tidal volume pattern in which changes in minute ventilation (VE) are most economically produced solely by changes in f. Because reductions in tidal volume drastically reduce alveolar ventilation volume while dead space remains constant, the same arguments do not apply to alveolar minute ventilation (VA). In terms of alveolar minute ventilation, there is an optimum combination of f and VT for each level of VA, with changes in VA being most economically produced by almost equal changes in both f and VT
Role of Total, Red, Processed, and White Meat Consumption in Stroke Incidence and Mortality: A Systematic Review and Meta‐Analysis of Prospective Cohort Studies

Background Previous meta‐analyses on meat intake and risk of stroke did not report the effect of white meat (poultry meat, excluding fish) and did not examine stroke incidence and mortality separately. We aimed to investigate the relationship of total (red and processed meat), red (unprocessed or fresh red meat), and processed (processed red meat) consumption along with white meat on risk of stroke incidence and mortality. Methods and Results Articles were identified from databases and reference lists of relevant studies up to October 28, 2016. We selected prospective cohort studies on meat consumption specified by types of meat and stroke incidence and mortality reporting relative risks and 95% confidence intervals. The pooled relative risk was estimated using the random‐effects model. Based on the inclusion criteria, 10 articles containing 15 studies (5 articles with 7 studies including 9522 cases of stroke incidence and 254 742 participants and 5 articles with 8 studies containing 12 999 cases of stroke mortality and 487 150 participants) were selected for quantitative synthesis. The pooled relative risks (95% confidence intervals) for total, red, processed and white meat consumption and total stroke incidence were 1.18 (1.09–1.28), 1.11 (1.03–1.20), 1.17 (1.08–1.25), and 0.87 (0.78–0.97), respectively. Total meat consumption (0.97 [0.85–1.11]) and red meat consumption 0.87 (0.64–1.18) were not significantly associated with stroke‐related death. Conclusions The relationship between meat intake and risk of stroke may differ by type of meat. Recommendations for replacing proportions of red and processed meats to white meat for the prevention of stroke may be considered in clinical practice.
Competition as a selective mechanism for larger offspring size in guppies

Highly competitive environments are predicted to select for larger offspring. Guppies Poecilia reticulata from low-predation populations have evolved to make fewer, larger offspring than their counterparts from high-predation populations. As predation co-varies with the strength of competition in natural guppy populations, here I present two laboratory experiments that evaluate the role of competition in selecting for larger offspring size. In the first experiment, paired groups of large and small newborns from either a high- or a low-predation population were reared in mesocosms under a high- or a low-competition treatment. While large newborns retained their size advantage over small newborns in both treatments, newborn size increased growth only in the high-competition treatment. Moreover, the increase in growth with size was greater in guppies derived from the low-predation population. In the second experiment, pairs of large and small newborns were reared in a highly competitive environment until reproductive maturity. Small size at birth delayed maturation and the effect of birth size on male age of maturity was greater in the low-predation population. These results support the importance of competition as a selective mechanism in offspring size evolution.