Miracle-dz/UniFAR-FTUs huggingface dataset:
Involvement of the mutated M protein in altered budding polarity of a pantropic mutant, F1-R, of Sendai virus

Wild-type Sendai virus buds at the apical plasma membrane domain of polarized epithelial MDCK cells, whereas a pantropic mutant, F1-R, buds at both the apical and basolateral domains. In F1-R-infected cells, polarized protein transport and the microtubule network are impaired. It has been suggested that the mutated F and/or M proteins in F1-R are responsible for these changes (M. Tashiro, J. T. Seto, H.-D. Klenk, and R. Rott, J. Virol. 67:5902-5910, 1993). To clarify which gene or mutation(s) was responsible for the microtubule disruption which leads to altered budding of F1-R, MDCK cell lines containing the M gene of either the wild type or F1-R were established. When wild-type M protein was expressed at a level corresponding to that synthesized in virus-infected cells, cellular polarity and the integrity of the microtubules were affected to some extent. On the other hand, expression of the mutated F1-R M protein resulted in the formation of giant cells about 40 times larger than normal MDCK cells. Under these conditions, the effects on the microtubule network were enhanced. The microtubules were disrupted and polarized protein transport was impaired as indicated by the nonpolarized secretion of gp80, a host cell glycoprotein normally secreted from the apical domain, and bipolar budding of wild-type and F1-R Sendai viruses. The mutated F glycoprotein of F1-R was transported bipolarly in cells expressing the F1-R M protein, whereas it was transported predominantly to the apical domain when expressed alone or in cells coexpressing the wild-type M protein. These findings indicate that the M protein of F1-R is involved in the disruption of the microtubular network, leading to impairment of cellular polarity, bipolar transport of the F glycoprotein, and bipolar budding of the virus.
HIF–prolyl hydroxylases and cardiovascular diseases

Prolyl hydroxylases belong to the family of iron- and 2-oxoglutamate-dependent dioxygenase enzyme. Several distinct prolyl hydroxylases have been identified. The hypoxia-inducible factor (HIF) prolyl hydroxylase termed prolyl hydroxylase domain (PHD) enzymes play an important role in oxygen regulation in the physiological network. There are three isoforms that have been identified: PHD1, PHD2 and PHD3. Deletion of PHD enzymes result in stabilization of HIFs and offers potential treatment options for many ischemic disorders such as peripheral arterial occlusive disease, myocardial infarction, and stroke. All three isoforms are oxygen sensors that regulate the stability of HIFs. The degradation of HIF-1α is regulated by hydroxylation of the 402/504 proline residue by PHDs. Under hypoxic conditions, lack of oxygen causes hydroxylation to cease HIF-1α stabilization and subsequent translocation to the nucleus where it heterodimerizes with the constitutively expressed β subunit. Binding of the HIF-heterodimer to specific DNA sequences, named hypoxia-responsive elements, triggers the transactivation of target genes. PHD regulation of HIF-1α-mediated cardioprotection has resulted in considerable interest in these molecules as potential therapeutic targets in cardiovascular and ischemic diseases. In recent years, attention has been directed towards identifying small molecule inhibitors of PHD. It is postulated that such inhibition might lead to a clinically useful strategy for protecting the myocardium against ischemia and reperfusion injury. Recently, it has been reported that the orally absorbed PHD inhibitor GSK360A can modulate HIF-1α signaling and protect the failing heart following myocardial infarction. Furthermore, PHD1 deletion has been found to have beneficial effects through an increase in tolerance to hypoxia of skeletal muscle by reprogramming basal metabolism. In the mouse liver, such deletion has resulted in protection against ischemia and reperfusion. As a result of these preliminary findings, PHDs is attracting increasing interest as potential therapeutic targets in a wide range of diseases.
The Effects of Exchange Rate Change on the Trade Balance of Slovakia

This paper empirically investigates the impact of change in exchange rate on export and import flows between Slovakia and its major trading partners. Devaluation or depreciation of a currency worsens the trade balance before improving it, resulting in a J-curve pattern. For the purpose of this paper, aggregated and disaggregated approaches are used. This paper investigates J-curve phenomenon using quarterly time series data over the period 1997:1 to 2013:4. The results provide evidence that the classical J-curve effect does not exist in Slovakia on the aggregated level. Instead, currency depreciation (increase in real effective exchange rate) is accompanied only by positive change in trade balance with no deterioration under initial value. On the bilateral level, there exists J- curve in trade with Hungary.
Genetic analysis reveals diverse kin‐directed routes to helping in the rifleman Acanthisitta chloris

The social organization of cooperatively breeding species is extremely variable, with diverse social group composition and patterns of relatedness. Species that exhibit alternative routes to helping within the same population are potentially useful systems to investigate the causes and fitness consequences of diverse evolutionary pathways to cooperative behaviour. In this study, we use microsatellite markers and field observations to describe helping behaviour and patterns of relatedness in the unusual cooperative breeding system of the rifleman Acanthisitta chloris. First, we show that rifleman helpers consist of a remarkably diverse demographic, including males and females, who may be adult or juvenile, failed breeders or nonbreeders, or even successful breeders that simultaneously feed their own brood. Adult helpers mostly helped at first‐brood nests, while first‐brood juveniles assisted their parents at second broods. Second, we show that rifleman pairs are strictly sexually monogamous, and helpers did not gain any current reproductive success through helping. Third, genotyping showed that contrary to previous assumptions, helpers were closely related to the recipients of their care and preferentially directed care towards relatives over contemporaneous nests of nonrelatives. Finally, we show that variation in helper provisioning effort was attributed to age: juvenile helpers provisioned less than adults and were less responsive to the demands of a growing brood. Overall, our results show that the diverse routes to helping in this unusual species are driven by the common theme of kinship between helper and recipients, resulting in a previously underestimated potential for helpers to gain indirect fitness benefits.
Proteasomal inhibition leads to formation of ubiquitin/α‐synuclein‐immunoreactive inclusions in PC12 cells

Proteasomal dysfunction has been recently implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and diffuse Lewy body disease. We have developed an in vitro model of proteasomal dysfunction by applying pharmacological inhibitors of the proteasome, lactacystin or ZIE[O‐tBu]‐A‐leucinal (PSI), to dopaminergic PC12 cells. Proteasomal inhibition caused a dose‐dependent increase in death of both naive and neuronally differentiated PC12 cells, which could be prevented by caspase inhibition or CPT‐cAMP. A percentage of the surviving cells contained discrete cytoplasmic ubiquitinated inclusions, some of which also contained synuclein‐1, the rat homologue of human α‐synuclein. However the total level of synuclein‐1 was not altered by proteasomal inhibition. The ubiquitinated inclusions were present only within surviving cells, and their number was increased if cell death was prevented. We have thus replicated, in this model system, the two cardinal pathological features of Lewy body diseases, neuronal death and the formation of cytoplasmic ubiquitinated inclusions. Our findings suggest that inclusion body formation and cell death may be dissociated from one another.
A broad-based metabolic approach to study VLDL apoB100 metabolism in patients with ESRD and patients treated with peritoneal dialysis.

BACKGROUND Dyslipidemia is often observed in patients with end-stage renal disease (ESRD) and is associated with cardiovascular diseases. Peritoneal dialysis treatment may further deteriorate the lipoprotein abnormalities, suggesting that peritoneal dialysis alters lipid metabolism. METHODS To study the mechanisms involved in these abnormalities in peritoneal dialysis, we measured insulin sensitivity, free fatty acids release, de novo lipogenesis (DNL), very low-density lipoprotein (VLDL) apoB100 kinetics and cholesterol synthesis in vivo in ESRD (N= 6), peritoneal dialysis patients (N= 5), and controls (N= 7) using stable isotopes. RESULTS Insulin sensitivity, as assessed by an euglycemic hyperinsulinemic clamp, tended to be lower in ESRD and peritoneal dialysis compared to controls [P= 0.08 by analysis of variance (ANOVA)]. Free fatty acid release during the euglycemic hyperinsulinemic clamp tended to be higher in ESRD and peritoneal dialysis compared to controls (P= 0.08 by ANOVA), while DNL and fractional cholesterol synthesis were normal. VLDL-1 apoB100 (P < 0.05) and VLDL-2 apoB100 pool sizes (P < 0.05) were significantly higher in peritoneal dialysis patients compared to controls. The increased VLDL-1 apoB100 pool size was explained by increased VLDL-1 apoB100 synthesis (P < 0.05) in combination with reduced VLDL-1 apoB100 catabolism (P < 0.01), while the increased VLDL-2 apoB100 pool was explained by reduced catabolism (P < 0.01). CONCLUSION Both VLDL-1 apoB100 and VLDL-2 apoB100 pool sizes are increased in peritoneal dialysis patients, due to disturbances both in synthesis and catabolism. VLDL-1 apoB100 production is, at least partially, explained by increased free fatty acid availability secondary to peripheral insulin resistance, thus identifying insulin resistance as potential therapeutic target in peritoneal dialysis patients.
Dietary cadmium exposure alters characteristics of training, substitution, and tolerance when morphine is used as a discriminative stimulus.

This study examined the possibility that cadmium, a toxicant in high concentration in all tobacco products, may alter the stimulus properties of morphine. Adult male rats were exposed to regular laboratory chow (Group Control) or chow containing 100 ppm added cadmium chloride (Group Cadmium). Following an initial 30 day exposure period, control and cadmium-exposed animals were trained to discriminate between i.p. injections of 3.00 mg/kg morphine sulfate and vehicle (distilled water) in a two-choice drug discrimination task. Subsequently, the morphine dose-effect generalization function (0.75-6.00 mg/kg) was determined for control and cadmium-exposed animals. Additional substitution tests were conducted with increasing doses of the high efficacy mu agonist fentanyl (0.0016-0.04 mg/kg), the intermediate efficacy mu agonist (-)-metazocine (0.60-5.00 mg/kg), and the kappa agonist (+/-)-bremazocine (0.03-0.12 mg/kg). Also, increasing doses of the selective mu antagonist naloxone (0.0008-0.50 mg/kg) were presented against the training dose of morphine (3.00 mg/kg) and 0.02 mg/kg fentanyl. Finally, training was discontinued, and control and cadmium-exposed animals were injected with 8.00 mg/kg morphine in the home cage every 12 hr for 2 weeks, prior to redetermining the morphine dose effect function. Following a 1 week recovery period where morphine injections were discontinued, a final determination of the morphine dose-effect function was made. The results of the investigation indicated that cadmium exposure, without affecting the rate-changing properties of the drugs, slowed initial acquisition of the morphine discrimination, decreased the potency of selective doses of naloxone with respect to antagonizing the stimulus effects of morphine and fentanyl, and blocked the development of tolerance to morphine. Morphine, fentanyl, and (-)-metazocine generalized (substituted) equally across both groups, while (+/-)-bremazocine failed to substitute for the morphine stimulus in either group. These findings add to the growing literature on the interaction between metal poisoning and drug selection/abuse.
Molecular demarcation of surface domains as established by label-fracture cytochemistry of boar spermatozoa.

We used "label-fracture" (J Cell Biol 99:1156, 1984) to establish high-resolution maps of wheat germ agglutinin (WGA) and concanavalin A (ConA) receptor sites on the cell surface of boar spermatozoa and to investigate the possible association of these receptors to integral membrane components. Label-fracture reveals intense WGA labeling over the region of the plasma membrane that overlies the acrosome, including the equatorial segment. The density of WGA receptors decreases from the post-acrosomal area to the posterior ring. The WGA receptor domain changes abruptly into a microdomain with an unusually high density of WGA receptors over a sharply delimited, particle-free zone at the base of the head. Over the tail, the density of WGA receptors in the tail is high and uniform over the midpiece, annulus, and principal piece, but narrow patches of rectilinear arrays of pits close to the annulus are not labeled. Labeling of the entire sperm head by ConA is both intense and uniform, except for the particle-free zone at the base of the head, which is barren of receptors. Over the tail, ConA labeling is strong over the midpiece, absent over the annulus, and sparse over the principal piece and the end piece. In contrast to WGA, ConA receptors co-distribute with the intramembrane particles. Our results confirm the potential of label-fracture for high-resolution mapping of the distribution of cell surface receptors. They show that in this specialized cell membrane domains can be sharply defined, i.e., apparent without free lateral diffusion of components.
Independence of Biomechanical Forces and Craniofacial Pneumatization in Cebus

Several different factors have been hypothesized as explanations of variation in primate paranasal sinus size. Biomechanical forces, particularly those associated with mastication, are frequently evoked to account for differences in primate craniofacial pneumatization. To test whether masticatory stresses are responsible for maxillary sinus volume diversity, two platyrrhine species of the genus Cebus (C. apella and C. albifrons) were examined. The former has been identified as a hard object feeder, and many morphological differences between the two species are attributable to differences in the mechanical properties of their respective diets. Sinus volumes were derived from serial coronal CT scans of the crania of adults. Several external cranial measurements were used to scale sinus volume relative to the size of the face. Relative measures of maxillary sinus volume were compared using standard statistical techniques. In all comparisons, the two capuchin species do not differ from one another significantly at P < 0.05. Thus, this “natural experiment” fails to support the interpretation that biomechanical forces acting on the facial skeleton substantially affect the degree of paranasal pneumatization in primates. This result suggests that it is unlikely that the maxillary sinus performs any function in relation to masticatory stress; other factors must be responsible for the variation in sinus volume among primates. Anat Rec, 291:1414–1419, 2008. © 2008 Wiley‐Liss, Inc.
Climate change and oak growth decline: Dendroecology and stand productivity of a Turkey oak (Quercus cerris L.) old stored coppice in Central Italy

Abstract• We combined stem volume increment analysis with dendroecological tools to address two unresolved issues concerning oak dieback in Mediterranean areas: early detection of changes in stand growth, and identification of mechanisms for observed growth declines. • We reconstructed productivity of a stored coppice formed by Turkey oak (Quercus cerris) to test if its growth decline was linked to climatic variability, while also accounting for age-related and sociological factors. • Drought in May–June and in prior-year late summer-autumn was negatively correlated with current growth during 1974–2006. Previous November water balance was the strongest signal. Moving Correlation Functions (11 y windows) indicated that the May–June signal remained dominant until 1996, thereafter falling to non-significant values in parallel with the May–June water balance drying trend; at the same time the previous autumn correlations reached significant values. Since 1994 there was a two-year lagged response to June water balance, suggesting that, when growth declined, loss of current-year climate signals was accompanied by the emergence of previous-year ones. • Growth and productivity of deciduous oaks in Mediterranean environments is linked to late spring-early summer hydrologic balance; at both annual and decadal timescales, oak growth decline was associated with a delayed response to climate.
Dietary Antioxidants and Melanoma: Evidence from Cohort and Intervention Studies

Melanoma is the most serious form of skin cancer affecting mostly people of Caucasian origin and is associated with high exposure to solar ultraviolet (UV) radiation. Antioxidants in the diet are thought to prevent UV-induced DNA damage and oxidative stress and laboratory-based studies have shown that high antioxidant intakes inhibit melanoma development. Corresponding epidemiological evidence is inconsistent, however. We therefore reviewed results from prospective observational studies and randomized controlled trials (RCTs) to clarify whether consumption of antioxidant vitamin C, E (tocopherol), and A (retinol), carotenoids and selenium, as food, supplements, or both, or high fruit and vegetable intake, reduce the incidence of cutaneous melanoma. A total of 9 studies (2 cohort, 1 nested case-control, 6 RCTs) were included. Neither antioxidant nutrients, individually or combined, nor fruit and vegetable intake showed any strong and significant associations with melanoma, though the number of relevant studies was limited and several had methodological shortcomings. In particular, melanoma was not a primary disease outcome in any of the RCTs and therefore, none adequately accounted for potential confounding by sun exposure. In conclusion, available evidence is currently inadequate to assess possible beneficial effects of antioxidant intake on melanoma risk.
Gene expression of neuropeptide Y in the nucleus of the solitary tract is activated in rats under restricted daily feeding but not under 48‐h food deprivation

The two neuropeptide Y (NPY) systems innervating the hypothalamic paraventrivular nucleus were examined regarding their roles in the prefeeding corticosterone peak developed under restricted daily feeding (RF). Protein and mRNA levels of NPY were measured in the arcuate nucleus (ARC) and the nucleus of the solitary tract (NST) in rats under 48‐h food deprivation (48‐hFD), RF, and 72‐h food deprivation imposed after RF (post‐RF 72‐hFD) with 7 days of ad libitum feeding in between. NPY protein and mRNA levels in the ARC significantly increased with 48‐hFD and decreased with re‐feeding, whereas those in the NST were not changed by 48‐hFD. When rats had RF imposed with free access to food from 10.00 to 12.00 h (lights on from 06.00 to 18.00 h) for 3 weeks, NPY concentrations in the ARC increased at 10.00 h, just prior to the daily meal, but those in the NST did not change significantly throughout the period examined. On the other hand, NPY mRNA levels in both the ARC and NST increased before the meal supply and remained high for 4 h after feeding. Under post‐RF 72‐hFD, the prefeeding peak of NPY mRNA was detected in the NST, but NPY mRNA levels in the ARC were continuously high throughout the 24‐h period. These findings indicate that the NPY neurons from the NST are specifically activated by RF, whereas those from the ARC are generally stimulated by an increased food demand.
Species differences and substrate specificity of CYP3A heteroactivation by efavirenz

Abstract 1. The purpose of this study was to clarify species differences in the heteroactivation of CYP3A substrates by efavirenz, which is known from clinical studies to activate midazolam 1′-hydroxylation, and to assess the feasibility of an animal model. 2. In monkey and human liver microsomes, efavirenz activated CYP3A-mediated midazolam 1′-hydroxylation, but had no effect in rat liver microsomes. The activating effect of efavirenz was also observed with recombinant human CYP3A4 and CYP3A5. Midazolam 4-hydroxylation, testosterone 6β-hydroxylation and the oxidation of nifedipine were not activated by efavirenz in any of the microsomes. 3. In an in vivo study using monkeys, the AUC ratio of midazolam/1′-hydroxymidazolam was reduced from 0.85 to 0.30 by efavirenz treatment, which was comparable to that obtained in clinical studies. However, the AUC changes of midazolam caused by efavirenz were smaller than those observed in clinical results, therefore the effect of efavirenz on monkeys was not completely consistent with that seen in humans. 4. In conclusion, this is the first report that efavirenz specifically activates midazolam 1′-hydroxylation only in monkey and human liver microsomes, revealing marked species differences and high substrate specificity in the heteroactivation. A further study is required to clarify whether this in vitro result reflects the in vivo situation.
Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR Imaging--correlation with molecular transporters and histopathologic features.

PURPOSE To analyze the correlation between signal intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance (MR) imaging and the expression of hepatocyte transporters with histopathologic features in hepatocellular carcinoma (HCC). MATERIALS AND METHODS Institutional ethics committee approval and informed consent were obtained. Forty surgically resected HCCs were classified as hypointense (n = 32) or iso- or hyperintense (n = 8) on the basis of findings in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging. The following were compared between hypointense and iso- or hyperintense HCCs: the time-signal intensity curves at gadoxetic acid-enhanced MR imaging, the expression levels of seven transporters (four organic anion-transporting polypeptides [OATPs] and three multidrug-resistant proteins [MRPs]) at polymerase chain reaction (PCR) (for 22 nodules), results of immunostaining of OATP8, and histologic features. Statistical analysis (unpaired t test, Mann-Whitney test, chi(2) test, and Fisher exact test) was performed for each result. RESULTS On the time-signal intensity curves, hypointense HCCs showed a decreasing pattern, whereas iso- or hyperintense HCCs showed an increasing pattern after the dynamic phase. PCR revealed that expression of OATP8 (an uptake transporter) in hypointense HCCs was lower and that in iso- or hyperintense HCCs was higher than in background liver (P < .001). The expression level of MRP3 (a sinusoidal export transporter) showed a similar trend to that of OATP8 (P < .001). Immunostaining revealed that OATP8 expression was weak in hypointense HCCs, whereas it was sustained in iso- or hyperintense HCCs (P < .001). At histologic examination, a pseudoglandular proliferation pattern with bile plugs was more commonly observed in iso- or hyperintense HCCs than in hypointense HCCs (P = .01 for proliferation patterns and P = .006 for bile plugs). CONCLUSION The enhancement ratio of HCCs in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging positively correlated with expression levels of OATP8 and MRP3, indicating that gadoxetic acid is taken up by OATP8 and excreted by MRP3.