Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of the PI3K/Akt, mTOR, and STK11/LKB1 pathways in the tumorigenesis of sclerosing hemangioma of the lung

Although the histogenesis of sclerosing hemangioma (SH) of the lung is now thought to be respiratory epithelial in origin, the genetic abnormalities that mediate its development are not known. Because pathophysiology of several syndromes associated with benign tumors may converge on the tuberous sclerosis complex (TSC), serine/threonine kinase 11 (STK11), and mammalian target of rapamycin (mTOR) pathways, the purpose of the present paper was to investigate their roles in the development of SH. Semiquantitative immunohistochemical analysis was done to assess the expression of phospho‐mTOR, phospho‐S6 ribosomal protein, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phospho‐Akt, STK11, tuberin, hamartin, vascular endothelial growth factor (VEGF), and hypoxia‐inducible factor‐1α (HIF‐1α) in 19 cases of typical SH. To determine whether genetic alteration of STK11 is involved in the development of SH, all encoding exons of STK11 were analyzed by polymerase chain reaction (PCR) amplification and direct sequencing of genomic DNA of six specimens. The six specimens were also investigated for whether promoter hypermethylation exists as an alternative inactivating mechanism for STK11. All specimens showed moderate to marked reaction to phospho‐S6 ribosomal protein and PTEN; 16 specimens (84%) showed slight to moderate reaction to phospho‐mTOR, negative reaction to STK11, and slight to moderate reaction to hamartin; 11 (58%) showed slight to moderate reaction to phospho‐Akt; 18 (95%) showed slight to moderate reaction to tuberin and positive reaction for HIF‐1α; and 17 (90%) showed moderate reaction to VEGF. No somatic mutation of STK11 was found and the six specimens were unmethylated in the promoter region. These data imply that aberrant mTOR signaling may play a role in the development of SH, and its vascular nature may be due partially to high levels of VEGF caused by dysregulation of mTOR signaling.
Effect of Intrauterine Growth Restriction on the Number of Cardiomyocytes in Rat Hearts

Epidemiologic studies have linked intrauterine growth restriction (IUGR) with an increased incidence of cardiovascular disease later in life; reduced cardiomyocyte number in IUGR hearts may underlie such prenatal programming. Our aim was to examine the effect of IUGR, as a result of maternal protein restriction, on the number of cardiomyocytes in the rat heart at birth. Rats were fed either a low-protein diet (LPD) or a normal-protein diet (NPD) during pregnancy. At birth, the offspring were killed and the hearts were immersion-fixed. The number of cardiomyocyte nuclei in the hearts were stereologically determined using an optical disector-fractionator approach. In some litters, cardiomyocytes were enzymatically isolated from freshly excised hearts and the proportion of binucleated cells was determined. Taking into account the number of binucleated cells, the nuclear counts were adjusted to estimate total cardiomyocyte number. Birth weight and heart weight were significantly reduced in the LPD offspring. This was accompanied by a significant reduction in the number of cardiomyocytes per heart in the LPD offspring compared with the NPD offspring (1.18 ± 0.05 × 107 and 1.41 ± 0.06 × 107, respectively; p = 0.001). The number of binucleated cardiomyocytes was low (∼3%) and equal in both groups. In conclusion, IUGR as a result of maternal protein restriction leads to a reduction in the number of cardiomyocytes per heart. As cardiomyocyte proliferation is rare after birth, it is plausible that this reduction in cardiomyocytes may lead to compromised cardiac function later in life.
INFLUENCE OF PHENOBARBITAL AND DIPHENYLHYDANTOIN ON PLASMA CARBAMAZEPINE LEVELS IN PATIENTS WITH EPILEPSY

A total of 123 patients with epilepsy, trigeminal neuralgia or other pains were treated with carbamazepine, which was given alone in 30, with diphenylhydantoin in 48, with phenobarbital in 18 and in 27 cases all three drugs were given. Carbamazepine was determined by quantitative thin‐layer chromatography with subsequent in situ measurement of fluorescence. The plasma level of carbamazepine was higher when the patients were treated with carbamazepine alone than when they were treated as well with diphenylhydantoin or phenobarbital or with both. The difference was highly significant. Various possible explanations for this difference are discussed.
Two sets of RNAi components are required for heterochromatin formation in trans triggered by truncated transgenes

Across kingdoms, RNA interference (RNAi) has been shown to control gene expression at the transcriptional- or the post-transcriptional level. Here, we describe a mechanism which involves both aspects: truncated transgenes, which fail to produce intact mRNA, induce siRNA accumulation and silencing of homologous loci in trans in the ciliate Paramecium. We show that silencing is achieved by co-transcriptional silencing, associated with repressive histone marks at the endogenous gene. This is accompanied by secondary siRNA accumulation, strictly limited to the open reading frame of the remote locus. Our data shows that in this mechanism, heterochromatic marks depend on a variety of RNAi components. These include RDR3 and PTIWI14 as well as a second set of components, which are also involved in post-transcriptional silencing: RDR2, PTIWI13, DCR1 and CID2. Our data indicates differential processing of nascent un-spliced and long, spliced transcripts thus suggesting a hitherto-unrecognized functional interaction between post-transcriptional and co-transcriptional RNAi. Both sets of RNAi components are required for efficient trans-acting RNAi at the chromatin level and our data indicates similar mechanisms contributing to genome wide regulation of gene expression by epigenetic mechanisms.
The construction of a pharmacokinetic model for the disposition of polychlorinated biphenyls in the rat

The construction of a preliminary pharmacokinetic model for the distribution, long‐term storage sites, excretion, and metabolism of selected polychlorinated biphenyls (PCBs) in the rat is described. Following intravenous administration of radioactive PCBs, several metabolites of each PCB isomer were detected in urine or feces, excreted primarily as glucuronide conjugates. The relative and absolute amount of metabolites excreted depended upon the degree of chlorination and the position of the chlorine on the biphenyl molecule. Concerning long‐term storage sites, an unanticipatedjinding was accumulation in skin, as revealed by the particularly long half‐life of the 6‐CB isomer in skin. A flow diagram of the model is presented, as are the differential equations, solved by computer for a given dose schedule, for the individual mass balances on parent and metabolite in each of the compartments that represent the organs or regions in which the concentration is assumed to be uniform. Low‐level, long‐term doses of PCBs produce a variety of toxicologic symptoms which appear only after long‐time exposure. Such models should be useful in explaining and predicting the toxicities induced by exposure to PCBs and similar contaminants and the time required to reach a steady‐state tissue concentration for given long‐term doses.
Epstein–Barr virus load monitoring: its role in the prevention and management of post‐transplant lymphoproliferative disease

Abstract: The Epstein–Barr virus load in the peripheral blood at the time of diagnosis of post‐transplant lymphoproliferative disease (PTLD) is elevated 1000‐ to 10,000‐fold compared to the level detected in normal latency. With the use of quantitative polymerase chain reaction (PCR), changes in the viral load over time can be measured with a two‐ to fourfold accuracy. This has allowed early detection of first‐time infections and reactivations that may lead to PTLD and has provided an opportunity to intervene before symptomatic disease has occured. Viral load monitoring has also been used to follow patients with PTLD and, along with other parameters, provided an assessment of the effectiveness of therapeutic protocols. Viral load monitoring has led to the discovery that at least two‐thirds of transplant recipients become persistent viral load carriers. While the persistent load appears to be largely carried in latently infected memory B cells, more work is needed to clearly define this type of persistent infection and determine the risks associated with it. New diagnostic tests need to be developed to distinguish the persistent latent viral loads from viral loads that are likely to become symptomatic PTLD.
Production, characterization and pharmacokinetic properties of antibodies with N-linked Mannose-5 glycans

The effector functions of therapeutic antibodies are strongly affected by the specific glycans added to the Fc domain during post-translational processing. Antibodies bearing high levels of N-linked mannose-5 glycan (Man5) have been reported to exhibit enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) compared with antibodies with fucosylated complex or hybrid glycans. To better understand the relationship between antibodies with high levels of Man5 and their biological activity in vivo, we developed an approach to generate substantially homogeneous antibodies bearing the Man5 glycoform. A mannosidase inhibitor, kifunensine, was first incorporated in the cell culture process to generate antibodies with a distribution of high mannose glycoforms. Antibodies were then purified and treated with a mannosidase for trimming to Man5 in vitro. This 2-step approach can consistently generate antibodies with > 99% Man5 glycan. Antibodies bearing varying levels of Man5 were studied to compare ADCC and Fcγ receptor binding, and they showed enhanced ADCC activity and increased binding affinity to the FcγRIIIA. In addition, the clearance rate of antibodies bearing Man8/9 and Man5 glycans was determined in a pharmacokinetics study in mice. When compared with historical data, the antibodies bearing the high mannose glycoform exhibited faster clearance rate compared with antibodies bearing the fucosylated complex glycoform, while the pharmacokinetic properties of antibodies with Man8/9 and Man5 glycoforms appeared similar. In addition, we identified the presence of a mannosidase in mouse serum that converted most Man8/9 to Man6 after 24 h.
Midazolam Induces Expression of c-Fos and EGR-1 by a Non-GABAergic Mechanism

Gene expression changes induced by general anesthetics have not been extensively examined. In this investigation, we treated rat pheochromocytoma PC12 cells with IV anesthetics, and assessed expression of immediate early gene products, c-Fos and EGR-1, by immunoblot analysis. Thiopental, ketamine, propofol, and diazepam did not significantly change the expression level of c-Fos and EGR-1. In contrast, midazolam dose- and time-dependently induced expression of c-Fos and EGR-1, which was not affected by antagonists of the benzodiazepine receptors, flumazenil and PK11195. The midazolam-induced c-Fos and EGR-1 expression was abolished by PD98059, an inhibitor for mitogen- activated protein kinase/extracellular signal-regulated kinase kinase, suggesting the involvement of extracellular signal-regulated kinases (ERKs). Immunoblot analysis demonstrated that midazolam induces phosphorylation and activation of ERKs. These results indicate that midazolam induces the expression of c-Fos and EGR-1, by activation of ERKs through a mechanism independent from &ggr;-aminobutyric acidA receptors, in PC12 cells, and suggest the possibility that midazolam can induce long-term changes of neural functions by changing gene expression.
The genetic basis of colony opacity in Streptococcus pneumoniae: evidence for the effect of box elements on the frequency of phenotypic variation

Streptococcus pneumoniae undergoes spontaneous phase variation in colony morphology. Differences in colony opacity have previously been shown to correlate with differences in the ability of organisms to colonize the mucosal surface of the nasopharynx in an animal model. The genetic basis of opacity variation was identified in transformation experiments. A DNA library, from a strain that varies at high frequency, was screened to identify a single clone capable of transforming a transparent recipient strain which varies at low frequency to an opaque phenotype. Analysis of this opacity locus revealed two genes, glpD and glpF, with similarity to genes required for glycerol metabolism in other bacteria. Following the pneumococcal glpF, repetitive intergenic elements, boxes A and C, were identified. These stem‐loop‐forming elements were not present in the same locus of the recipient strain. Although not required for phase variation in colony opacity, the box element was necessary for expression of phase variation at high frequency. Introduction of the box elements during transformation affected colony morphology, possibly by altering expression of a putative regulatory gene downstream from the box element. Mutagenesis within this region confirmed the contribution of the putative regulatory gene to the expression of colony opacity. Growth characteristics of strains generated in this study provide additional evidence for an association of differences in cell wall autolysis and variation in colony opacity.
Assessment of Bet v 1-Specific CD4+ T Cell Responses in Allergic and Nonallergic Individuals Using MHC Class II Peptide Tetramers1

In this study, we used HLA-DRB1*0101, DRB1*0401, and DRB1*1501 peptide tetramers combined with cytokine surface capture assays to characterize CD4+ T cell responses against the immunodominant T cell epitope (peptide 141–155) from the major birch pollen allergen Bet v 1, in both healthy and allergic individuals. We could detect Bet v 1-specific T cells in the PBMC of 20 birch pollen allergic patients, but also in 9 of 9 healthy individuals tested. Analysis at a single-cell level revealed that allergen-specific CD4+ T cells from healthy individuals secrete IFN-γ and IL-10 in response to the allergen, whereas cells from allergic patients are bona fide Th2 cells (producing mostly IL-5, some IL-10, but no IFN-γ), as corroborated by patterns of cytokines produced by T cell clones. A fraction of Bet v 1-specific cells isolated from healthy, but not allergic, individuals also expresses CTLA-4, glucocorticoid-induced TNF receptor, and Foxp 3, indicating that they represent regulatory T cells. In this model of seasonal exposure to allergen, we also demonstrate the tremendous dynamics of T cell responses in both allergic and nonallergic individuals during the peak pollen season, with an expansion of Bet v 1-specific precursors from 10−6 to 10−3 among circulating CD4+ T lymphocytes. Allergy vaccines should be designed to recapitulate such naturally protective Th1/regulatory T cell responses observed in healthy individuals.
Assessment of the genetic components and trait associations in diverse set of fieldpea (Pisum sativum L.) genotypes

One hundred and 40 genotypes of fieldpea were used to assess the genetic divergence for various agronomic traits. The study revealed that all the accessions were significantly different for the traits and a wide range of variability exists for most of the traits. Correlation studies exhibited that seed yield had positive significant correlation with most of the traits. Cluster analysis classified 140 genotypes into 12 distinct groups. A large number of genotypes (30) were placed in cluster IV followed by cluster III with 24 genotypes. The maximum inter-cluster distance was observed between clusters III and IV indicating the possibility of high heterotic effect if the individuals from these clusters are cross-bred. Principal component analysis yielded 12 Eigen vectors and PCA analysis revealed significant variations among traits with seven major principal components explaining about 90% of variations. The estimates of Eigen value associated with the principal components and their respective relative and accumulated variances explained 50.16% of total variation in the first two components. The characters with highest weight in component first were biological yield, pods/plant, yield/plant and branches/plant which explained 34.22% of the total variance. The results of principal component analysis were closely in line with those of the cluster analysis. The grouping of genotypes and hybridization among genetically diverse genotypes of different cluster would be helpful in broadening the genetic base of fieldpea and producing desirable recombinants for developing new fieldpea varieties. DOI: http://dx.doi. org/10.3329/bjb.v43i3. 21605 Bangladesh J. Bot. 43 (3): 323-330, 2014 (December)
Reactogenicity of Tetanus, Diphtheria, 5-Component Acellular Pertussis Vaccine Administered as a Sixth Consecutive Acellular Pertussis Vaccine Dose to Adolescents

Background: Safety of a sixth consecutive dose of acellular pertussis vaccine in adolescents was assessed in a 2-armed, randomized study. Methods: Adolescents who had received 5 doses of acellular pertussis vaccine combined with diphtheria and tetanus toxoids (6-dose group) received 1 dose of reduced 5-component acellular pertussis vaccine combined with tetanus toxoid and reduced diphtheria toxoid (Tdap). Adolescents who had received a primary series of 3 doses of whole-cell pertussis and 1 acellular or whole-cell pertussis booster received 1 dose of Tdap vaccine (5-dose group). Results: Of 214 participants, 176 (82%) reported an injection-site reaction with pain (80%), erythema (22%), and swelling (19%) most frequently reported. A systemic reaction was reported by 169 of 214 (79%) with myalgia (66%), headache (42%), malaise (39%), and fever (9%) most frequently reported. The overall rate of solicited reactions was lower in the 6-dose group than in the 5-dose group (for injection-site reactions: 76.1% vs. 89.7%; for systemic reactions 72.6% vs. 86.6%). Significant differences were observed for injection-site pain, erythema, and for grade 1 or grade 2 increases in arm circumference. Fever, myalgia, and headache were reported at a significantly lower rate in the 6-dose group. Swelling >10 cm was observed in 5 patients (2%), 4 in the 5-dose group. Conclusions: Tdap vaccine was safe when given to adolescents who had received 5 prior doses of acellular pertussis vaccine.
Calcium Co-regulates Oxidative Metabolism and ATP Synthase-dependent Respiration in Pancreatic Beta Cells

Background: Nutrients stimulate calcium dependent activation of energy metabolism, in pancreatic beta cells. Results: Glucose-induced ATP synthase-dependent respiration is strictly calcium-dependent, with little or no effect of calcium on the NAD(P)H response. Conclusion: Calcium coordinates oxidative metabolism and respiration in pancreatic beta cells. Significance: Calcium has novel mitochondrial targets downstream of mitochondrial dehydrogenases. Mitochondrial energy metabolism is essential for glucose-induced calcium signaling and, therefore, insulin granule exocytosis in pancreatic beta cells. Calcium signals are sensed by mitochondria acting in concert with mitochondrial substrates for the full activation of the organelle. Here we have studied glucose-induced calcium signaling and energy metabolism in INS-1E insulinoma cells and human islet beta cells. In insulin secreting cells a surprisingly large fraction of total respiration under resting conditions is ATP synthase-independent. We observe that ATP synthase-dependent respiration is markedly increased after glucose stimulation. Glucose also causes a very rapid elevation of oxidative metabolism as was followed by NAD(P)H autofluorescence. However, neither the rate of the glucose-induced increase nor the new steady-state NAD(P)H levels are significantly affected by calcium. Our findings challenge the current view, which has focused mainly on calcium-sensitive dehydrogenases as the target for the activation of mitochondrial energy metabolism. We propose a model of tight calcium-dependent regulation of oxidative metabolism and ATP synthase-dependent respiration in beta cell mitochondria. Coordinated activation of matrix dehydrogenases and respiratory chain activity by calcium allows the respiratory rate to change severalfold with only small or no alterations of the NAD(P)H/NAD(P)+ ratio.
The clock drawing test and questionable dementia: reliability and validity

In order to evaluate the suitability of the clock drawing test (CDT) for the detection of questionable dementia (QD), we assessed the inter–rater reliabilities and intercorrelations of four common scoring methods of the CDT in a sample of non‐demented subjects and determined the concurrent validity.
A broad-band VHF mixer exhibiting high image rejection over a multidecade baseband frequency range

Image-suppressing frequency converters operating over greater than octave RF and LO input bandwidths in the VHF frequency range are described. The devices, designed for RF to video conversion, exhibit very flat conversion loss response and greater than 34 dB rejection of the undesired sideband at any baseband frequency between 186 kHz and 50 MHz.
Therapy gloves for patients with rheumatoid arthritis: a review

Rheumatoid arthritis is a chronic inflammatory disease that causes pain, joint stiffness and swelling leading to impaired hand function and difficulty with daily activities. Wearing therapy gloves has been recommended by occupational therapists as one of the alternative treatment methods for rheumatoid arthritis. This study aims to review the available literature on the effects of wearing therapy gloves on patients’ hand function and symptoms as well as to discuss the attributes of gloves that might influence the glove performance. An electronic databases search of MEDLINE, Physiotherapy Evidence Database, Occupational Therapy Systematic Evaluation of Evidence, Wiley Online Library, ScienceDirect and Cochrane Central Register of Controlled Trial was performed. Eight articles met the inclusion criteria, and covered seven clinical trials and one case study. Seven outcome measures were identified from the included studies and were then classified into two categories: hand function and hand symptoms. The hand symptoms such as pain, stiffness and swelling improve substantially when the therapy gloves are used. However, marginal or no improvement in hand function (with the exception of grip strength) linked to the use of therapy gloves is being reported. Further research is needed to quantify the effectiveness of therapy gloves, especially in improvement of hand function and in patients’ interest in wearing therapy gloves. Furthermore, future studies should include parameters which might influence therapy gloves’ performance, such as duration of trials, interface pressure generated by the gloves on the underlying skin and tissue, glove fit and construction, as well as thermophysiological comfort.