Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular farming in tobacco hairy roots by triggering the secretion of a pharmaceutical antibody

Recombinant pharmaceutical proteins expressed in hairy root cultures can be secreted into the medium to improve product homogeneity and to facilitate purification, although this may result in significant degradation if the protein is inherently unstable or particularly susceptible to proteases. To address these challenges, we used a design of experiments approach to develop an optimized induction protocol for the cultivation of tobacco hairy roots secreting the full‐size monoclonal antibody M12. The antibody yield was enhanced 30‐fold by the addition of 14 g/L KNO3, 19 mg/L 1‐naphthaleneacetic acid and 1.5 g/L of the stabilizing agent polyvinylpyrrolidone. Analysis of hairy root cross sections revealed that the optimized medium induced lateral root formation and morphological changes in the inner cortex and pericycle cells, indicating that the improved productivity was at least partially based on the enhanced efficiency of antibody secretion. We found that 57% of the antibody was secreted, yielding 5.9 mg of product per liter of induction medium. Both the secreted and intracellular forms of the antibody could be isolated by protein A affinity chromatography and their functionality was confirmed using vitronectin‐binding assays. Glycan analysis revealed three major plant complex‐type glycans on both forms of the antibody, although the secreted form was more homogeneous due to the predominance of a specific glycoform. Tobacco hairy root cultures therefore offer a practical solution for the production of homogeneous pharmaceutical antibodies in containment. Biotechnol. Bioeng. 2014;111: 336–346. © 2013 Wiley Periodicals, Inc.
LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis.

RATIONALE Human genome-wide association studies have revealed novel genetic loci that are associated with coronary heart disease. One such locus resides in LNK/SH2B3, which in mice is expressed in hematopoietic cells and suppresses thrombopoietin signaling via its receptor myeloproliferative leukemia virus oncogene. However, the mechanisms underlying the association of LNK single-nucleotide polymorphisms with coronary heart disease are poorly understood. OBJECTIVE To understand the functional effects of LNK single-nucleotide polymorphisms and explore the mechanisms whereby LNK loss of function impacts atherosclerosis and thrombosis. METHODS AND RESULTS Using human cord blood, we show that the common TT risk genotype (R262W) of LNK is associated with expansion of hematopoietic stem cells and enhanced megakaryopoiesis, demonstrating reduced LNK function and increased myeloproliferative leukemia virus oncogene signaling. In mice, hematopoietic Lnk deficiency leads to accelerated arterial thrombosis and atherosclerosis, but only in the setting of hypercholesterolemia. Hypercholesterolemia acts synergistically with LNK deficiency to increase interleukin 3/granulocyte-macrophage colony-stimulating factor receptor signaling in bone marrow myeloid progenitors, whereas in platelets cholesterol loading combines with Lnk deficiency to increase activation. Platelet LNK deficiency increases myeloproliferative leukemia virus oncogene signaling and AKT activation, whereas cholesterol loading decreases SHIP-1 phosphorylation, acting convergently to increase AKT and platelet activation. Together with increased myelopoiesis, platelet activation promotes prothrombotic and proatherogenic platelet/leukocyte aggregate formation. CONCLUSIONS LNK (R262W) is a loss-of-function variant that promotes thrombopoietin/myeloproliferative leukemia virus oncogene signaling and platelet and leukocyte production. In mice, LNK deficiency is associated with both increased platelet production and activation. Hypercholesterolemia acts in platelets and hematopoietic progenitors to exacerbate thrombosis and atherosclerosis associated with LNK deficiency.
Diphenhydramine Alters the Disposition of Venlafaxine Through Inhibition of CYP2D6 Activity in Humans

CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subjects with a low CYP2D6 activity have increased plasma concentrations of venlafaxine that may predispose them to cardiovascular side effects. In vitro and in vivo studies showed that diphenhydramine, a nonprescription antihistamine, can inhibit CYP2D6 activity. Therefore, the authors investigated in this study a potential drug interaction between diphenhydramine and venlafaxine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxine hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasions (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine samples were collected for 12 hours under steady-state conditions. In EMs, diphenhydramine decreased venlafaxine oral clearance from 104 ± 60 L/hr to 43 ± 23 L/hr (mean ± SD; p < 0.05) without any effect on renal clearance (4 ± 1 L/hr during venlafaxine alone and 4 ± 2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydramine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Diphenhydramine disposition was only slightly affected by genetically determined low CYP2D6 activity or concomitant administration of venlafaxine. In conclusion, diphenhydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of venlafaxine in humans. Clinically significant interactions could be encountered during the concomitant administration of diphenhydramine and other antidepressant or antipsychotic drugs that are substrates of CYP2D6.
Yeast Mannans inhibit binding and phagocytosis of zymosan by mouse peritoneal macrophages

We have examined the effects of various mannans, glycoproteins, oligosaccharides, monosaccharides, and sugar phosphates on the binding and phagocytosis of yeast cell walls (zymosan) by mouse peritoneal macrophages. A phosphonomannan (PO(4):mannose ratio = 1:8:6) from kloeckera brevis was the most potent inhibitor tested; it inhibited binding and phagocytosis by 50 percent at concentrations of approximately 3-5 μg/ml and 10 μg/ml, respectively. Removal of the phosphate from this mannan by mild acid and alkaline phosphatase treatment did not appreciably reduce its capacity to inhibit zymosan phagocytosis. The mannan from saccharomyces cerevisiae mutant LB301 inhibits phagocytosis by 50 percent at 0.3 mg/ml, and a neutral exocellular glucomannan from pichia pinus inhibited phagocytosis by 50 percent at 1 mg/ml. Cell wall mannans from wild type S. cervisiae X2180, its mnn2 mutant which contains mannan with predominantly 1(arrow)6- linked mannose residues, yeast exocellular mannans and O-phosphonomannans were less efficient inhibitors requiring concentrations of 1-5 mg/ml to achieve 50 percent reduction in phagocytosis. Horseradish peroxidase, which contains high-mannose type oligosaccharides, was also inhibitory. Mannan is a specific inhibitor of zymosan binding and phagocytosis. The binding and ingestion of zymosan but not of IgG- or complement-coated erythrocytes can be obliterated by plating macrophages on substrates coated with poly-L-lysin (PLL)-mannan. Zymosan uptake was completely abolished by trypsin treatment of the macrophages and reduced by 50-60 percent in the presence of 10 mM EGTA. Pretreatment of the macrophages with chloroquine inhibited zymosan binding and ingestion. These results support the proposal that the macrophage mannose/N-acetylglucosamine receptor (P. Stahl, J.S. Rodman, M.J. Miller, and P.H. Schlesinger, 1978, Proc. Natl. Acad. Sci. U.S.A. 75:1399-1403, mediates the phagocytosis of zymosan particles.
Chondrogenic potential of human articular chondrocytes and skeletal stem cells: A comparative study

Regenerative medicine strategies have increasingly focused on skeletal stem cells (SSCs), in response to concerns such as donor site morbidity, dedifferentiation and limited lifespan associated with the use of articular chondrocytes for cartilage repair. The suitability of SSCs for cartilage regeneration, however, remains to be fully determined. This study has examined the chondrogenic potential of human STRO-1-immunoselected SSCs (STRO-1+ SSCs), in comparison to human articular chondrocytes (HACs), by utilising two bioengineering strategies, namely “scaffold-free” three-dimensional (3-D) pellet culture and culture using commercially available, highly porous, 3-D scaffolds with interconnected pore networks. STRO-1+ SSCs were isolated by magnetic-activated cell sorting from bone marrow samples of haematologically normal osteoarthritic individuals following routine hip replacement procedures. Chondrocytes were isolated by sequential enzymatic digestion of deep zone articular cartilage pieces dissected from femoral heads of the same individuals. After expansion in monolayer cultures, the harvested cell populations were centrifuged to form high-density 3-D pellets and also seeded in the 3-D scaffold membranes, followed by culture in serum-free chondrogenic media under static conditions for 21 and 28 days, respectively. Chondrogenic differentiation was determined by gene expression, histological and immunohistochemical analyses. Robust cartilage formation and expression of hyaline cartilage-specific markers were observed in both day-21 pellets and day-28 explants generated using HACs. In comparison, STRO-1+ SSCs demonstrated significantly lower chondrogenic differentiation potential and a tendency for hypertrophic differentiation in day-21 pellets. Culture of STRO-1+ SSCs in the 3-D scaffolds improved the expression of hyaline cartilage-specific markers in day-28 explants, however, was unable to prevent hypertrophic differentiation of the SSC population. The advantages of application of SSCs in tissue engineering are widely recognised; the results of this study, however, highlight the need for further development of cell culture protocols that may otherwise limit the application of this stem cell population in cartilage bioengineering strategies.
What does fetal movement predict about behavior during the first two years of life?

This study evaluated whether motor activity prior to birth is predictive of motor behavior and temperament in neonates, infants, and toddlers. Three measures of fetal motor activity (activity level, amplitude, and number of movements) were collected at 24, 30, and 36 weeks of gestation in 52 healthy fetuses using Doppler-based actography. Postnatal data collection included a neurobehavioral assessment at 2-weeks postpartum (n = 41), and laboratory-based behavioral observations at 1 and 2 years of age (ns = 35). Individual stability in motor activity was present during gestation. Predictive relations between fetal movement and neonatal behavior were inconsistent; significant but small positive associations were detected between motor behavior at 36 weeks and neonatal irritability and motor development. Fetal activity level at 36 weeks was positively associated with observed 1-year activity level for boys (but inversely related for girls) and maternal report of activity level at 2 years. Fetal movement was consistently and negatively predictive of distress to limitations at 1 year and behavioral inhibition at 2 years, accounting for 21 to 43% of the variance in these measures. Intrafetal variability in motor behavior makes this a relatively unstable metric for prediction to neonatal maturational outcomes, which are relatively constrained, but fetal motor activity appears to predict temperament attributes related to regulatory behaviors in early childhood.
Opioid Detection in Maternal and Neonatal Hair and Meconium: Characterization of an At-Risk Population and Implications to Fetal Toxicology

Identification of maternal opioid abuse in pregnancy is often difficult to ascertain in the absence of a reliable self-report. We aimed to characterize an at-risk neonatal population for opioid exposures as well as other drugs of abuse and alcohol. From June 2007 to January 2009, 563 neonatal hair and 1318 meconium specimens were assessed for opioids and were positive in 11.4% and 17.0%, respectively. Neonates testing positive for opioids in hair or meconium analysis were also more likely to test positive for other licit and illicit substances (odds ratiohair, 1.75; 95% confidence interval, 1.03-2.97; odds ratiomeconium, 1.61; 95% confidence interval, 1.16-2.22). Specifically, a positive neonatal hair test for opioids also predicted a positive result for oxycodone. In addition, a positive meconium test result for opioids was associated with positive results for cocaine, oxycodone, methadone, benzodiazepines, and fatty acid ethyl esters (alcohol). Finally, there was a significant correlation between maternal and neonatal hair test results for opioids (Spearman rank rho = 0.657, P = 0.03). Understanding the addiction profiles of these women may lead to better clinical and social management and may largely benefit an at-risk population.
Evaluation of a national process of reforming curricula in postgraduate medical education

Context: A national reform of the postgraduate medical education in Denmark introduced (1) Outcome-based education, (2) The CanMEDS framework of competence related to seven roles of the doctor, and (3) In-training assessment. Objectives: The purpose of the study was to evaluate the process of developing new curricula for 38 specialist training programmes. The research question was: which conditions promote and which conditions impede the process? Methods: Evaluation of the process was conducted among 76 contact-persons, who were chairing the curriculum development process within the specialties. Quantitative and qualitative data from a questionnaire survey and telephone interviews were triangulated for data analysis. Results: The response rate of the questionnaire survey was 83% (63/76). Twenty-six telephone interviews were conducted. Identified promoting factors included positive attitude and motivation in faculty and support from written guidelines and seminars. Identified impeding factors included insufficient pedagogical support, poor introduction to the task, changing and inconsistent information from authorities, replacement of advisors, and stressful deadlines. Conclusions: This study identified promoting and impeding factors in a national postgraduate curriculum development process. Surprisingly the study indicates that pedagogical support provided throughout a process in some aspects might not be useful. General suggestions regarding curriculum reform processes are formulated.
Intra-articular morphine after arthroscopic knee operation.

Reports on pain relief with intra-articular morphine after arthroscopic knee operation are conflicting. To assess the long-term antinociceptive effect of intraarticular morphine, we studied pain at rest, pain on standing and ability to walk for 7 days after intraarticular injection of bupivacaine 100 mg (group 1, n = 11), bupivacaine 100 mg and morphine 1 mg (group 2, n = 10) and bupivacaine 100 mg and morphine 3 mg (group 3, n = 10) at the end of operation. Pain and walking were assessed by visual analogue and walking scales, respectively. Pain was treated with morphine i.v. in the recovery room and Tylenol No. 3 after discharge. Assessments were made before operation, and 1, 3, 6 and 12 h after injection and on days 1-7 after operation. There were significant differences between the groups in pain scores (pain at rest, P < 0.05; pain on standing, P < 0.01). The pain scores in group 3 were lower than those in group 1. The differences in pain scores at rest were significant at 12 h and on day 1 after operation and differences in pain scores on standing were significant at 12 h and on days 1 and 2 after operation. The scores in group 2 were intermediate between those in groups 1 and 3. The walking scores in group 3 were significantly better than those in group 1 at 12 h. The amount of analgesics received in groups 2 and 3 was significantly less than that in group 1 until day 3 after operation. (ABSTRACT TRUNCATED AT 250 WORDS)
Evolution and the psychology of intergroup conflict: the male warrior hypothesis

The social science literature contains numerous examples of human tribalism and parochialism—the tendency to categorize individuals on the basis of their group membership, and treat ingroup members benevolently and outgroup members malevolently. We hypothesize that this tribal inclination is an adaptive response to the threat of coalitional aggression and intergroup conflict perpetrated by ‘warrior males’ in both ancestral and modern human environments. Here, we describe how male coalitional aggression could have affected the social psychologies of men and women differently and present preliminary evidence from experimental social psychological studies testing various predictions from the ‘male warrior’ hypothesis. Finally, we discuss the theoretical implications of our research for studying intergroup relations both in humans and non-humans and discuss some practical implications.
Experimental assessment of parallel systems

In the research reported in this paper, transient faults were injected in the nodes and in the communication subsystem (by using software fault injection) of a commercial parallel machine running several real applications. The results showed that a significant percentage of faults caused the system to produce wrong results while the application seemed to terminate normally, thus demonstrating that fault tolerance techniques are required in parallel systems, not only to assure that long-running applications can terminate but also (and more important) that the results produced are correct. Of the techniques tested to reduce the percentage of undetected wrong results only ABFT proved to be effective. For other simple error detection methods to be effective, they have to be designed in, and not added as an after thought. Faults injected in the communication subsystem proved the effectiveness of end-to-end CRCs on the data movements between processors.
Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome

Mendelian randomisation (MR) estimates causal effects of modifiable phenotypes on an outcome by using genetic variants as instrumental variables, but its validity relies on the assumption of no pleiotropy, that is, genes influence the outcome only through the given phenotype. Excluding pleiotropy is difficult, but the use of multiple instruments can indirectly address the issue: if all genes represent valid instruments, their MR estimates should vary only by chance. The Sargan test detects pleiotropy when individual phenotype, outcome and genotype data are measured in the same subjects. We propose an alternative approach to be used when only summary genetic data are available or data on gene‐phenotype and gene‐outcome come from different subjects. The presence of pleiotropy is investigated using the between‐instrument heterogeneity Q test (together with the I2 index) in a meta‐analysis of MR Wald estimates, derived separately from each instrument. For a continuous outcome, we evaluate the approach through simulations and illustrate it using published data. For the scenario where all data come from the same subjects, we compare it with the Sargan test. The Q test tends to be conservative in small samples. Its power increases with the degree of pleiotropy and the sample size, as does the precision of the I2 index, in which case results are similar to those of the Sargan test. In MR studies with large sample sizes based on summary data, the between‐instrument Q test represents a useful tool to explore the presence of heterogeneity due to pleiotropy or other causes. Copyright © 2015 John Wiley & Sons, Ltd.
FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen

On October 23, 2015, the FDA approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks with dacarbazine 1,000 mg/m2 i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS), with a PFS of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively (HR, 0.55; 95% confidence interval, 0.44–0.70; unstratified log-rank test, P < 0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A postmarketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was the use of PFS as an endpoint to support regular approval of trabectedin. Clin Cancer Res; 23(24); 7448–53. ©2017 AACR.
Prevalence of health related disability among community dwelling urban elderly from middle socioeconomic strata in Bangaluru, India.

BACKGROUND & OBJECTIVES Research has shown that health related conditions and socio-economic factors influence disability in the elderly. We examined the prevalence of health related disability in community dwelling elderly (> or =65 yr) residents in a suburb of Bangaluru, Karnataka, India, and assessed the association of disability with various socio-economic variables and current health status. METHODS Using the International Classification of Functioning, Disability and Health (ICF) disability was measured in 356 elderly in the Koramangala suburb of Bangaluru city. Various socio-economic and health related factors associated with disability were documented. RESULTS A total of 85 per cent of the respondents reported current medical problems. Based on a total disability score computed from the participation section of the ICF, 27 per cent of the respondents had mild disability while 37 per cent had higher level of disability. Disablement was significantly associated with age > 75 yr and impairment in cognitive and sensory functions especially hearing. INTERPRETATION & CONCLUSION In this urban elderly population while majority had current medical conditions, a significant proportion did not experience any difficulties in activities of daily living. Restriction in participation in activities of daily living was more influenced by increasing age and impairment in cognitive functions and not current health status. A multidimensional measure of disability as captured by the ICF needs to be applied to other populations such as urban poor and rural elderly to get a more comprehensive picture of disability among the elderly in India.