Miracle-dz/UniFAR-FTUs huggingface dataset:
Lysis of Salmonella Typhi Intracellularly Infected U937 Cells by Human Natural Killer Cells: Effect of Protein Kinase Inhibitors

We examined the effect of Salmonella typhi (wild-type Ty2 and mutant strain TYT1231)-infected U937 cells on natural killer cell (NKC) cytotoxicity of peripheral blood mononuclear cells (PBMCs) and highly purified NKC (HPNKCs; CD16+/CD56+ > 95%; the rest corresponding to CD3+ T cells). We also analyzed the possible role of various protein kinases involved in natural cytotoxicity on these processes. PBMC cytotoxicity against S typhi-infected U937 cells was significantly higher (paired Student t test;P < 0.05) than its lytic effect against noninfected cells (control) at the various effector-to-target cell ratios used (30:1 [24.4 ± 9.7, 25.1 ± 11.8, and 17.5 ± 8.6]; 50:1 [26.6 ± 9.7, 26.7 ± 12.8, and 21.2 ± 7.5] and 70:1 [32.4 ± 14.4, 30.1 ± 12.4, and 23.1 ± 7.2], respectively). PBMC NKC activity seemed to be dependent on such ratios and was similar against both Salmonella strains studied. Approximately half of the individual samples tested (n = 12; 8 male and 4 female subjects of comparable age) showed at least a 20% specific lysis increase against their own control; essentially no changes or smaller increases in NKC activity were observed in all other samples. Similar results were obtained using HPNKCs as effector cells (5:1 ratio [38.9 ± 12.3, 43.3 ± 11.2, and 27.5 ± 4.9] and 10:1 ratio [51.3 ± 9.1, 46.1 ± 9.8, and 37.7 ± 15.5, respectively]). In general, specimens significantly lysed after incubation with PBMCs responded in a similar manner to a challenge with HPNKCs. PBMC and HPNKC cytotoxicity against S typhi wild-type-infected U937 cells was significantly decreased in a dose-dependent manner by the addition of genistein (50–200 &mgr;mol) or GFX (0.5–2.0 &mgr;mol) to the cytotoxicity assay mixture. NKC activity was almost completely inhibited at the highest genistein and GFX concentrations. In similar experiments, wortmannin (100–500 nmol) failed to inhibit PBMC cytotoxicity and significantly decreased HPNKC activity only at the highest concentration tested. These results show that in the process of NKC recognition and lysis of S typhi-infected U937 cells, there is not a requisite for full bacterial intracellular survival capacity and that S typhi-infected U937 cells are a significantly better target than noninfected U937 cells. NKC signaling pathways activated during the S typhi-infected U937 cell recognition and lysis process are mainly protein tyrosine kinase and protein kinase-C, and they can be blocked by the same protein kinase inhibitors known to inhibit natural cytotoxicity.
The link between family history and early onset alcoholism: earlier initiation of drinking or more rapid development of dependence?

OBJECTIVE This study examines the association between early onset alcoholism and family history to determine whether family history of alcoholism is predictive of earlier initiation of drinking, more rapid onset of dependence once drinking has begun, or both. METHOD Using cross-sectional, retrospective data from a large, nationally representative sample of U.S. adults, discrete time proportional hazards models were used to assess the effects of family history saturation (% of alcoholic first- and second-degree relatives) on: ( 1) the risk of initiating drinking among all adults (N = 42,862; 58.4% female) and (2) the risk of progressing from initiation of drinking to onset of dependence among lifetime drinkers (n = 27,616; 50.7% male). Models were estimated for different time periods, to see if the effect of family history saturation varied over time in a manner suggestive of a stronger association with early onset dependence. RESULTS The positive effect of family history saturation on the risk of initiating drinking was strongest prior to age 15 and declined steadily with increasing age. It was slightly weaker for men than women. After controlling for early initiation of drinking, the direct positive effect of family history saturation on the risk of progressing to dependence increased over time and was slightly reduced among individuals who started drinking before age 18. The indirect effect of family history on the risk of developing dependence, via its effect on early drinking as a risk factor for dependence, was strongest in the interval from 3 to 9 years after initiation of drinking. CONCLUSIONS The association between family history and early onset alcoholism appears to be driven most clearly by family history predicting earlier initiation of drinking. The weak effect of family history on the development of dependence within the first 3 years after initiation of drinking may reflect the preponderance of developmentally limited dependence during this time period. The data are consistent with the links established between novelty seeking, impulsivity and early onset alcoholism. While supporting the possibility of genetic effects via dopaminergic and serotonergic function, these findings also suggest that environmental factors may play an important part in helping to explain the association between family history and early onset alcoholism.
Ammonium and methylammonium transport in Rhodobacter sphaeroides

Rhodobacter sphaeroides maintained intracellular ammonium pools of 1.1 to 2.6 mM during growth in several fixed nitrogen sources as well as during diazotrophic growth. Addition of 0.15 mM NH4+ to washed, nitrogen-free cell suspensions was followed by linear uptake of NH4+ from the medium and transient formation of intracellular pools of 0.9 to 1.5 mM NH4+. Transport of NH4+ was shown to be independent of assimilation by glutamine synthetase because intracellular pools of over 1 mM represented NH4+ concentration gradients of at least 100-fold across the cytoplasmic membrane. Ammonium pools of over 1 mM were also found in non-growing cell suspensions in nitrogen-free medium after glutamine synthetase was inhibited with methionine sulfoximine. In NH4+-free cell suspensions, methylammonium (14CH3NH3+) was taken up rapidly, and intracellular concentrations of 0.4 to 0.5 mM were maintained. The 14CH3NH3+ pool was not affected by methionine sulfoximine. Unlike NH4+ uptake, 14CH3NH3+ uptake in nitrogen-free cell suspensions was repressed by growth in NH4+. These results suggest that R. sphaeroides may produce an NH4+-specific transport system in addition to the NH4+/14CH3NH3+ transporter. This second transporter is able to produce normal-size NH4+ pools but has very little affinity for 14CH3NH3+ and is not repressed by growth in high concentrations of NH4+.
Synthesis and Accumulation of Cyanophycin in Transgenic Strains of Saccharomyces cerevisiae

ABSTRACT Cyanophycin [multi-l-arginyl-poly(l-aspartic acid) (CGP)] was, for the first time, produced in yeast. As yeasts are very important production organisms in biotechnology, it was determined if CGP can be produced in two different strains of Saccharomyces cerevisiae. The episomal vector systems pESC (with the galactose-inducible promoter GAL1) and pYEX-BX (with the copper ion-inducible promoter CUP1) were chosen to express the cyanophycin synthetase gene from the cyanobacterium Synechocystis sp. strain PCC 6308 (cphA6308) in yeast. Expression experiments with transgenic yeasts revealed that the use of the CUP1 promoter is much more efficient for CGP production than the GAL1 promoter. As observed by electrophoresis of isolated CGP in sodium dodecyl sulfate-polyacrylamide gels, the yeast strains produced two different types of polymer: the water-soluble and the water-insoluble CGP were observed as major and minor forms of the polymer, respectively. A maximum CGP content of 6.9% (wt/wt) was detected in the cells. High-performance liquid chromatography analysis showed that the isolated polymers consisted mainly of the two amino acids aspartic acid and arginine and that, in addition, a minor amount (2 mol%) of lysine was present. Growth of transgenic yeasts in the presence of 15 mM lysine resulted in an incorporation of up to 10 mol% of lysine into CGP. Anti-CGP antibodies generated against CGP isolated from Escherichia coli TOP10 harboring cphA6308 reacted with insoluble CGP but not with soluble CGP, if applied in Western or dot blots.
Contribution of Discretionary Foods and Drinks to Australian Children’s Intake of Energy, Saturated Fat, Added Sugars and Salt

Interventions are required to reduce children’s consumption of discretionary foods and drinks. To intervene we need to identify appropriate discretionary choice targets. This study aimed to determine the main discretionary choice contributors to energy and key nutrient intakes in children aged 2–18 years. Secondary analyses were performed with population weighted, single 24 h dietary recall data from the 2011–2012 National Nutrition and Physical Activity Survey. Cakes, muffins, and slices; sweet biscuits; potato crisps and similar snacks; and, processed meats and sugar-sweetened drinks were relatively commonly consumed and were within the top three to five contributors to per capita energy, saturated fat, sodium, and/or added sugars. Per consumer intake identified cereal-based takeaway foods; cakes, muffins and slices; meat pies and other savoury pastries; and, processed meats as top contributors to energy, saturated fat, and sodium across most age groups. Subgroups of sugar-sweetened drinks and cakes, muffins and slices were consistently key contributors to added sugars intake. This study identified optimal targets for interventions to reduce discretionary choices intake, likely to have the biggest impact on moderating energy intake while also reducing intakes of saturated fat, sodium and/or added sugars.
Intrahepatic Cholangiocarcinoma With Predominant “Ductal Plate Malformation” Pattern: A New Subtype

Ten cases of intrahepatic cholangiocarcinoma showing a highly differentiated adenocarcinoma mimicking ductal plate malformation (DPM) are reported. The patients included 7 males and 3 females with an average age of 69.5 years. Six cases were associated with chronic liver disease and the remaining 4 cases showed mild fatty change in the parenchyma and/or minimal to mild portal inflammation. Grossly, the tumor was a single nodule 1.5 to 6.6 cm in diameter, and was whitish and solid without a fibrous capsule. Microscopically, the tumor was composed of many vague, small nodular carcinomatous areas with desmoplastic reactions, and neoplastic glands had an irregularly dilated lumen lined with a single layer of cuboidal or low columnar carcinoma cells and irregular protrusions and bulges, resembling DPM. At its border, the carcinoma seemed to replace the non-neoplastic hepatic lobules or regenerative nodules. The central parts of the tumor were variably hypocellular and fibrotic. Although these carcinomas were negative for mucin and HepParI, they were frequently positive for CK19, epithelial cell adhesion molecule, and epithelial membrane antigen. Neural cell adhesion molecule was also expressed variably. The Ki-67 labeling index was <10% and p53 was scarcely expressed. In conclusion, a new subtype of intrahepatic cholangiocarcinoma with predominant DPM pattern was identified.
Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users

Abstract Performance impairment during Δ9-tetrahydrocannabinol (THC) intoxication has been well described in occasional cannabis users. It is less clear whether tolerance develops to the impairing effects of THC in heavy users of cannabis. The aim of the present study was to assess neurocognitive performance during acute THC intoxication in occasional and heavy users. Twenty-four subjects (12 occasional cannabis users and 12 heavy cannabis users) participated in a double-blind, placebo-controlled, two-way mixed model design. Both groups received single doses of THC placebo and 500 μg/kg THC by smoking. Performance tests were conducted at regular intervals between 0 and 8 h after smoking, and included measures of perceptual motor control (critical tracking task), dual task processing (divided attention task), motor inhibition (stop signal task) and cognition (Tower of London). THC significantly impaired performance of occasional cannabis users on critical tracking, divided attention and the stop signal task. THC did not affect the performance of heavy cannabis users except in the stop signal task, i.e. stop reaction time increased, particularly at high THC concentrations. Group comparisons of overall performance in occasional and heavy users did not reveal any persistent performance differences due to residual THC in heavy users. These data indicate that cannabis use history strongly determines the behavioural response to single doses of THC.
Survival following lobectomy and limited resection for the treatment of stage I non-small cell lung cancer<=1 cm in size: a review of SEER data.

BACKGROUND Although lobectomy is the standard treatment for stage I non-small cell lung cancer (NSCLC), recent studies have suggested that limited resection may be a viable alternative for small-sized tumors. The objective of this study was to compare survival after lobectomy and limited resection among patients with stage IA tumors≤1 cm by using a large, US-based cancer registry. METHODS Using the Surveillance, Epidemiology, and End Results (SEER) registry, we identified 2,090 patients with stage I NSCLC≤1 cm in size who underwent lobectomy or limited resection (segmentectomy or wedge resection). We used propensity score analysis to adjust for potential differences in the baseline characteristics of patients in the two treatment groups. Overall and lung cancer-specific survival rates of patients undergoing lobectomy vs limited resection were compared in stratified and adjusted analyses, controlling for propensity scores. RESULTS Overall, 688 (33%) patients underwent limited resection. For the entire cohort, we were not able to identify a difference in outcomes among patients treated with lobectomy vs limited resection, as demonstrated by an adjusted hazard ratio (HR) for overall survival (1.12; 95% CI, 0.93-1.35) and lung cancer-specific survival (HR, 1.24; 95% CI, 0.95-1.61). Similarly, when the cohort was divided into propensity score quintiles, we did not find a difference in survival rate between the two groups. CONCLUSIONS Limited resection and lobectomy may lead to equivalent survival rates among patients with stage I NSCLC tumors≤1 cm in size. If confirmed in prospective studies, limited resection may be preferable for the treatment of small tumors because it may be associated with fewer complications and better postoperative lung function.
Effect of noxious stimulation on sympathetic vasoconstrictor outflow to human muscles.

1. In fifteen healthy volunteers, muscle nerve sympathetic activity (MSA) was recorded from the peroneal nerve using microneurography. Blood pressure and electrocardiogram were also recorded. 2. Painful stimuli, adjusted to the subject's tolerance level, were delivered over 30‐60 s via (a) pressure to the nail‐bed of different digits, and to the trigeminal region, (b) electrical stimulation (5 Hz) of digital nerves and of the supraorbital nerve, or (c) instillation of soap solution into one eye. Non‐painful ocular pressure was also applied. 3. All procedures except electrical stimulation of digital nerves caused a marked increase in MSA (mean, 160‐248%) with preserved pulse synchrony and a rise in blood pressure. Stimulation of digits induced tachycardia, whereas stimulation of the trigeminal region tended to cause bradycardia. 4. Despite similar pain ratings, electrical stimulation of digital nerves caused a smaller MSA response than the other stimuli (mean increase, 40%). 5. It is concluded that sustained noxious stimulation in awake humans evokes a generalized MSA increase; the activity is still under baroreflex control, but the inhibitory level is reset. Both spinal and brainstem reflexes may contribute; a defence reaction is an unlikely explanation. It is suggested that the number of afferent C fibres activated by electrical stimulation of digital nerves was insufficient to induce any marked MSA response. 6. The non‐painful oculo‐cardiac reflex is associated with a strong increase in MSA.
Population pharmacokinetics of levosimendan in patients with congestive heart failure.

AIMS The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.
The politics of vulnerability: affect, relationality, and resistance in UK austerity

The increasing prevalence of vulnerability as a descriptive concept in policy, political and social discourses occurs alongside a renewed, undeniably “vexed” (Murphy 2012:70), interdisciplinary feminist investment in the term as a crucial concept for social justice. This thesis contends that vulnerability must be understood as an affective and malleable concept, and one which performs changing work depending on the sites, subjects, and discourses to which it is attached. My analysis of the affective and discursive workings of this politics of vulnerability contributes to recent feminist theorisations of vulnerability as a key ethical political concept. It also extends feminist theorisations of care and relationality, temporality, and resistance through analysis of the cultural and affective ‘work’ that claims to vulnerability perform. In doing so, this thesis provides a critical analysis of the workings of vulnerability in relation to gender, disability, illness, citizenship, and nation in the context of recent UK austerity. Reading for the ways in which vulnerability appears across three key sites of (what has elsewhere been termed) “public feeling”, my analysis highlights the ambivalent politics produced through claims to vulnerability which seek to challenge conditions of precarity, debility and violence exposed through austerity processes. To do so, this thesis provides analysis of: responses to changes to illness and disability benefits and processes of assessment; feminist activist and advocate responses to the closure of domestic violence services; and media representations of the funding and staffing ‘crisis’ facing the NHS. The thesis draws together interdisciplinary literatures across the fields of queer feminist cultural studies, affect, feminist disability studies, violence, care and the state. It argues that reading for vulnerability across, and in relation to, changing political subjectivities, contextual debates, and critical attachments enables a better grasp of both the possibilities and significant limits to feminist investments in its transformative potential.
Pediatric intensive care sedation: survey of fellowship training programs.

Children hospitalized in a pediatric intensive care unit are frequently distressed. The purpose of this study was to identify the patterns of use of sedative agents in pediatric critical care patients. A questionnaire survey was mailed to 45 directors of Pediatric Critical Care Fellowship Training Programs listed in Critical Care Medicine, January 1989. The response rate was 75.6% (34 questionnaires). The most commonly identified goals of sedation were reduced patient discomfort or distress and fewer unplanned extubations. The agents most frequently employed for this purpose were opioids (morphine or fentanyl), chloral hydrate, or benzodiazepines. Although conventional doses are used, opioids and benzodiazepines are often given hourly or by continuous infusion. Satisfaction with the efficacy and safety of commonly used opioids was greater (most common response "very satisfied") than for the benzodiazepines ("somewhat satisfied"). The physician's or nurse's clinical impression was reported to be the "most important" criterion for deciding when a patient required a dose of sedative; objective criteria were selected as less important. The majority of patients (65.7%) in the surveyed units were ideally "sedated to the point of no distress with as-needed medication. " The majority of respondents (76.4%) identified efficacy as the major problem with sedation. Drug withdrawal was considered to be the major problem with sedative use by only a minority of respondents (6.9%). Although withdrawal is seen in 61.8% of units, it is generally treated when recognized, rather than prevented by routine tapering of sedation. Optimal sedation of pediatric intensive care unit patients is considered problematic, despite the use of frequent doses of many sedatives. Systematic investigation of pharmacodynamic response to these agents in the pediatric critical care population is indicated.
Parental psychopathology and expectations for the futures of children with autism spectrum disorder

BACKGROUND The influence of parental psychopathology and parental expectations on child well-being is well documented among typically developing populations. However, to date little research has examined the relationship among these factors in families of children with autism spectrum disorder (ASD). This study examines an observed relationship between parental psychopathology and expectations in families with children with ASD in the light of research in other populations. METHOD Twenty-four parents of children diagnosed with ASD were assessed for symptoms of psychopathology. Parents completed measures of child ASD severity as well as their expectations for possible outcomes of their child. RESULTS Two main effects were found: higher parental psychopathology and ASD severity were both related to lower expectations. Interaction of ASD severity and parental psychopathology in relation to parent expectations was not observed. CONCLUSION These results emphasize the necessity of providing services not only to individuals diagnosed with ASD, but to caregivers as well.