The aim of this article is to take stock of nineteenth-century transnational urban history. After a short introduction to transnational history, general urban histories are analysed with respect to ...the ways in which transnational perspectives are incorporated into the narratives. Specific contributions to urban history in a transnational perspective are analysed. Approaches to urban planning history that focus on transnational linkages and international organization are discussed. Approaches to urban history within enlarged geographical scales that go beyond the nation-state framework, with a particular focus on cities as nodes in translocal networks, are analysed. The article concludes with a critical discussion of nineteenth-century transnational urban history.
Adipocyte precursor cells give raise to two major cell populations with different physiological roles: white and brown adipocytes. Here we demonstrate that the retinoblastoma protein (pRB) regulates ...white vs. brown adipocyte differentiation. Functional inactivation of pRB in wild-type mouse embryo fibroblasts (MEFs) and white preadipocytes by expression of simian virus 40 large T antigen results in the expression of the brown fat-specific uncoupling protein 1 (UCP-1) in the adipose state. Retinoblastoma genedeficient (Rb-/-) MEFs and stem cells, but not the corresponding wild-type cells, differentiate into adipocytes with a gene expression pattern and mitochondria content resembling brown adipose tissue. pRB-deficient MEFs exhibit an increased expression of the Forkhead transcription factor Foxc2 and its target gene cAMP-dependent protein kinase regulatory subunit RIα, resulting in increased cAMP sensitivity. Suppression of cAMP-dependent protein kinase activity in Rb-/-MEFs blocked the brown adipocyte-like gene expression pattern without affecting differentiation per se. Immunohistochemical studies revealed that pRB is present in the nuclei of white but not brown adipocyte precursor cells at a developmental stage where both cell types begin to accumulate lipid and brown adipocytes express UCP-1. Furthermore, pRB rapidly undergoes phosphorylation upon cold-induced neodifferentiation and up-regulation of UCP-1 expression in brown adipose tissue. Finally, down-regulation of pRB expression accompanies transdifferentiation of white into brown adipocytes in response to β3-adrenergic receptor agonist treatment. We propose that pRB acts as a molecular switch determining white vs. brown adipogenesis, suggesting a previously uncharacterized function of this key cell cycle regulator in adipocyte lineage commitment and differentiation.
As a part of developing new systems for continuously monitoring the presence of pesticides in groundwater, a microfluidic amperometric immunosensor was developed for detecting the herbicide residue ...2,6-dichlorobenzamide (BAM) in water. A competitive immunosorbent assay served as the sensing mechanism and amperometry was applied for detection. Both the immunoreaction chip (IRC) and detection (D) unit are integrated on a modular microfluidic platform with in-built micro-flow-injection analysis (μFIA) function. The immunosorbent, immobilized in the channel of the IRC, was found to have high long-term stability and withstand many regeneration cycles, both of which are key requirements for systems utilized in continuous monitoring. The IRC was regenerated during 51 cycles in a heterogeneous competitive assay out of which 27 were without the analyte (the highest possible signal level) in order to assess the regeneration capability of the immunosorbent. Detection of BAM standard solutions was performed in the concentration range from 62.5 μg L(-1) to 0.0008 μg L(-1). Non-linear regression of the data using the four-parameter logistic equation generated a sigmoidal standard curve showing an IC50 value (concentration that reduces the signal by 50%) of 0.25 μg L(-1). The strongest signal variation is observed in the concentration range between 0.02 and 2.5 μg L(-1), which includes the 0.1 μg L(-1) threshold limit set by the European Commission for BAM in drinking water. The presented results demonstrate the potential of the constructed μFIA immunosensor as an at-line monitoring system for controlling the quality of ground water supply.
The potent toxin microcystin is frequently released during cyanobacterial blooms in eutrophic waters and may impose a risk to human health, when surface water is used for drinking water. For removal ...of microcystin in surface waters, infiltration through sediment is commonly used. In the present study, mineralization of
14C-labelled microcystin (accumulation of
14CO
2) and concentration changes (protein phosphatase inhibition assay) demonstrated that indigenous microorganisms in the sediment of a water recharge facility were capable of degrading microcystin. At oxic or microaerophilic (<2% O
2) conditions, microcystin added to sediment slurries at 70
μg
l
−1 was reduced to <20
μg
l
−1 in 1–2 weeks, and less than 3
μg
l
−1 after 7 weeks. At anoxic conditions (<0.3% O
2) and with addition of nitrate, the degradation was significantly stimulated, reducing microcystin from 100 to <20
μg
l
−1 within 1 day. The simultaneous production of N
2O in the samples suggests that the microcystin degradation was coupled to dissimilative nitrate reduction (denitrification). Since aquifers and sediments beneath drinking water reservoirs often are anoxic, nitrate respiration may be an important process in removal and detoxification of microcystin.
Hypoglycaemic events, particularly nocturnal, affect health-related quality of life (HRQoL) via acute symptoms, altered behaviour and fear of future events. We examined the respective disutility ...associated with a single event of daytime, nocturnal, severe and non-severe hypoglycaemia.
Representative samples were taken from Canada, Germany, Sweden, the United States and the United Kingdom. Individuals completed an internet-based questionnaire designed to quantify the HRQoL associated with different diabetes- and/or hypoglycaemia-related health states. HRQoL was measured on a utility scale: 1 (perfect health) to 0 (death) using the time trade-off method. Three populations were studied: 8286 respondents from the general population; 551 people with type 1 diabetes; and 1603 with type 2 diabetes. Respondents traded life expectancy for improved health states and evaluated the health states of well-controlled diabetes and diabetes with non-severe/severe and daytime/nocturnal hypoglycaemic events.
In the general population, non-severe nocturnal hypoglycaemic events were associated with a 0.007 disutility compared with 0.004 for non-severe daytime episodes, equivalent to a significant 63% increase in negative impact. Severe daytime and nocturnal events were associated with a 0.057 and a 0.062 disutility, respectively, which were not significantly different.
This study applies an established health economic methodology to derive disutilities associated with hypoglycaemia stratified by onset time and severity using a large multinational population. It reveals substantial individual and cumulative detrimental effects of hypoglycaemic events - particularly nocturnal - on HRQoL, reinforcing the clinical imperative of avoiding hypoglycaemia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
Objectives:
Infectious diarrhea, a leading cause of morbidity and deaths, is less prevalent in breastfed infants compared with infants fed infant formula. The dominant human milk ...oligosaccharide (HMO), α‐1,2‐fucosyllactose (2′‐FL), has structural homology to bacterial adhesion sites in the intestine and may in part explain the protective effects of human milk. We hypothesized that 2′‐FL prevents diarrhea via competitive inhibition of pathogen adhesion in a pig model for sensitive newborn infants.
Methods:
Intestinal cell studies were coupled with studies on cesarean‐delivered newborn pigs (n = 24) without (control) or with inoculation of enterotoxigenic Escherichia coli F18 (7.5 × 1010/day for 8 days) fed either no (F18) or 10 g/L 2′‐FL (2FL‐F18).
Results:
In vitro studies revealed decreased pathogen adhesion to intestinal epithelial cells with 2′‐FL (5 g/L; P < 0.001). F18 pigs showed more diarrhea than control pigs (P < 0.01). Administration of 2′‐FL to F18 pigs failed to prevent diarrhea, although the relative weight loss tended to be reduced (−19 vs −124 g/kg, P = 0.12), higher villi were observed in the distal small intestine (P < 0.05), and a trend toward increased proportion of mucosa and activities of some brush border enzymes in the proximal small intestine. In situ abundance of α‐1,2‐fucose and E coli was similar between groups, whereas sequencing showed higher abundance of Enterobacteriaceae in F18, Enterococcus in control and Lachnospiraceae in 2FL‐F18 pigs.
Conclusions:
2′‐FL inhibited in vitro adhesion of E coli F18 to epithelial cells, but had limited effects on diarrhea and mucosal health in newborn pigs challenged with E coli F18.
Eph receptors are a family of receptor tyrosine kinases that control directional cell movement during various biological processes, including embryogenesis, neuronal pathfinding, and tumor formation. ...The biochemical pathways of Eph receptors are context-dependent in part because of the varied composition of a heterotypic, oligomeric, active Eph receptor complex. Downstream of the Eph receptors, little is known about the essential phosphorylation events that define the context and instruct cell movement. Here, we define a pathway that is required for Eph receptor B2 (EphB2)–mediated cell sorting and is conserved among multiple Eph receptors. Utilizing a HEK293 model of EphB2+/ephrinB1+ cell segregation, we found that the scaffold adaptor protein SH2 domain–containing adaptor protein B (Shb) is essential for EphB2 functionality. Further characterization revealed that Shb interacts with known modulators of cytoskeletal rearrangement and cell mobility, including Nck adaptor protein (Nck), p120-Ras GTPase-activating protein (RasGAP), and the α- and β-Chimaerin Rac GAPs. We noted that phosphorylation of Tyr297, Tyr246, and Tyr336 of Shb is required for EphB2–ephrinB1 boundary formation, as well as binding of Nck, RasGAP, and the chimaerins, respectively. Similar complexes were formed in the context of EphA4, EphA8, EphB2, and EphB4 receptor activation. These results indicate that phosphotyrosine-mediated signaling through Shb is essential in EphB2-mediated heterotypic cell segregation and suggest a conserved function for Shb downstream of multiple Eph receptors.
Protein phosphorylation dynamically regulates cellular activities in response to environmental cues. Sequence conservation analysis of recent proteome-wide phosphorylation data revealed that many ...previously unidentified phosphorylation sites are not well-conserved leading to the proposal that many are non-functional. However, this is based on the assumption that protein phosphorylation modulates protein function through specific position on protein sequence. Based on emerging understanding on phospho-regulation of cellular activities, we argue, with examples, that non-positionally conserved phosphorylation sites can very well be functional. We previously identified phosphorylation events that need not be conserved at same positions across orthologous proteins but are likely maintained by evolutionary conserved signaling networks through orthologous kinases. We found that proteins with such conserved phosphorylation patterns are statistically over-represented with protein and DNA-binding annotation. Here, we further correlated these proteins with protein-protein interaction data from an independent systematic study and observed they indeed interact frequently with other proteins. Hence, we speculate that non-positionally conserved phosphorylation site could be modulating biomolecular association of phosphorylated proteins possibly through fine-tuning protein's bulk electrostatic charge and through creating binding sites for phospho-binding interaction domains. We, therefore, advocate the development of complementary evolutionary approaches to interpret physiological important sites.
Two single nucleotide polymorphisms (SNP TXNIP and SNP ARNT), both on chromosome 4, have been reported to be associated with roundworm (Ascaris suum) burden in pigs. In the present study, we selected ...pigs with two SNP TXNIP genotypes (AA; n = 24 and AB; n = 24), trickle-infected them with A. suum from 8 weeks of age until necropsy 8 weeks later, and tested the hypothesis that pigs with the AA genotype would have higher levels of resistance than pigs of AB genotype. We used different indicators of resistance (worm burden, fecal egg counts (FEC), number of liver white spots and A. suum-specific serum IgG antibody levels). Pigs of the AA genotype had lower mean macroscopic worm burden (2·4 vs 19·3; P = 0·06), lower mean total worm burden (26·5 vs 70·1; P = 0·09) and excreted fewer A. suum eggs at week 8 PI (mean number of eggs/g feces: 238 vs 1259; P = 0·14) than pigs of the AB genotype, as expected based on prior associations. The pigs were also genotyped at another locus (SNP ARNT) which showed a similar trend. This study provides suggestive evidence that resistant pigs may be selected using a genetic marker, TXNIP, and provides further support to the quantitative trait locus on chromosome 4.
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