Miracle-dz/UniFAR-FTUs huggingface dataset:
Nonlinearity and facilitation in phosphoinositide signaling studied by the use of caged inositol trisphosphate in Xenopus oocytes

The phosphoinositide signaling pathway, which mediates neurotransmitter responses, was studied in Xenopus oocytes by recording membrane currents evoked using lightflash photolysis of caged inositol trisphosphate (caged IP3) to produce rapid and reproducible transients in intracellular IP3 levels. Photolysis of caged IP3 evoked currents which were carried largely by chloride ions and depended upon intracellular, but not extracellular, calcium. A given light flash evoked larger responses when the amount of caged IP3 loaded into the oocyte was increased, and illumination of the vegetal hemisphere gave larger responses than the animal. Long (10 sec) light exposures produced oscillatory currents, resembling responses to serotonin and other agonists, which became larger, more transient, and of shorter latency as the light intensity was increased. Brief (ca. 100 msec) flashes evoked a single “spike” of current. The caged IP3 response showed a threshold, in that light flashes had to be greater than a certain intensity and duration before currents could be detected. Associated with this, sub- and suprathreshold light flashes caused a long-lasting (seconds or minutes) potentiation of responses to subsequent test flashes. The lightflash response was also potentiated by a preceding intracellular injection of IP3 and by extracellular application of an agonist thought to induce IP3 liberation. However, intracellular injections of calcium depressed the response. We conclude that the liberation of calcium from intracellular stores varies nonlinearly with the intracellular level of IP3. This phenomenon may explain earlier observations, including the long latency of currents evoked by low doses of agonists such as acetylcholine and serotonin, and the nonlinear facilitation seen between these agonists. Further, it suggests a mechanism for “chemical integration,” which may be important in the functioning of neurons and other cells which use IP3 as an intracellular messenger.
Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo

The tangles of Alzheimer's disease (AD) are comprised of the tau protein displaying numerous alterations, including phosphorylation at serine 422 (S422) and truncation at aspartic acid 421 (D421). Truncation at the latter site appears to result from activation of caspases, a class of proteases that cleave specifically at aspartic acid residues. It has been proposed that phosphorylation at or near caspase cleavage sites could regulate the ability of the protease to cleave at those sites. Here, we use tau pseudophosphorylated at S422 (S422E) to examine the effects of tau phosphorylation on its cleavage by caspase 3. We find that S422E tau is more resistant to proteolysis by caspase 3 than non‐pseudophosphorylated tau. Additionally, we use antibodies directed against the phosphorylation site and against the truncation epitope to assess the presence of these epitopes in neurofibrillary tangles in the aged human brain. We show that phosphorylation precedes truncation during tangle maturation. Moreover, the distribution of the two epitopes suggests that a significant length of time (perhaps as much as two decades) elapses between S422 phosphorylation and cleavage at D421. We further conclude that tau phosphorylation at S422 may be a protective mechanism that inhibits cleavage in vivo.
An improved text classification model for mobile data security testing

In the view of mobile data security detection, text classification model can be realized in the application layer to detect malicious attacks. Since traditional C4.5 decision tree has the disadvantage of no considering about interaction influence between properties in attribute selection, an improved model of C4.5 decision tree based on AdaBoost algorithm is put forward. The problem in measuring the properties of the optimal weak assumptions is to be solved by introducing the weight coefficient of Boosting, which would generate an adaptive adjustment weights at the end of each iteration calculation, so as to reduce the feature subset attribute redundancy and meanwhile, improve the robustness of the classification model. Experimental results illustrate that the proposed text classification model is superior to the traditional method in terms of detection rate and classification accuracy.
DNA Microarray Analysis of the Hyperthermophilic Archaeon Pyrococcus furiosus: Evidence for a New Type of Sulfur-Reducing Enzyme Complex

ABSTRACT DNA microarrays were constructed by using 271 open reading frame (ORFs) from the genome of the archaeon Pyrococcus furiosus. They were used to investigate the effects of elemental sulfur (S°) on the levels of gene expression in cells grown at 95°C with maltose as the carbon source. The ORFs included those that are proposed to encode proteins mainly involved in the pathways of sugar and peptide catabolism, in the metabolism of metals, and in the biosynthesis of various cofactors, amino acids, and nucleotides. The expression of 21 ORFs decreased by more than fivefold when cells were grown with S° and, of these, 18 encode subunits associated with three different hydrogenase systems. The remaining three ORFs encode homologs of ornithine carbamoyltransferase and HypF, both of which appear to be involved in hydrogenase biosynthesis, as well as a conserved hypothetical protein. The expression of two previously uncharacterized ORFs increased by more than 25-fold when cells were grown with S°. Their products, termed SipA and SipB (for sulfur-induced proteins), are proposed to be part of a novel S°-reducing, membrane-associated, iron-sulfur cluster-containing complex. Two other previously uncharacterized ORFs encoding a putative flavoprotein and a second FeS protein were upregulated more than sixfold in S°-grown cells, and these are also thought be involved in S° reduction. Four ORFs that encode homologs of proteins involved in amino acid metabolism were similarly upregulated in S°-grown cells, a finding consistent with the fact that growth on peptides is a S°-dependent process. An ORF encoding a homolog of the eukaryotic rRNA processing protein, fibrillarin, was also upregulated sixfold in the presence of S°, although the reason for this is as yet unknown. Of the 20 S°-independent ORFs that are the most highly expressed (at more than 20 times the detection limit), 12 of them represent enzymes purified from P. furiosus, but none of the products of the 34 S°-independent ORFs that are not expressed above the detection limit have been characterized. These results represent the first derived from the application of DNA microarrays to either an archaeon or a hyperthermophile.
Community Attitudes to the Acceptability of User Fees in Natural Settings

A large-scale survey explored community attitudes towards the application of user fees in natural environment settings used for tourism and recreation. The study was undertaken in two Northern Australian cities where there is considerable tourism use and some existing application of a user fees approach. The study explored the acceptability of user fees for 14 different types of settings. Data revealed that a user fees approach was considered acceptable for tourism sites when tourists were being charged. There was some recognition that all users could pay user fees for the tourism sites. Seven recreation sites were seen as inappropriate locations for user fees irrespective of who was using the sites. Additional analyses identified clusters of respondents with common systems of knowledge or social representations about user fees. Further use of this systems of knowledge approach was recommended for advancing understanding and informing practice in this controversial area of tourism management.
A Tale of Two Cities: ‘Authentic’ Tourism in Belfast

The purpose of this paper is to consider the role of tour guides in presenting ‘authentic’ versions of the conflict and post-conflict situation in Belfast. The paper is based on how post-conflict Belfast and relationships between Catholics and Protestants are presented by tour operators to tourists visiting the city. The paper is based on eight tours undertaken in 2008 involving twelve tour guides. The paper compares and contrasts the discourses produced by former paramilitary combatants who are now employed as tour guides by Coiste (an organisation that focuses on supporting former political prisoners) with ‘neutral’ tour guides who provide ‘official’ Belfast City Sightseeing tours. Each claim to be giving an ‘authentic’ account of the past and present and the paper will explore the various dimensions of ‘biased authenticity’1 presented.
Niedriglohnbeschäftigung in Deutschland – Sprungbrett oder Sackgasse?

Abstract Seit Mitte der neunziger Jahre ist die Niedriglohnbeschäftigung in Deutschland stark gestiegen. Im europäischen Vergleich hat Deutschland mittlerweile einen der höchsten Werte unter den kontinentaleuropäischen Ländern. Gleichzeitig ist die Aufstiegsmobilität aus dem Niedriglohnbereich in besser bezahlte Tätigkeiten zurückgegangen. Besonders für gering Qualifizierte, Frauen und Ältere sind die Chancen, ihr Einkommen zu verbessern, erheblich schlechter als für hoch qualifizierte Beschäftigte. Das Ausmaß der Niedriglohnbeschäftigung und die Aufstiegschancen aus dem Niedriglohnbereich sind politisch hoch relevant, da gerade das Argument, dass Niedriglohnjobs gute Möglichkeiten bieten würden, in besser bezahlte Tätigkeiten aufzusteigen, häufig genutzt wird, um eine Ausweitung von Niedriglöhnen zu rechtfertigen. Die im folgenden Artikel vorgestellte Untersuchung basiert auf Datensätzen der Bundesagentur für Arbeit und dem Sozio-ökonomischen Panel. Neben der Entwicklung der Niedriglohnbeschäftigung und der Aufstiegsmobilität in den letzten 20 Jahren werden die Aufstiegsperspektiven aus dem Niedriglohnbereich nach Beschäftigtenmerkmalen differenziert untersucht.
West Nile Virus-Infected Dead Corvids Increase the Risk of Infection in Culex Mosquitoes (Diptera: Culicidae) in Domestic Landscapes

Abstract A comparative study of West Nile virus (family Flaviviridae, genus Flavivirus, WNV) infection rates in Culex mosquitoes collected at 13 sites, seven reporting WNV-positive dead corvids (case sites) and six without reported dead birds (control sites) was conducted in Davis, CA, from 14 to 21 July at the beginning of the 2006 WNV outbreak. In total, 3,051 Culex mosquitoes were collected using gravid traps and CO2-baited traps; WNV-infected mosquitoes were only collected with CO2-baited traps. WNV-infected Culex pipiens L. were collected at one of the seven case sites. Six of seven case sites yielded WNV-infected Culex tarsalis Coquillett, whereas only one of six control sites had WNV-infected Cx. tarsalis. Overall, the odds of finding WNV-positive mosquitoes were 19.75 times greater at sites reporting a WNV-infected dead corvid than sites without a WNV-infected dead corvid. Maximum likelihood estimates of the overall infection rates at the case sites were 3.48/1,000 for Cx. tarsalis and 8.69/1,000 for Cx. pipiens compared with 1.02/1,000 in Cx. tarsalis collected at the control sites. Results indicate that Cx. tarsalis was important in early season enzootic transmission within Davis and that sites reporting WNV-infected dead corvids are areas to focus control and surveillance efforts.
Effect of nucleoside analogue therapy on duck hepatitis B viral replication in hepatocytes and bile duct epithelial cells in vivo

Background : Recent studies have implicated bile duct epithelial cells (BDEC) as a reservoir of hepatitis B virus (HBV) infection that may be particularly important in the development of post‐liver transplant recurrence of hepatitis B. The aim of this study was to compare the effects of antiviral therapy on duck HBV (DHBV) expression in hepatocytes and BDEC and to determine if this was affected by biliary hyperplasia.
Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.
Importance of renin in blood pressure regulation and therapeutic potential of renin inhibition

Despite improvements in its detection and treatment, hypertension remains a significant public health problem worldwide. In recent years, many international hypertension societies and organisations have set increasingly rigorous blood pressure (BP) targets, with the aim of reducing cardiovascular complications, and this has in turn necessitated the use of more antihypertensive medications to reach these targets in individual patients. There is therefore an ongoing need to develop antihypertensive drugs with new mechanisms of action. Renin inhibitors represent a novel class of compounds which offer considerable promise as BP‐lowering agents. Here, we review the rationale for renin inhibition as a therapeutic target and examine the preclinical and clinical evidence for the antihypertensive effectiveness of the renin inhibitors.
Sera from neuromyelitis optica patients disrupt the blood–brain barrier

Objective In neuromyelitis optica (NMO), the destruction of the blood–brain barrier (BBB) has been considered to be the first step of the disease process. It is unclear whether sera from patients with NMO can open the BBB, and which component of patient sera is most important for this disruption. Methods The effects of sera from antiaquaporin4 (AQP4) antibody positive NMO patients, multiple sclerosis patients and control subjects were evaluated for expression of tight junction proteins and for transendothelial electrical resistance (TEER) of human brain microvascular endothelial cells (BMECs). Whether antibodies against human BMECs as well as anti-AQP4 antibodies exist in NMO sera was also examined using western blot analysis. Results Expression of tight junction proteins and TEER in BMECs was significantly decreased after exposure to NMO sera. However, this effect was reversed after application of an antivascular endothelial growth factor (VEGF) neutralising antibody. Antibodies against BMECs other than anti-AQP4 antibodies were found in the sera of NMO patients whereas no specific bands were detected in the sera of healthy and neurological controls. These antibodies apparently disrupt the BBB by increasing the autocrine secretion of VEGF by BMECs themselves. Absorption of the anti-AQP4 antibody by AQP4 transfected astrocytes reduced AQP4 antibody titres but was not associated with a reduction in BBB disruption. Conclusions Sera from NMO patients reduce expression of tight junction proteins and disrupt the BBB. Autoantibodies against BMECs other than anti-AQP4 antibodies may disrupt the BBB through upregulation of VEGF in BMECs.
Providing Continuity of Care for Chronic Diseases in the Aftermath of Katrina: From Field Experience to Policy Recommendations

ABSTRACT This study sought to elicit challenges and solutions in the provision of health care to those with chronic diseases after Hurricane Katrina in coastal Alabama and Mississippi. In-depth interviews with 30 health and social service providers (key informants) and 4 focus groups with patients with chronic diseases were conducted. Subsequently an advisory panel of key informants was convened. Findings were summarized and key informants submitted additional feedback. The chronic diseases identified as medical management priorities by key informants were mental health, diabetes mellitus, hypertension, respiratory illness, end-stage renal disease, cardiovascular disease, and cancer. The most frequently mentioned barrier to providing care was maintaining continuity of medications. Contributing factors were inadequate information (inaccessible medical records, poor patient knowledge) and financial constraints. Implemented or suggested solutions included relaxation of insurance limitations preventing advance prescription refills; better predisaster patient education to improve medical knowledge; promotion of personal health records; support for information technology systems at community health centers, in particular electronic medical records; improved allocation of donated medications/medical supplies (centralized coordination, decentralized distribution); and networking between local responders and external aid. (Disaster Med Public Health Preparedness. 2009;3:174–182)
The 30-Amino-Acid Deletion in the Nsp2 of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Emerging in China Is Not Related to Its Virulence

ABSTRACT During the past 2 years, an atypical clinical outbreak, caused by a highly pathogenic porcine reproductive and respiratory syndrome virus (PRRSV) with a unique 30-amino-acid deletion in its Nsp2-coding region, was pandemic in China. In this study, we generated four full-length infectious cDNA clones: a clone of the highly virulent PRRSV strain JXwn06 (pWSK-JXwn), a clone of the low-virulence PRRSV strain HB-1/3.9 (pWSK-HB-1/3.9), a chimeric clone in which the Nsp2 region containing the 30-amino-acid deletion was replaced by the corresponding region of the low-virulence PRRSV strain HB-1/3.9 (pWSK-JXwn-HB1nsp2), and a mutated HB-1/3.9 clone with the same deletion in Nsp2 as JXwn06 (pWSK-HB1-ND30). We also investigated the pathogenicities of the rescued viruses (designated RvJXwn, RvJXwn-HB1nsp2, RvHB-1/3.9, and RvHB1-ND30, respectively) in specific-pathogen-free piglets in order to determine the role of the 30-amino-acid deletion in the virulence of the highly pathogenic PRRSV. All the rescued viruses could replicate stably in MARC-145 cells. Our findings indicated that RvJXwn-HB1nsp2 retained high virulence for piglets, like RvJXwn and the parental virus JXwn06, although the survival time of piglets infected with RvJXwn-HB1nsp2 was obviously prolonged. RvHB1-ND30 exhibited low virulence for piglets, like RvHB-1/3.9 and the parental virus HB-1/3.9. Therefore, we conclude that the 30-amino-acid deletion is not related to the virulence of the highly pathogenic PRRSV emerging in China.
Monocyte 15-Lipoxygenase Expression Is Regulated by a Novel Cytosolic Signaling Complex with Protein Kinase C δ and Tyrosine-Phosphorylated Stat31

Our previous studies demonstrated that the IL-13-induced 15-lipoxygenase expression in primary human monocytes is regulated by the activation of both Stat1 and Stat3 and by protein kinase C (PKC)δ. IL-13 stimulated the phosphorylation of Stat3 on both Tyr705 and Ser727. In this study we show that IL-13 induces the association of PKCδ with Stat3, not with Stat1, and is required for Stat3 Ser727 phosphorylation. We found a novel IL-13-dependent cytosolic signaling complex of PKCδ and tyrosine-phosphorylated Stat3. A tyrosine kinase inhibitor blocked PKCδ association with Stat3 as well as Stat3 Ser727 phosphorylation. We therefore hypothesized that tyrosine phosphorylation was required for Stat3 interaction with PKCδ and subsequent PKCδ-dependent phosphorylation of Stat3 Ser727. We developed an efficient transfection protocol for human monocytes. Expression of Stat3 containing a mutation in Tyr705 inhibited the association of PKCδ with Stat3 and blocked Stat3 Ser727 phosphorylation, whereas transfection with wild-type Stat3 did not. Furthermore, by transfecting monocytes with Stat3 containing mutations in Tyr705 or Ser727 or with wild-type Stat3, we demonstrated that both Stat3 tyrosine and serine phosphorylations are required for optimal binding of Stat3 with DNA and maximal expression of 15-lipoxygenase, an important regulator of inflammation and apoptosis.
Reanalysis suggests long‐term upward trends in European storminess since 1871

Regional trends of wind storm occurrence in Europe are investigated using the 20th Century Reanalysis (20CR). While based on surface observations only, this dataset produces storm events in good agreement with the traditional ERA40 and NCEP reanalyses. Time series display decadal‐scale variability in the occurrence of wind storms since 1871, including a period of enhanced storm activity during the early 20th century. Still, significant upward trends are found in central, northern and western Europe, related to unprecedented high values of the storminess measures towards the end of the 20th century, particularly in the North Sea and Baltic Sea regions.
Amyloid load and cerebral atrophy in Alzheimer's disease: An 11C‐PIB positron emission tomography study

To determine the relationship between cerebral amyloid plaque load and rates of cerebral atrophy in Alzheimer's disease. 11C‐PIB(11C‐6‐OH benzothiazole)PET (positron emission tomography) findings were correlated with volumetric magnetic resonance imaging (MRI) measurements in nine subjects with mild to moderate AD. Analysis revealed a positive correlation between rates of whole brain atrophy and whole brain (p = 0.019) and regional 11C‐PIB uptake. This provides support for the central role of amyloid deposition in the pathogenesis of AD. Ann Neurol 2006;60:145–147