Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural studies unravel the active conformation of apo RORγt nuclear receptor and a common inverse agonism of two diverse classes of RORγt inhibitors

The nuclear receptor retinoid acid receptor-related orphan receptor γt (RORγt) is a master regulator of the Th17/IL-17 pathway that plays crucial roles in the pathogenesis of autoimmunity. RORγt has recently emerged as a highly promising target for treatment of a number of autoimmune diseases. Through high-throughput screening, we previously identified several classes of inverse agonists for RORγt. Here, we report the crystal structures for the ligand-binding domain of RORγt in both apo and ligand-bound states. We show that apo RORγt adopts an active conformation capable of recruiting coactivator peptides and present a detailed analysis of the structural determinants that stabilize helix 12 (H12) of RORγt in the active state in the absence of a ligand. The structures of ligand-bound RORγt reveal that binding of the inverse agonists disrupts critical interactions that stabilize H12. This destabilizing effect is supported by ab initio calculations and experimentally by a normalized crystallographic B-factor analysis. Of note, the H12 destabilization in the active state shifts the conformational equilibrium of RORγt toward an inactive state, which underlies the molecular mechanism of action for the inverse agonists reported here. Our findings highlight that nuclear receptor structure and function are dictated by a dynamic conformational equilibrium and that subtle changes in ligand structures can shift this equilibrium in opposite directions, leading to a functional switch from agonists to inverse agonists.
Single transistor latch phenomena in Junctionless Nanotransistors

In this work, we analyze the dependence of steep subthreshold (S-slope) on device and bias parameters of Junctionless (JL) MOSFETs. It is observed that for certain parameters and bias conditions, the JL transistor cannot be turned OFF resulting in a single transistor latch. This phenomenon is an extreme case of impact ionization in JL MOSFETs. It is shown that thicker values of silicon film thickness and gate oxide along with higher drain bias can drive the JL MOSFET in to the latch state.
Characterization of the First Aquaporin Gene from the Egyptian Cotton Leafworm , Spodoptera littoralis

Aquaporins (AQPs) are integral membrane proteins belong to the Major Intrinsic Proteins (MIP) superfamily identified in different tissues from all living organisms including mammals, plants, invertebrates and microorganisms. Only few AQPs isolated and studied from terrestrial insects. In the present study, we report the cloning of a partial cDNA sequence of AQP1 gene from Spodoptera littoralis. The cDNA is 1148bp with an open reading frame of 684bp encoding for 227 amino acids with similarity of 98% and 76% to Spodoptera litura and Grapholita molesta, respectively. Protein structure analysis showed the presence of conserved features found in all studied AQPs such as six transmembrane domains, two conserved motifs of NPA, and the aromatic/arginine (ar/R) selectivity filter. Our study revealed that AQP1 gene is expressed in all insect developmental stages (eggs, larvae, pupae, and adults including males and females). Furthermore, AQP1 expression was detected in tissues of the digestive and excretory system (foregut, midgut, hindgut and Malpighian tubules) of fourth, fifth and sixth larval instars. Gene expression was also detected in the reproductive system of adult females and males. Therefore, we suggest that this AQP1 gene has critical role in maintaining water balance in Spodoptera littoralis insects.
New methods for assessing the impact of traffic safety countermeasures

This paper investigates new methods for assessing the impact of traffic safety countermeasures on the number of accidents or injuries. The primary aim of this paper is to show in general how statistical methods that take development over time into account may be used when assessing the impact on traffic safety data. A secondary aim is to specifically investigate the effect of a change in the police accident reporting routine in 1997 on the injury classification. A salient characteristic in most monthly traffic safety data is a fluctuating trend and seasonal pattern. Some of the fluctuation can be explained, but in order to have a reliable assessment of the countermeasures the evaluation methods have to capture this fluctuation. So-called State Space models provide a framework, where these characteristics can be investigated and modelled explicitly. The change in the police reporting practice lead in 1998 to a 49% [35%; 60%] decrease in the reported number of head injuries in Copenhagen and in 1997 to a 37 % [27%, 46%] decrease outside Copenhagen. An estimate of the actual traffic safety in 1998 measured in the number of serious injuries could be the reported number corrected by an additional 670 injuries due to this change in the reporting.
FACTORS PREDICTIVE OF OUTCOMES 1 YEAR AFTER 3 MONTHLY RANIBIZUMAB INJECTIONS AND AS-NEEDED REINJECTIONS FOR POLYPOIDAL CHOROIDAL VASCULOPATHY IN JAPANESE PATIENTS

Purpose: To determine baseline factors predictive of outcomes 1 year after 3 monthly intravitreal ranibizumab injections followed by as-needed injections for polypoidal choroidal vasculopathy. Methods: A nonrandomized prospective 1-year trial collected data from 144 Japanese patients (144 eyes) with symptomatic polypoidal choroidal vasculopathy who received one 0.5-mg intravitreal ranibizumab injection monthly for 3 months followed by as-needed retreatments. Statistical analysis evaluated baseline independent factors predictive of better visual acuity and the need for fewer injections 1 year after the first injection. Results: After the initial 3 monthly injections, a mean ± standard deviation of 1.2 ± 1.1 as-needed injections was administered. The mean visual acuity improved significantly (P < 0.01) from 20/80 to 20/50. Better visual acuity and no history of photodynamic therapy or clusters of grape-like polypoidal lesions were significant independent baseline factors predictive of better visual acuity 1 year after the first injection. No factors were significantly associated with a need for fewer ranibizumab reinjections during follow-up. Conclusion: The baseline clinical characteristics predicted favorable visual acuity outcomes. These findings might be useful to explaining the prognosis of ranibizumab treatment to the patients with polypoidal choroidal vasculopathy.
Rapid 20th-Century Increase in Coastal Upwelling off Northwest Africa

Near-shore waters along the northwest African margin are characterized by coastal upwelling and represent one of the world's major upwelling regions. Sea surface temperature (SST) records from Moroccan sediment cores, extending back 2500 years, reveal anomalous and unprecedented cooling during the 20th century, which is consistent with increased upwelling. Upwelling-driven SSTs also vary out of phase with millennial-scale changes in Northern Hemisphere temperature anomalies (NHTAs) and show relatively warm conditions during the Little Ice Age and relatively cool conditions during the Medieval Warm Period. Together, these results suggest that coastal upwelling varies with NHTAs and that upwelling off northwest Africa may continue to intensify as global warming and atmospheric CO2 levels increase.
Stock Return Dependence and Product Market Linkages

We study the implications of interfirm product market linkages for dependence among the daily stock returns of US publicly traded firms using a spatial econometric regression. The effects of rivals and major customers change with various characteristics related to the product market network. We find that the competitive effect dominates the contagion effect for firms competing in highly concentrated industries, while the contagion effect becomes stronger in industries with higher product-market variability. We also find that a concentrated customer base and weak product uniqueness increase the sensitivity of the firms to their major customers.
Identification of two different hemolysin determinants in uropathogenic Proteus isolates

DNA sequences similar to those of the Escherichia coli hemolysin genes were detected among uropathogenic isolates of Proteus vulgaris and Morganella morganii by using the Southern blotting technique and hly gene-specific DNA probe. Immunoblotting revealed that among the hemolytic P. vulgaris and M. morganii isolates there was expressed a polypeptide species similar in molecular size (110 kilodaltons) and antigenicity to Escherichia coli HlyA. A plasmid-mediated P. vulgaris hemolysin determinant identified by Southern blotting analysis was molecularly cloned, and the recombinant plasmid (pWPV100) was characterized by restriction endonuclease fragment mapping. A second recombinant library of genomic DNA prepared from a hemolytic, urinary tract isolate of Proteus mirabilis was constructed in E. coli. A 5.5-kilobase XhoI fragment encoding an extracellular hemolytic activity was molecularly cloned (pWPM100), and this plasmid was subjected to transposon-mediated mutagenesis with TnphoA. The P. mirabilis hemolytic phenotype was determined to be encoded by a polypeptide species (HpmA) with an estimated molecular size of 140 kilodaltons based on minicell polypeptide analysis of pWPM100 and its mutant derivatives. Southern blotting analysis with a HpmA-specific DNA probe revealed that this novel determinant is commonly found in both Proteus species but is not present in hemolytic isolates of M. morganii, E. coli, Citrobacter freundii, and Serratia marcescens.
Serial monitoring of faecal calprotectin for the assessment of endoscopic recurrence in asymptomatic patients after ileocolonic resection for Crohn’s disease: a long-term prospective study

Background: It is recommended that ileocolonoscopy is performed within 1 year after resection for Crohn’s disease (CD). Nevertheless, optimal monitoring strategies for recurrence after the ileocolonoscopy remain to be elucidated. This prospective study was to evaluate the value of serial monitoring of faecal calprotectin (FC) after ileocolonoscopy for the assessment of endoscopic recurrence in asymptomatic patients. Methods: Patients in clinical remission who had no endoscopic recurrence at ileocolonoscopy 6–12 months after ileocolonic resection were studied. FC levels were measured every 2 months up to 24 months after the ileocolonoscopy. When the FC level was elevated (⩾140 µg/g), a second ileocolonoscopy was immediately undertaken. In contrast, patients who maintained low FC levels (<140 µg/g) during the 24-month follow up underwent a second ileocolonoscopy at the end of the study. Endoscopic recurrence was defined as a Rutgeerts score ⩾i2. Results: A total of 30 patients were studied. In eight patients, the FC level was raised during the 24-month follow up. Six of the eight patients (75%) had endoscopic recurrence. Of 22 patients who maintained low FC levels, 20 (91%) had no endoscopic recurrence, whereas two showed endoscopic recurrence at the end of the follow up. The incidence of endoscopic recurrence was significantly higher in patients with elevation of FC levels versus those with maintained low FC levels (75% versus 9%). A cut-off value of 140 µg/g for FC had a sensitivity of 75%, a specificity of 91%, a positive predictive value of 75%, a negative predictive value of 91% and a diagnostic accuracy of 87% to detect endoscopic recurrence. Conclusions: Consecutive monitoring of FC is useful for the assessment of endoscopic recurrence after the initial ileocolonoscopy. Increased FC levels indicate a need for repeat ileocolonoscopy, while sustained low FC levels predict a low risk of endoscopic recurrence. In patients maintaining low FC levels, unnecessary invasive endoscopic examinations can be avoided.
Dopamine Inhibits Forskolin‐ and 3‐Isobutyl‐1‐Methylxanthine‐Induced Dark‐Adaptive Retinomotor Movements in Isolated Teleost Retinas

We have been investigating the mechanisms of diurnal and circadian regulation of teleost retinomotor movements. In the retinas of lower vertebrates, photoreceptors and melanin pigment granules of the retinal pigment epithelium (RPE) undergo movements at dawn and dusk. These movements continue to occur at subjective dawn and dusk in animals maintained in constant darkness. Cone myoids contract at dawn and elongate at dusk; RPE pigment disperses into the epithelial cells’ long apical processes at dawn and aggregates into the cell bodies at dusk. We report here that forskolin, an adenylate cyclase activator, and 3‐isobutyl‐1‐methylxanthine (IBMX), a phosphodiesterase inhibitor, each induces dark‐adaptive cone and RPE retinomotor movements in isolated light‐adapted green sunfish retinas cultured in constant light. Forskolin induces a 22‐fold elevation in retinal cyclic AMP content. Forskolin‐ and IBMX‐induced movements are inhibited approximately 65% and 95%, respectively, by 3,4‐dihydroxyphenylethylamine (dopamine). However, dopamine does not inhibit dark‐adaptive movements induced by dibutyryl cyclic AMP. Epinephrine is much less effective than dopamine in inhibiting forskolin‐induced movements, while phenylephrine and clonidine are totally ineffective. These results are consistent with our previous findings that treatments that increase intracellular cyclic AMP content promote darkadaptive retinomotor movement. They further suggest that dopamine inhibits adenylate cyclase activity in photoreceptors and RPE cells and thereby favors light‐adaptive retinomotor movements.
Comparison of Eulerian and Lagrangian numerical techniques for the Stokes equations in the presence of strongly varying viscosity

Numerical modeling of geodynamic problems typically requires the solution of the Stokes equations for creeping, highly viscous flows. Since material properties such as effective viscosity of rocks can vary many orders of magnitudes over small spatial scales, the Stokes solver needs to be robust even in the case of highly variable viscosity. A number of different techniques (e.g. finite difference (FD), finite element (FE) and spectral methods) are presently in use. The purpose of this study is to evaluate the accuracies of several of these techniques. Specifically, these are staggered grid, stream function and rotated staggered grid finite difference method (FDM) and an unstructured finite element method (FEM) with various arrangements of elements. Results are compared with two different analytical solutions: (1) stress distribution inside and around strong or weak viscous inclusions subjected to pure-shear and (2) density-driven flow of a simple two-layer system. The comparison shows, in case of the three FD techniques, that the manner in which viscosity parameters are defined in the numerical grid plays an important role. The application of different viscosity interpolation methods yields differences in accuracy of up to one order of magnitude. In case of the FEM, results show that the arrangement of the elements in the region of material interfaces and the way in which material properties are defined also strongly affects the accuracy. We derived a 1D analytical solution for a simple physical model where an interface separates two domains of different viscosities. If the interface is located between two nodal points the effective viscosity for this cell is a harmonic average of the two viscosities weighted according to the fraction of each material in this cell. Numerically, fractions were evaluated by using markers bearing the material property information. The 2D problem differs from the 1D problem in that in 2D, two viscosities are necessary for a conservative FD formulation, one in the center and one at nodal points of a cell. Harmonic (in some cases geometric) averaging of the viscosity from markers to center points and a second harmonic averaging from center to nodal points is shown to give the most accurate FD results. In presence of density variations additionally a marker based arithmetic average for density should be applied. Results obtained by an unstructured FEM with elements following exactly the material boundaries show accuracies of one to two orders of magnitude better then results produced by Eulerian FD or FE methods. If viscosities are ation elds s
EXPLORATION OF PROSTHETIC STATUS AND TREATMENT NEEDS AMONG ELDERLY POPULATION IN BANGALORE CITY

Background: Comprehensive data on the prosthetic status and dental treatment needs of the elderly population in India is deficient. AIM: To assess the prosthetic status and prosthetic treatment needs among adults aged 50 years and above in and around Bangalore. Material and methods: A cross sectional survey was carried out in and around Bangalore, a total of 784 subjects whose age was 50 years or above were considered for the study. A survey proforma was prepared with the help of Oral Health Assessment Form, WHO (1997) and this modified proforma recorded data on socio-demographic status, prosthetic status and need of the study population. Results: 490 (58.5%) were wearing denture of any type, 149(16.5%) persons were wearing bridge, 169(20.2%) were wearing partial denture in one or both arch,72(21.9%) wearing complete denture in one or both the arch. Total of 546(69.6%) subjects in study population needed prosthetic treatment. It was found that prosthetic treatment need increased with age and highest was among ≥70 years age group. Conclusion: It was evident more than half of the study population is having prosthesis in either arches and around 70% of the subjects have the prosthetic needs. There is an urgent need of looking into the geriatric dental care in Bangalore.
Anthelmintic metabolism in parasitic helminths: proteomic insights

SUMMARY Anthelmintics are the cornerstone of parasitic helminth control. Surprisingly, understanding of the biochemical pathways used by parasitic helminths to detoxify anthelmintics is fragmented, despite the increasing global threat of anthelmintic resistance within the ruminant and equine industries. Reductionist biochemistry has likely over-estimated the enzymatic role of glutathione transferases in anthelmintic metabolism and neglected the potential role of the cytochrome P-450 superfamily (CYPs). Proteomic technologies offers the opportunity to support genomics, reverse genetics and pharmacokinetics, and provide an integrated insight into both the cellular mechanisms underpinning response to anthelmintics and also the identification of biomarker panels for monitoring the development of anthelmintic resistance. To date, there have been limited attempts to include proteomics in anthelmintic metabolism studies. Optimisations of membrane, post-translational modification and interaction proteomic technologies in helminths are needed to especially study Phase I CYPs and Phase III ABC transporter pumps for anthelmintics and their metabolites.
Sexual dimorphism in campylobacteriosis

SUMMARY Sexual dimorphism in infectious diseases whereby disease incidence is more prevalent in one gender has been reported repeatedly in the scientific literature. Both behavioural and physiological differences have been suggested as a cause of this gender bias but there is a paucity of data to support either of these viewpoints. Here it is hypothesized that for campylobacteriosis physiological factors play an important role in the higher incidence in males. We demonstrate in the human population (from several countries in three continents) that this bias exists in young children (<1 year) where behavioural differences between genders are likely to be minimal. Further we demonstrate this difference in an animal model where both infection rates and shedding rates of the organism are greater in male mice.
MIXING THE STREAMS OF GENETICS AND NEUROBIOLOGY IN FRAGILE X SYNDROME Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.
Perspective on School Development in the Barents Region of Northern Europe

This article is about school development, based on empirical data taken from Sweden's northernmost county, Norrbotten, situated in the Barents region of northern Europe. The survey includes all of the county's 13 municipalities. The aim of this article is to illustrate school leaders' views of school development in the organisation and municipality where they work. We chose a quantitative study as the method for obtaining answers to our questions. A questionnaire relating to leadership and school development was sent to 170 addressees. The statements in the questionnaire were put to respondents on the basis of previous research results that showed the importance of collective learning, leadership and the organisation of educational activities. The results from the survey show overwhelmingly positive answers from the respondents; they usually agree completely or partially with the statements. The result shows, for example, that there is a developed vision, there is consensus within the organisation, lessons learned in activities are documented, and teachers/educationists are encouraged to talk to each other about the structure of their teaching. The result is a picture of awareness on the part of the respondents of the importance of school leadership for children and young people's development into citizens. The mainly positive answers that the respondents have submitted, however, mean that there is a gap between what is actually implemented in activities and the respondents' own views. In order to verify the results, the study needs to be continued in more detail through interviews with a number of the respondents and take into account teachers' opinions regarding school development and leadership.