Miracle-dz/UniFAR-FTUs huggingface dataset:
Determinants that contribute to cytoplasmic stability of human c-fos and beta-globin mRNAs are located at several sites in each mRNA

We have analyzed the contributions to cytoplasmic stability in an mRNA species with a very short half-life (human c-fos) and an mRNA species with a very long half-life (human beta-globin). When the human c-fos promoter was used to drive the expression of human c-fos, beta-globin, and chimeric DNAs between c-fos and beta-globin in transfected cells, a pulse of mRNA synthesis was obtained following induction of transcription by refeeding quiescent cells with medium containing 15% calf serum. The mRNA half-life was determined by using Northern (RNA) blot analysis of mRNAs prepared at various times following the pulse of transcription. Under these conditions human c-fos mRNA exhibited a half-life of 6.6 min and human beta-globin mRNA exhibited a half-life of 17.5 h. Replacement of the 3' end of the c-fos mRNA with the 3' end of the beta-globin mRNA increased the half-life of the resultant RNA from 6.6 to 34 min. The reciprocal chimera had a half-life of 34.6 min compared with the 17.5-h half-life of beta-globin mRNA. These results suggest that sequences which make a major contribution to mRNA stability reside in the 3' end of either or both molecules. A chimera in which the 5' untranslated region of globin was replaced by part of the 5' untranslated region of fos led to destabilization of the encoded mRNA. This construct produced an mRNA with a half-life of 6.8 h instead of the 17.5-h half-life of globin. This result suggests that additional determinants of stability reside in the 5' end of these mRNA molecules. Substitution of part of the 5' untranslated region of fos by the 5' untranslated region of beta-globin yielded an mRNA with stability similar to fos mRNA. These results suggest that interactions among sequences within each mRNA contribute to the stability of the respective molecules.
A Path Analysis of Inspiration, Purpose in Life, Gratitude and Subjective Well-Being among Filipino Workforce

The relationship among inspiration and subjective well-being as mediated by purpose in life and gratitude has been postulated (Thrash & Elliot, 2010). In the present study, a sample of 254 Filipino employees was used to verify whether some types of inspiration influence purpose in life and gratitude. Satisfaction With Life Scale (SWLS), Inspiration Scale (IS), Purpose in Life Scale (PLS), and the Gratitude Questionnaire with Six Items (GQSI) were used to respectively assess subjective well-being, inspiration, purpose in life, and gratitude. The results of path analysis showed that purpose in life mediated the relationship under investigation but contrary to Thrash and Elliot’s (2010) theory, gratitude did not.
Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo

To decrease therapy-induced autoimmunity due to on-target toxicity against normal tissues, Lanitis and colleagues developed a trans-signaling CAR-based immunotherapy strategy in which the T-cell activation signal is physically dissociated from the costimulatory signal in two CARs of differing antigen specificity. Their findings show that this dual-specificity, trans-signaling CAR approach can potentiate the therapeutic efficacy of CAR-T cells against cancer while minimizing parallel reactivity against normal tissues bearing single antigen. Adoptive immunotherapy using T lymphocytes genetically modified to express a chimeric antigen receptor (CAR-T) holds considerable promise for the treatment of cancer. However, CAR-based therapies may involve on-target toxicity against normal tissues expressing low amounts of the targeted tumor-associated antigen (TAA). To specify T cells for robust effector function that is selective for tumor but not normal tissue, we developed a trans-signaling CAR strategy, whereby T-cell activation signal 1 (CD3ζ) is physically dissociated from costimulatory signal 2 (CD28) in two CARs of differing antigen specificity: mesothelin and a-folate receptor (FRa). Human T cells were genetically modified to coexpress signal 1 (anti-Meso scFv-CD3ζ) and signal 2 (anti-FRa scFv-CD28) CARs in trans. Trans-signaling CAR-T cells showed weak cytokine secretion against target cells expressing only one TAA in vitro, similar to first-generation CAR-T cells bearing CD3ζ only, but showed enhanced cytokine secretion upon encountering natural or engineered tumor cells coexpressing both antigens, equivalent to that of second-generation CAR-T cells with dual signaling in cis. CAR-T cells with dual specificity also showed potent anticancer activity and persistence in vivo, which was superior to first-generation CAR-T cells and equivalent to second-generation CARs. Importantly, second-generation CAR-T cells exhibited potent activity against cells expressing mesothelin alone, recapitulating normal tissue, whereas trans-signaling CAR-T cells did not. Thus, a dual specificity, trans-signaling CAR approach can potentiate the therapeutic efficacy of CAR-T cells against cancer while minimizing parallel reactivity against normal tissues bearing single antigen. Cancer Immunol Res; 1(1); 43–53. ©2013 AACR.
Changes in Oxidative Damage, Inflammation and [NAD(H)] with Age in Cerebrospinal Fluid

An extensive body of evidence indicates that oxidative stress and inflammation play a central role in the degenerative changes of systemic tissues in aging. However a comparatively limited amount of data is available to verify whether these processes also contribute to normal aging within the brain. High levels of oxidative damage results in key cellular changes including a reduction in available nicotinamide adenine dinucleotide (NAD+), an essential molecule required for a number of vital cellular processes including DNA repair, immune signaling and epigenetic processing. In this study we quantified changes in [NAD(H)] and markers of inflammation and oxidative damage (F2-isoprostanes, 8-OHdG, total antioxidant capacity) in the cerebrospinal fluid (CSF) of healthy humans across a wide age range (24–91 years). CSF was collected from consenting patients who required a spinal tap for the administration of anesthetic. CSF of participants aged >45 years was found to contain increased levels of lipid peroxidation (F2-isoprostanes) (p = 0.04) and inflammation (IL-6) (p = 0.00) and decreased levels of both total antioxidant capacity (p = 0.00) and NAD(H) (p = 0.05), compared to their younger counterparts. A positive association was also observed between plasma [NAD(H)] and CSF NAD(H) levels (p = 0.03). Further analysis of the data identified a relationship between alcohol intake and CSF [NAD(H)] and markers of inflammation. The CSF of participants who consumed >1 standard drink of alcohol per day contained lower levels of NAD(H) compared to those who consumed no alcohol (p<0.05). An increase in CSF IL-6 was observed in participants who reported drinking >0–1 (p<0.05) and >1 (p<0.05) standard alcoholic drinks per day compared to those who did not drink alcohol. Taken together these data suggest a progressive age associated increase in oxidative damage, inflammation and reduced [NAD(H)] in the brain which may be exacerbated by alcohol intake.
UK NEQAS for leucocyte immunophenotyping: the first 10 years

In the past decade, cellular immunophenotyping has become a new discipline in diagnostic haematology and immunology, and is invaluable in the rapid diagnosis of leukaemia and monitoring disease progression in human immunodeficiency virus infected individuals. The introduction of bench top flow cytometers has meant that immunophenotyping is now also used for the quantitation of CD34+ peripheral blood stem cells (PBSCs) to ensure the correct timing and adequacy of haematopoietic progenitor cell harvests. Furthermore, flow cytometry has become an important tool for the counting of leucocytes in blood components after leucocyte depletion. Because this new discipline is now such a major diagnostic and prognostic tool in the clinical arena, its use must be subject to both internal and external quality control. Such a requirement was first recognised as early as 1986 when an Inter-Regional Quality Assessment Scheme (IRQAS) was initiated for laboratories that undertook the immunocytochemical diagnosis of leukaemia using the alkaline phosphates anti-alkaline phosphatase technique. This programme began with around 25 UK laboratories. In 1990, after the introduction of two more programmes (one for leukaemia diagnosis using UV microscopy and latterly flow cytometry, and one for the enumeration of CD4+ T cells) the IRQAS achieved UK National External Quality Assessment Scheme (UK NEQAS) status and changed its title to UK NEQAS for Leucocyte Immunophenotyping. In the past decade the once small IRQAS programme has evolved into the largest international scheme of its kind, providing EQA to over 650 laboratories world wide for leukaemia immunophenotyping, lymphocyte subset analysis, PBSCs, and more recently low level leucocyte counting. Over the years, this EQA programme has highlighted important problems, such as the inappropriate use of fluorochromes and antibody titre, and the identification of effective gating strategies, all of which have contributed directly to the high interlaboratory variations seen in cellular immunophenotyping. Furthermore, particularly in absolute counting of lymphocyte subsets, PBSCs, and the enumeration of low numbers of leucocytes, UK NEQAS for Leucocyte Immunophenotyping programmes have been instrumental in highlighting the differences that occur between single and dual platform flow cytometric technologies. As a result of these findings, UK NEQAS for Leucocyte Immunophenotyping has helped to reduce the variation seen on an interlaboratory basis and enabled greater standardisation both in the UK and internationally. These advances have been attributable to the development, by UK NEQAS for Leucocyte Immunophenotyping, of a unique whole blood stabilising process that ensures the retention of the physical characteristics (both light scatter and antigenic profile) required of cells to ensure successful cellular immunophenotyping. This major technological advancement has enabled the distribution of specimens for EQA purposes on a global scale that have minimal matrix effect and behave in a manner identical to fresh blood for several months after stabilisation.
Ongoing dynamics in large-scale functional connectivity predict perception

Significance Most brain activity is not directly evoked by specific external events. This ongoing activity is correlated across distant brain regions within large-scale networks. This correlation or functional connectivity may reflect communication across brain regions. Strength and spatial organization of functional connectivity changes dynamically over seconds to minutes. Using functional MRI, we show that these ongoing changes correlate with behavior. The connectivity state before playback of a faint sound predicted whether the participant was going to perceive the sound on that trial. Connectivity states preceding missed sounds showed weakened modular structure, in which connectivity was more random and less organized across brain regions. These findings suggest that ongoing brain connectivity dynamics contribute to explaining behavioral variability. Most brain activity occurs in an ongoing manner not directly locked to external events or stimuli. Regional ongoing activity fluctuates in unison with some brain regions but not others, and the degree of long-range coupling is called functional connectivity, often measured with correlation. Strength and spatial distributions of functional connectivity dynamically change in an ongoing manner over seconds to minutes, even when the external environment is held constant. Direct evidence for any behavioral relevance of these continuous large-scale dynamics has been limited. Here, we investigated whether ongoing changes in baseline functional connectivity correlate with perception. In a continuous auditory detection task, participants perceived the target sound in roughly one-half of the trials. Very long (22–40 s) interstimulus intervals permitted investigation of baseline connectivity unaffected by preceding evoked responses. Using multivariate classification, we observed that functional connectivity before the target predicted whether it was heard or missed. Using graph theoretical measures, we characterized the difference in functional connectivity between states that lead to hits vs. misses. Before misses compared with hits and task-free rest, connectivity showed reduced modularity, a measure of integrity of modular network structure. This effect was strongest in the default mode and visual networks and caused by both reduced within-network connectivity and enhanced across-network connections before misses. The relation of behavior to prestimulus connectivity was dissociable from that of prestimulus activity amplitudes. In conclusion, moment to moment dynamic changes in baseline functional connectivity may shape subsequent behavioral performance. A highly modular network structure seems beneficial to perceptual efficiency.
Titanium allergy in dental implant patients: a clinical study on 1500 consecutive patients.

BACKGROUND In dentistry, allergic reactions to Ti implants have not been studied, nor considered by professionals. Placing permanent metal dental implants in allergic patients can provoke type IV or I reactions. Several symptoms have been described, from skin rashes and implant failure, to non-specific immune suppression. OBJECTIVE Our objective was to evaluate the presence of titanium allergy by the anamnesis and examination of patients, together with the selective use of cutaneous and epicutaneous testing, in patients treated with or intending to receive dental implants of such material. MATERIAL AND METHODS Thirty-five subjects out of 1500 implant patients treated and/or examined (2002-2004) were selected for Ti allergy analysis. Sixteen presented allergic symptoms after implant placement or unexplained implant failures [allergy compatible response group (ACRG)], while 19 had a history of other allergies, or were heavily Ti exposed during implant surgeries or had explained implant failures [predisposing factors group (PFG)]. Thirty-five controls were randomly selected (CG) in the Allergy Centre. Cutaneous and epicutaneous tests were carried out. RESULTS Nine out of the 1500 patients displayed positive (+) reactions to Ti allergy tests (0.6%): eight in the ACRG (50%), one in the PFG (5.3%)(P=0.009) and zero in the control group. Five positives were unexplained implant failures (five out of eight). CONCLUSIONS Ti allergy can be detected in dental implant patients, even though its estimated prevalence is low (0.6%). A significantly higher risk of positive allergic reaction was found in patients showing post-op allergy compatible response (ACRG), in which cases allergy tests could be recommended.
Effect of pigment composition on absorption properties of phytoplankton

Absorption spectra of several phytoplankton species were decomposed, after correction for the particle effect, to estimate in vivo absorption properties of the major light-harvesting pigments in algae. A Gaussian shape is suitable, theoretically and empirically, to represent the absorption spectra of individual photosynthetic components. The Gaussian parameters agreed well with the expected pigment compositions of 3 groups of algae, and the peak heights were linearly correlated with the concentrations of any one of the 4 major pigments measured in the samples. The linear relationship did not vary with phytoplankton species. We present here the first estimates of the 'true' in vivo specific absorption coefficients of 4 major pigments, after correction for particle effect. The results are used to reconstruct the in vivo absorption spectrum of a multi-species sample.
The Effects of WebTrust Assurance on Consumers' Web Purchase Decisions: An Experiment

Purpose – The purpose of this paper is to examine the effects of WebTrust assurance, issued by Certified Public Accountant (CPA) firms, on web purchase behaviour and to examine such effects provided by different‐sized CPA firms.Design/methodology/approach – In an experiment, several scenarios were manipulated to simulate a number of web purchase environments in which participants make decisions online.Findings – The results indicate that the WebTrust assurance seal has a significant effect on consumers' web purchase willingness. An “ordering effect” was also found, in that, removing the seal has more impact than obtaining the seal, and an assurance seal issued by big firms has greater impact than one issued by smaller firms.Originality/value – This study contributes to the existing literature by focusing on an important yet rarely addressed issue of brand assurance services. The paper helps to understand this phenomenon in a global sense. Compared to the student participants used in the previous literatur.
Evidence of further genetic heterogeneity in autosomal dominant medullary cystic kidney disease.

BACKGROUND Autosomal dominant medullary cystic kidney disease is a genetically heterogeneous nephropathy with clinical and morphological features similar to recessively inherited juvenile nephronophthisis. Recently, a second gene locus on chromosome 16p12, MCKD2 has been mapped [1] in addition to the known locus on chromosome 1q21 (MCKD1) [2]. In a previous study we have excluded linkage for three caucasian families to the MCKD1 locus [3]. METHODS Haplotype analysis was performed on 72 individuals (including 24 affected subjects), using a set of seven microsatellite markers spanning the critical region on chromosome 16p12-p13 of about 10.5 cM. RESULTS We report on haplotype analysis of closely linked markers to the MCKD2 locus in the previously studied families and two additional families. CONCLUSION In all five families the association of MCKD2 with the disease was excluded by a multipoint LOD score <-2, thus suggesting the involvement of a third MCKD locus.
Goodput and throughput comparison of single-hop and multi-hop routing for IEEE 802.11 DCF-based wireless networks under hidden terminal existence

We investigate how multi-hop routing affects the goodput and throughput performances of IEEE 802.11 distributed coordination function-based wireless networks compared with direct transmission single hopping, when medium access control dynamics such as carrier sensing, collisions, retransmissions, and exponential backoff are taken into account under hidden terminal presence. We propose a semi-Markov chain-based goodput and throughput model for IEEE 802.11-based wireless networks, which works accurately with both multi-hopping and single hopping for different network topologies and over a large range of traffic loads. Results show that, under light traffic, there is little benefit of parallel transmissions and both single-hop and multi-hop routing achieve the same end-to-end goodput. Under moderate traffic, concurrent transmissions are favorable as multi-hopping improves the goodput up to 730% with respect to single hopping for dense networks. At heavy traffic, multi-hopping becomes unstable because of increased packet collisions and network congestion, and single-hopping achieves higher network layer goodput compared with multi-hop routing. As for the link layer throughput is concerned, multi-hopping increases throughput 75 times for large networks, whereas single hopping may become advantageous for small networks. The results point out that the end-to-end goodput can be improved by adaptively switching between single hopping and multi-hopping according to the traffic load and topology. Copyright © 2015 John Wiley & Sons, Ltd.
Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands

Recent data have expanded our understanding of Notch signaling by identifying a C2 domain at the N-terminus of Notch ligands which has both lipid- and receptor-binding properties. We present novel structures of human ligands Jagged2 and DLL4 and human Notch-2, together with functional assays, which suggest that ligand-mediated coupling of membrane recognition and Notch binding is likely to be critical in establishing the optimal context for Notch signaling. Comparisons between the Jagged and Delta family show a huge diversity in the structures of the loops at the apex of the C2 domain implicated in membrane recognition and Jagged1 missense mutations which affect these loops and are associated with extrahepatic biliary atresia lead to a loss of membrane recognition, but do not alter Notch binding. Taken together, these data suggest that C2 domain binding to membranes is an important element in tuning ligand-dependent Notch signaling in different physiological contexts.
Superresolution and Fluorescence Dynamics Evidence Reveal That Intact Liposomes Do Not Cross the Human Skin Barrier

In this study we use the combination of super resolution optical microscopy and raster image correlation spectroscopy (RICS) to study the mechanism of action of liposomes as transdermal drug delivery systems in human skin. Two different compositions of liposomes were applied to newly excised human skin, a POPC liposome and a more flexible liposome containing the surfactant sodium cholate. Stimulated emission depletion microscopy (STED) images of intact skin and cryo-sections of skin treated with labeled liposomes were recorded displaying an optical resolution low enough to resolve the 100 nm liposomes in the skin. The images revealed that virtually none of the liposomes remained intact beneath the skin surface. RICS two color cross correlation diffusion measurements of double labeled liposomes confirmed these observations. Our results suggest that the liposomes do not act as carriers that transport their cargo directly through the skin barrier, but mainly burst and fuse with the outer lipid layers of the stratum corneum. It was also found that the flexible liposomes showed a greater delivery of the fluorophore into the stratum corneum, indicating that they functioned as chemical permeability enhancers.
MM-align: a quick algorithm for aligning multiple-chain protein complex structures using iterative dynamic programming

Structural comparison of multiple-chain protein complexes is essential in many studies of protein–protein interactions. We develop a new algorithm, MM-align, for sequence-independent alignment of protein complex structures. The algorithm is built on a heuristic iteration of a modified Needleman–Wunsch dynamic programming (DP) algorithm, with the alignment score specified by the inter-complex residue distances. The multiple chains in each complex are first joined, in every possible order, and then simultaneously aligned with cross-chain alignments prevented. The alignments of interface residues are enhanced by an interface-specific weighting factor. MM-align is tested on a large-scale benchmark set of 205 × 3897 non-homologous multiple-chain complex pairs. Compared with a naïve extension of the monomer alignment program of TM-align, the alignment accuracy of MM-align is significantly higher as judged by the average TM-score of the physically-aligned residues. MM-align is about two times faster than TM-align because of omitting the cross-alignment zone of the DP matrix. It also shows that the enhanced alignment of the interfaces helps in identifying biologically relevant protein complex pairs.