Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulation of mTOR Complex 1 (mTORC1) by Raptor Ser863 and Multisite Phosphorylation*

The rapamycin-sensitive mTOR complex 1 (mTORC1) promotes protein synthesis, cell growth, and cell proliferation in response to growth factors and nutritional cues. To elucidate the poorly defined mechanisms underlying mTORC1 regulation, we have studied the phosphorylation of raptor, an mTOR-interacting partner. We have identified six raptor phosphorylation sites that lie in two centrally localized clusters (cluster 1, Ser696/Thr706 and cluster 2, Ser855/Ser859/Ser863/Ser877) using tandem mass spectrometry and generated phosphospecific antibodies for each of these sites. Here we focus primarily although not exclusively on raptor Ser863 phosphorylation. We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser863 via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. mTORC1 activation by other stimuli (e.g. amino acids, epidermal growth factor/MAPK signaling, and cellular energy) also promote raptor Ser863 phosphorylation. Rheb overexpression increases phosphorylation on raptor Ser863 as well as on the five other identified sites (e.g. Ser859, Ser855, Ser877, Ser696, and Thr706). Strikingly, raptor Ser863 phosphorylation is absolutely required for raptor Ser859 and Ser855 phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser863 phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser859 and Ser855). Importantly, mTORC1 containing phosphorylation site-defective raptor exhibits reduced in vitro kinase activity toward the substrate 4EBP1, with a multisite raptor 6A mutant more strongly defective that single-site raptor S863A. Taken together, these data suggest that complex raptor phosphorylation functions as a biochemical rheostat that modulates mTORC1 signaling in accordance with environmental cues.
Relaxivity of Gadopentetate Dimeglumine (Magnevist), Gadobutrol (Gadovist), and Gadobenate Dimeglumine (MultiHance) in Human Blood Plasma at 0.2, 1.5, and 3 Tesla

Objectives:We sought to determine the relaxivity and accurate relaxation rates of Gd-DTPA, Gd-BT-DO3A, and Gd-BOPTA at 0.2, 1.5, and 3 T in human blood plasma. Materials and Methods:Contrast media concentrations between 0.01 and 16 mM in human plasma were used for relaxation measurements. The R1 and R2 relaxation rates and r1 and r2 relaxivities were determined. Results:Gd-BOPTA produced the highest relaxation rates and relaxivities at all field strengths. The r1 and r2 values for Gd-BOPTA were 107–131% and 91–244% higher than for Gd-DTPA, respectively, and 72–98% and 82–166% higher than for Gd-BT-DO3A. Higher field strengths resulted in lower values of R1, R2, and r1 for all contrast agents tested and of r2 for Gd-DTPA and Gd-BT-DO3A. A linear dependence of R1 and R2 on concentration was found for Gd-DTPA and Gd-BT-DO3A and a nonlinear dependence for Gd-BOPTA for concentrations larger than 1 mM. The r1 and r2 relaxivity of Gd-BOPTA increased with decreasing concentration. Conclusions:Gd-BOPTA demonstrates the highest longitudinal r1 at all field strengths, which is ascribable to weak protein interaction. The R2/R1 ratio increases at higher field strength only for Gd-BOPTA, hence very short echo times are required for Gd-BOPTA to benefit from the higher longitudinal relaxivity.
Regulation of p 53 tumour suppressor target gene expression by the p 52 NF-j B subunit

The p52/p100 nuclear factor kappa B (NF-jB) subunit (NF-jB2) is aberrantly expressed in many tumour types and has been implicated as a regulator of cell proliferation. Here, we demonstrate that endogenous p52 is a direct regulator of Cyclin D1 expression. However, stimulation of Cyclin D1 expression alone cannot account for all the cell cycle effects of p52/p100 and we also find that p52 represses expression of the Cyclin-dependent kinase inhibitor p21. Significantly, this latter effect is dependent upon basal levels of the tumour suppressor p53. By contrast, p52 cooperates with p53 to regulate other known p53 target genes such as PUMA, DR5, Gadd45a and Chk1. p52 associates directly with these p53-regulated promoters where it regulates coactivator and corepressor binding. Moreover, recruitment of p52 is p53 dependent and does not require p52-DNA-binding activity. These results reveal a complex role for p52 as regulator of cell proliferation and p53 transcriptional activity. Furthermore, they imply that in some cell types, p52 can regulate p53 function and influence p53-regulated decision-making following DNA damage and oncogene activation. The EMBO Journal (2006) 25, 4820–4832. doi:10.1038/ sj.emboj. 7601343; Published online 21 September 2006 Subject Categories: chromatin & transcription; cell cycle
Implications of the Lymphatic System in CVI-Associated Edema

Lymph drainage is intimately linked with venous drainage in health and disease. Evidence exists to support the view that lymphatics frequently fail in venous disease, particularly in its advanced stages. The implications of this are to increase the risk of infection and the amount of edema, events which can only further the morbidity of venous disease.
Sensitization in atopic and non‐atopic hairdressers with hand eczema

To investigate the capability of atopics to be sensitized to contort allergens, 143 hairdressers With hand eczema, who had been patch tested with The hairdresser's series, were studied. The 125 women and 18 men were grouped according to their personal atopic Status. There were 45 eczematous atopics, 32 mucous membrane atopics and 66 non‐atopics, Sensitization to at least one of the hairdressing chemicals was found in 60% of the eczematous atopics, 53% of the mucous membrane atopics and 58% of the non‐atopics The commonest sensitizer in each group was glyceryl monothioglycolate followed by para‐phenylenediamine and related dyes. None of the 18 men were allergic to nickel but 40% of the women were thus sensitized. Jewelry rather than equipment was thought to be the cause No significant difference was found between the eczematous atopics, mucous membrane atopics and non‐atopics in their capacity to be sensitized to hairdressing allergens or to nickel.
Fine-Grained Semantic Conceptualization of FrameNet

Understanding verbs is essential for many natural language tasks. Tothis end, large-scale lexical resources such as FrameNet have beenmanually constructed to annotate the semantics of verbs (frames) andtheir arguments (frame elements or FEs) in example sentences.Our goal is to "semantically conceptualize" example sentences by connectingFEs to knowledge base (KB) concepts.For example, connecting Employer FE to company concept in the KB enables the understanding thatany (unseen) company can also be FE examples.However, a naive adoption of existing KB conceptualization technique, focusingon scenarios of conceptualizing a few terms,cannot 1) scale to many FE instances (average of 29.7 instances for all FEs) and 2) leverage interdependence betweeninstances and concepts.We thus propose a scalable k-truss clusteringand a Markov Random Field (MRF) model leveraging interdependence betweenconcept-instance, concept-concept, and instance-instance pairs. Our extensive analysis with real-life data validates that our approachimproves not only the quality of the identified concepts for FrameNet, but alsothat of applications such as selectional preference.
Mean platelet volume in brucellosis: correlation between brucella standard serum agglutination test results, platelet count, and C-reactive protein.

BACKGROUND Brucellosis, a zoonotic infection, was most widely diagnosed by the Brucella standard serum agglutination test (SAT). No previous publication has demonstrated a correlation between the degree of Brucella SAT agglutination positivity and the severity of brucellosis infection. OBJECTIVE To contribute to the clarification of the relationship between patelets and brucellosis. It is also aimed at evaluating the usefulness of the SAT titer as a measure of brucellosis severity. MATERIAL AND METHODS We compared the control (n=60) and patients (n=96) groups in terms of mean platelet volume (MPV), C-reactive protein (CRP) and platelet values. Patients were grouped according to their degree of agglutination positivity titers and compared by means of CRP, MPV and platelet values. We also investigated the relationship among logarithmic values of MPV, platelet and CRP parameters for each group. RESULTS Although statistically meaningful difference was observed between control and patients group in terms of MPV and platelet value, there were no statistically significant differences observed among patients groups. The physiological negative correlation between MPV and platelet count was not encountered in group 2 and 3. Logarithmic values of CRP were not correlated with logarithmic values of MPV and platelet counts. CONCLUSION The MPV could be a new parameter to evaluate hematologic abnormalities in patients with brucellosis. The SAT titer was not a useful measure for evaluation of the severity of brucellosis.
Rational approach to the clinical protocol design for drug combinations: a review.

Based on the median-effect equation of Chou and the combination index (CI) equation of Chou-Talalay, a computer software for automated dose-effect analysis has been developed. This method provides quantitation of synergism (CI < 1) and antagonism (CI > 1) at different dose and effect levels. Therefore, it allows the selection of the best pair (or triplet) of combination, optimal combination ratio, and the best schedule of treatment. These analyses has been shown to be useful for the clinical protocol design. (Chang et al. Cancer Res. 45: 2434-2439, 1985). The user-friendly computer program also gives dose-reduction index (DRI) which determines how many fold of dose-reduction is allowed for each drug in synergistic combinations. Dose reduction leads to reduced toxicity while maintaining the desired efficacy (Chou et al. Encyclopedia of Human Biology 2:675-683, 1997; Encyclopedia of Cancer 1:368-379, 1997). The Chou-Talalay method distincts from all other methods by the fact that it not only takes into account the "potency" but also the "shape" of dose-effect curves of each drug and their combinations (Chou & Hayball, CalcuSyn for Windows, Biosoft, Cambridge UK, 1996). This method has been applied in combination of anticancer agents, anti-HIV agents, purging leukemic cells for autologous bone marrow transplantation (Chang et al. Cancer Res. 47:119-122, 1987) and combination of immunosuppressants for organs transplants. Specific examples of the theoretical equations, the median-effect plot, the CI plot, the isobologram, and the polygonogram are illustrated.
International Classification of Functioning, Disability and Health in children with congenital central hypoventilation syndrome

Purpose. The main aim of this study is to examine the functioning of children with congenital central hypoventilation syndrome (CCHS), a rare disorder of respiratory control associated with physiological and anatomical manifestations of a generalised autonomic nervous system dysfunction, using WHO's International Classification of Functioning, Disability and Health, Children and Youth version (ICF-CY). Method. The data of 26 children, (F = 17) aged 1.5–17.5 years, were collected. Data were analysed in the following four age groups: <3, 3–6, 7–12 and 13–18 years, using only the ICF-CY questionnaires' cross-age items. Results. In the body functions, component breathing and paying attention were common problems for four age groups. In the activity and participation component, all children, except adolescents, showed problems with language. Furthermore, problems in social interaction were evident for all age ranges, except the youngest. Finally, in the environmental factors component, parents reported limitations concerning the natural environment and human-made changes to the environment that were common to all ages. Conclusions. The study supports the usefulness of supplementing diagnostic classifications with functional classifications to obtain complete information on health-related conditions in children with CCHS.
PTHrP enhances the secretory response of PTH to a hypocalcemic stimulus in rat parathyroid glands.

BACKGROUND The secretion of parathyroid hormone (PTH) from the parathyroid glands might be regulated by autocrine/paracrine factors, and a feedback regulatory mechanism of PTH on the secretion of PTH has been suggested. Because of the existence of a common receptor between PTH and PTH-related peptide (PTHrP), the aim of the present study was to examine the possible effects of PTHrP 1-40 and 1-86 on PTH secretion in rats. METHODS In vivo, the effect of PTHrP on Ca++-regulated PTH secretion was examined by the induction of hypocalcemia and hypercalcemia by an infusion of EGTA and Ca++, with and without PTHrP. The eventual effects of PTHrP on the peripheral metabolism of PTH were examined by infusion of human PTH (hPTH) with and without PTHrP. hPTH was measured by an intact hPTH assay not cross reacting with rat PTH or PTHrP. To examine whether near physiological levels of circulating PTH have an autoregulatory effect in vivo on PTH secretion from the parathyroid gland, an acute reduction of the circulating PTH was induced by an acute unilateral parathyroidectomy (UPTX). PTH secretion from the remaining parathyroid gland was followed in response to EGTA-induced hypocalcemia. In vitro investigations on the effect of PTHrP 1-40 on PTH secretion from whole rat parathyroid glands incubated in media containing a calcium concentration of 0.6 or 1.35 mmol/L were performed to confirm whether the effect of PTHrP was directly on the gland. The rat PTH assay was examined for cross reaction with PTHrP. RESULTS In vivo, the same rate of decrease of plasma Ca++ was induced in the experimental groups. The maximal response of PTH to hypocalcemia (218 +/- 16 pg/mL, N = 6) was significantly enhanced by PTHrP 1-40 (525 +/- 79 pg/mL, N = 6) and by PTHrP 1-86 (465 +/- 29 pg/mL, N = 6, P < 0.001). No effect of PTHrP on PTH secretion was found during normocalcemia or hypercalcemia. UPTX resulted in a 50% reduction of PTH secretion, and no compensatory increase of PTH was observed. PTHrP had no effect on the metabolism of PTH. In vitro, low-Ca++-induced PTH secretion was significantly augmented by 300% (P < 0.01) when the medium contained PTHrP 1-40. PTHrP did not cross react with the PTH assay. CONCLUSIONS PTHrP significantly enhanced the low-Ca++-stimulated PTH secretion in vivo and in vitro. An autocrine/paracrine role of PTHrP in the parathyroid glands is suggested. An autoregulatory effect of circulating PTH on the PTH secretion from parathyroid glands seems unlikely. The "maximal secretory capacity" of the parathyroid glands induced by hypocalcemia in vivo and in vitro is not the maximum, as PTH secretion can be increased even further, by several-fold.
The Management of Mycotic Aortic Aneurysms: Is there a Role for Endoluminal Treatment?

Abstract Background : Mycotic aneurysms are rare. Conventional surgical options include ligation or excision with in-situ or extra-anatomical reconstruction. The use of endoluminal stenting for mycotic aneurysms in the presence of sepsis is controversial, but may be a temporising measure, or sometimes the only option in the management of critically ill patients who are not fit for surgery. Methods : A literature review was undertaken using Medline, all relevant papers on endoluminal management of mycotic aneurysm were taken into account. Results : Open surgical repair of mycotic aortic aneurysm is associated with considerable peri-and post-operative morbidity and mortality. Endoluminal treatment with stent-grafts has been introduced as an alternative, and early results are promising. Conclusion : No level I evidence for the endoluminal treatment of mycotic aneurysms exists. Ideally a randomised controlled trial of open surgery versus endoluminal treatment should be performed but this may be difficult to perform because of the low incidence of infected aneurysms.
Porphyromonas gingivalis Lipopolysaccharide Weakly Activates M1 and M2 Polarized Mouse Macrophages but Induces Inflammatory Cytokines

ABSTRACT Porphyromonas gingivalis is associated with chronic periodontitis, an inflammatory disease of the tooth's supporting tissues. Macrophages are important in chronic inflammatory conditions, infiltrating tissue and becoming polarized to an M1 or M2 phenotype. As responses to stimuli differ between these phenotypes, we investigated the effect of P. gingivalis lipopolysaccharide (LPS) on M1 and M2 macrophages. M1 and M2 polarized macrophages were produced from murine bone marrow macrophages (BMMϕ) primed with gamma interferon (IFN-γ) or interleukin-4 (IL-4), respectively, and incubated with a low or high dose of P. gingivalis LPS or control TLR2 and TLR4 ligands. In M1-Mϕ, the high dose of P. gingivalis LPS (10 μg/ml) significantly increased the expression of CD40, CD86, inducible nitric oxide synthase, and nitric oxide secretion. The low dose of P. gingivalis LPS (10 ng/ml) did not induce costimulatory or antibacterial molecules but did increase the secretion of IL-1α, IL-6, IL-12p40, IL-12p70, and tumor necrosis factor alpha (TNF-α). P. gingivalis LPS marginally increased the expression of CD206 and YM-1, but it did enhance arginase expression by M2-Mϕ. Furthermore, the secretion of the chemokines KC, RANTES, eotaxin, and MCP-1 from M1, M2, and nonpolarized Mϕ was enhanced by P. gingivalis LPS. TLR2/4 knockout macrophages combined with the TLR activation assays indicated that TLR2 is the main activating receptor for P. gingivalis LPS and whole cells. In conclusion, although P. gingivalis LPS weakly activated M1-Mϕ or M2-Mϕ compared to control TLR ligands, it induced the secretion of inflammatory cytokines, particularly TNF-α from M1-Mϕ and IL-10 from M2-Mϕ, as well as chemotactic chemokines from polarized macrophages.
Innate γδT17 cells convert cancer-elicited inflammation into immunosuppression through myeloid-derived suppressor cells

Chronic inflammation has been linked to cancer development and metastasis. We have recently demonstrated that γδ T cells are the major cellular source of IL-17 (γδT17) and accumulation of γδT17 cells correlates with human colorectal cancer progression through recruitment and expansion of myeloid-derived suppressor cells, thus converting tumor-elicited inflammation into immunosuppression.
Role Differentiation in an Adolescent Victim-Offender Typology

The present study evaluates adolescent victimization and offending using cross-sectional survey data from 1,475 adolescents living in a disadvantaged Comuna in Medellin, Colombia, while paying particular attention to the ways in which both victimization and violent offending are operationalized. We find that 37% of respondents experienced no lifetime victimization, while 60% experienced vicarious, and 4% personal victimization. When restricting violent offending to behavior involving a weapon, the majority of offenders (81%) also experienced victimization while only 33% of victims were also weapons offenders. Our final analysis seeks to identify theoretical conditions which differentiate roles in a victim-offender typology, a result we determine varies significantly depending on how “violent offending” is measured.
Annotation: the therapeutic alliance--a significant but neglected variable in child mental health treatment studies.

BACKGROUND There has been relatively little research into therapeutic alliance in child and adolescent mental health and virtually no incorporation of alliance measures as a variable in treatment trials in Child and Adolescent Mental Health Services (CAMHS). METHOD A selective literature review on studies in therapeutic alliance in adulthood and childhood along with a theoretical formulation of possible mechanisms of alliance. RESULTS Therapeutic alliance is reliably measurable both by observation and questionnaire methods at all points in the treatment cycle. In both adult and child studies it shows a consistent, albeit modest, association with treatment outcome. In specific adult studies it has shown a high predictive validity in relation to outcome compared to other variables. In child studies alliance is particularly salient in externalising disorder and predicts outcome of inpatient treatment. Child alliance and parental alliance are independent factors. Theoretical models of alliance outlined in this paper suggest testable hypotheses regarding predictors for positive and negative alliance. CONCLUSIONS Therapeutic alliance in CAMHS is measurable and worth measuring. It is likely to be an important variable for treatment outcome studies and should be included in future trial designs.
Cortical thickness of supratemporal plane predicts auditory N1 amplitude

The auditory-evoked potential’s N1 component of the scalp electroencephalogram is a well-established measure of electrical brain activity. The N1 reflects basic auditory processing and is modulated by auditory experience, for instance, by musical training. Here, we explore a possible correlation between the auditory N1 amplitude and cortical architecture in the supratemporal plane. We hypothesize that individual differences in N1 amplitude reflect differential acuity, which might also be reflected by differences in auditory cortex anatomy. Auditory potentials evoked by sine wave tones and structural MRI were collected from 27 healthy volunteers. The thickness and surface area of the cortex were calculated using a surface-based morphometry approach. Cortical thickness, rather than surface area, in a cluster on the posterior supratemporal plane, predominantly located on Heschl’s sulcus and lateral aspects of Heschl’s gyrus, correlated with the N1 amplitude. In particular, lower cortical thickness was associated with larger N1 amplitudes. This is well in agreement with previous functional magnetic resonance studies reporting a thinner cortex to be related to a larger functional response.
The Wessex Recent In-Patient Suicide Study, 1

Background Psychiatric patients have a higher suicide risk following hospital discharge. Aims To identify social, clinical and health-care delivery factors in recently discharged patients. Method Retrospective case-control study of 234 patients who died within 1 year of hospital discharge, matched for age, gender, diagnosis and admission period with 431 controls. Odds ratios for identified risk factors were calculated using conditional multiple logistic regression. Results Independent increased-risk factors were: not being White; living alone; history of deliberate self-harm (DSH); suicidal ideation precipitating admission; hopelessness; admission under different consultant; onset of relationship difficulties; loss of job; in-patient DSH; unplanned discharge; significant care professional leaving/on leave. Reduced-risk factors were: shared accommodation; delusions at admission; misuse of non-prescribed substances; and continuity of contact. Conclusions Continuity of contact may reduce suicide risk. Discontinuity of care from a significant professional is associated with increased risk of suicide.