Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential expression of key regulators of Toll‐like receptors in ulcerative colitis and Crohn's disease: a role for Tollip and peroxisome proliferator‐activated receptor gamma?

The innate immune system is currently seen as the probable initiator of events which culminate in the development of inflammatory bowel disease (IBD) with Toll‐like receptors (TLRs) known to be involved in this disease process. Many regulators of TLRs have been described, and dysregulation of these may also be important in the pathogenesis of IBD. The aim of this study was to perform a co‐ordinated analysis of the expression levels of both key intestinal TLRs and their inhibitory proteins in the same IBD cohorts, both ulcerative colitis (UC) and Crohn's disease (CD), in order to evaluate the potential roles of these proteins in the pathogenesis of IBD. Of the six TLRs (TLRs 1, 2, 4, 5, 6 and 9) examined, only TLR‐4 was increased significantly in IBD, specifically in active UC. In contrast, differential alterations in expression of TLR inhibitory proteins were observed. A20 and suppressor of cytokine signalling 1 (SOCS1) were increased only in active UC while interleukin‐1 receptor‐associated kinase 1 (IRAK‐m) and B cell lymphoma 3 protein (Bcl‐3) were increased in both active UC and CD. In contrast, expression of both peroxisome proliferator‐activated receptor gamma (PPARγ) and Toll interacting protein (Tollip) was decreased in both active and inactive UC and CD and at both mRNA and protein levels. In addition, expression of both PPARγ and A20 expression was increased by stimulation of a colonic epithelial cell line Caco‐2 with both TLR ligands and commensal bacterial strains. These data suggest that IBD may be associated with distinctive changes in TLR‐4 and TLR inhibitory proteins, implying that alterations in these may contribute to the pathogenesis of IBD.
Physical Function Is Weakly Associated with Angiotensin-Converting Enzyme Gene I/D Polymorphism in Elderly Japanese Subjects

Background: The turning point in the deterioration of physical function seems to occur between the ages of 70 and 80 years. In particular, muscle strength may decline even more in subjects older than 75. A recent study found that the angiotensin-converting enzyme (ACE) genotype also affects physiological left ventricular hypertrophy. A very limited number of papers have examined genetic differences in resistance and endurance forms of a single sporting discipline. Objective: The purpose of this study was to evaluate the relationship between ACE genotype and physical function by controlling the known confounding factors including dental status. Methods:We selected 431 subjects who were aged 76 years and did not require special care for their daily activities. We conducted a medical examination, followed by 5 physical function tests, as follows: (1) maximum hand grip strength, (2) maximal isometric knee extensor strength, (3) maximal stepping rate for 10 s, (4) one-leg standing time with eyes open and (5) 10-meter maximum walking speed. Subjects were genotyped for the ACE intron 16 Alu insertion. In addition, serum concentrations of total cholesterol, total protein, IgA and IgG were measured at a commercial laboratory. The Eichner index was used as an indicator of occlusal condition. Multiple linear regression analysis was performed to evaluate the relationship between the ACE gene insertion/deletion (I/D) polymorphism and physical function considering confounding factors. Results: The ACE gene I/D polymorphism was positively associated with hand grip strength and 10-meter maximum walking speed. Betas of hand grip strength were 0.09 for I/D (p = 0.022) and 0.12 for insertion/insertion (I/I; p = 0.004). Betas of 10-meter walking speed were –0.11 for I/D (p = 0.093) and –0.14 for I/I (p = 0.039). Dental status such as Eichner index class C was significantly associated with one-leg standing time with eyes open (beta –0.11; p = 0.028). Conclusion: This study suggests that there is a significant relationship between ACE genotype and physical function. In particular, subjects with the ACE deletion/deletion genotype were associated with upper extremities.
Using the cluster-based tree structure of k-nearest neighbor to reduce the effort required to classify unlabeled large datasets

The usual practice in the classification problem is to create a set of labeled data for training and then use it to tune a classifier for predicting the classes of the remaining items in the dataset. However, labeled data demand great human effort, and classification by specialists is normally expensive and consumes a large amount of time. In this paper, we discuss how we can benefit from a cluster-based tree kNN structure to quickly build a training dataset from scratch. We evaluated the proposed method on some classification datasets, and the results are promising because we reduced the amount of labeling work by the specialists to 4% of the number of documents in the evaluated datasets. Furthermore, we achieved an average accuracy of 72.19% on tested datasets, versus 77.12% when using 90% of the dataset for training.
Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates

Background & objectives In drug resistant, especially multi-drug resistant (MDR) tuberculosis, fluoroquinolones (FQs) are used as second line drugs. However, the incidence of FQ-resistant Mycobacterium tuberculosis is rapidly increasing which may be due to extensive use of FQs in the treatment of various other diseases. The most important known mechanism i.e., gyrA mutation in FQ resistance is not observed in a significant proportion of FQ resistant M. tuberculosis isolates suggesting that the resistance may be because of other mechanisms such as an active drug efflux pump. In this study we evaluated the role of the efflux pumps in quinolone resistance by using various inhibitors such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP), 2,4-dinitrophenol (DNP) and verapamil, in clinical isolates of M. tuberculosis. Methods A total of 55 M. tuberculosis clinical isolates [45 ofloxacin (OFL) resistant and 10 ofloxacin sensitive] were tested by Resazurin microtitre assay (REMA) to observe the changes in ofloxacin minimum inhibitory concentration (MIC) levels in presence of efflux inhibitors as compared to control (without efflux inhibitor). Results The MIC levels of OFL showed 2-8 folds reduction in presence of CCCP (16/45; 35.5%), verapamil (24/45; 53.3%) and DNP (21/45; 46.6%) while in case of isolates identified as OFL sensitive these did not show any effect on ofloxacin MICs. In 11 of 45 (24.5%) isolates change in MIC levels was observed with all the three inhibitors. Overall 30 (66.6%) isolates had reduction in OFL MIC after treatment with these inhibitors. A total of eight isolates were sequenced for gyrA gene, of which, seven (87.5%) showed known mutations. Of the eight sequenced isolates, seven (87.5%) showed 2 to 8 fold change in MIC in presence of efflux inhibitors. Interpretation & conclusions Our findings suggest the involvement of active efflux pumps of both Major Facilitator Super Family (MFS) family (inhibited by CCCP and DNP) and ATP Binding Cassette (ABC) transporters (inhibited by verapamil) in the development of OFL resistance in M. tuberculosis isolates. Epidemiological significance of these findings needs to be determined in prospective studies with appropriate number of samples / isolates.
Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study.

CONTEXT IL-1, IL-6, and TNF-alpha play an important role in the pathogenesis of osteoporosis in animals; however, evidence that these play a similar role in bone loss in human studies is limited. OBJECTIVE Our objective was to determine the associations between serum markers of inflammation and changes in bone mineral density (BMD) and urinary pyridinoline (PYR) to creatinine (Cr) ratio over 2.9 yr in older adults. METHODS A total of 168 randomly selected subjects (mean 63 yr, range 52-78, 48% female) was studied. BMD was measured by dual-energy x-ray absorptiometry at baseline (mean T score: -0.18 to -0.61) and 2.9 yr later. Serum high-sensitivity (hs) C-reactive protein (CRP), IL-6, TNF-alpha, and the urinary PYR/Cr ratio were measured on both occasions. RESULTS The mean annual loss of BMD was 0.15, 0.15, and 0.34% at total body, spine, and hip, respectively. Change in total body BMD was associated with baseline hs-CRP, IL-6, and TNF-alpha, as well as change in hs-CRP (beta: -0.41%/U, 95% confidence interval -0.68%, -0.15%) and IL-6 (beta: -0.62%/U, 95% confidence interval -1.01%, -0.23%). If these markers were put in the same predictive model, only IL-6 remained largely unchanged. Changes in other BMD sites were significantly predicted by IL-6 (hip and spine) and TNF-alpha (spine only). Finally, change in the PYR/Cr ratio was positively associated baseline IL-6, hs-CRP, and their changes (all P < 0.05) in women, but not men. CONCLUSIONS Variation within the low levels of inflammatory markers observed in this study, especially IL-6, predicts bone loss and resorption, suggesting that targeted antiinflammatory therapy has potential for the prevention of osteoporosis.
From the Midwestern Vascular Surgical Society Carotid endarterectomy in octogenarians : Does increased age indicate “ high risk ? ”

Objective: Carotid endarterectomy (CEA) is proven to be the most effective treatment for symptomatic carotid artery stenosis of 50% or greater and asymptomatic carotid stenosis of 60% or greater. Although the prevalence of carotid artery disease increases with age, most prospective and randomized trials have excluded patients older than 80 years, implying that they are either at higher procedural risk or have decreased life expectancy. Since advanced age (>80 years) has been viewed as a “high-risk” indicator for CEA, age >80 years has been used as an indication for alternative treatment. The study was conducted to determine if age >80 years is related to increased morbidity, mortality, and length of stay in patients undergoing CEA. Methods: In the 12-year period from 1993 to 2004, 2217 CEAs were performed in 1961 patients. Three hundred sixty procedures were performed in 334 patients >80 years. Demographics, presentation, risk factors, operative outcome, and survival were analyzed. Contemporary literature was reviewed and the results summarized. Results: In patients aged >80 years, compared with their younger cohort, there was no difference in stroke (1.1% vs 0.8%, P .333) but there was a higher operative mortality (1.9% vs 0.8%, P .053). The combined stroke/death rate was higher in octogenarians (3.1% vs 1.5%, P .041). This difference was due to the greater stroke/death rate in symptomatic octogenarians vs asymptomatic octogenarians (6.0% vs 0.9%, P .007). The average postoperative length of stay was 3.2 4.8 days for octogenarians compared with 2.4 3.5 days for their younger counterparts (P < .001). Thirty-seven percent of the octogenarians were discharged on the first postoperative day vs 51% (P < .001), whereas 13% remained hospitalized beyond 5 days vs 8% (P .003). Although Kaplan-Meier survival curves show a higher mortality in octogenarians, survival after CEA approaches that of the overall population. A summary of the contemporary literature of CEA in 2204 patients >80 shows an operative stroke rate of 2.23% and death rate of 1.28%, with a combined stroke/death rate of 3.51%. Conclusion: CEA is a safe and effective procedure in the octogenarian. The combined stroke/death rate is increased in patients aged >80, indicating increased risk, predominantly in symptomatic patients. Although CEA risk in octogenarians is higher compared with a younger cohort, outcomes remain within acceptable national guidelines and within outcome measures known to confer benefit compared with best medical care. Therefore, the term “high risk” should not be arbitrarily applied to patients reaching the 80-year threshold. This is confirmed by the contemporary literature. (J Vasc Surg 2005;41:231-7.)
Do patients on oral chemotherapy have sufficient knowledge for optimal adherence? A mixed methods study

A new treatment paradigm has emerged with many patients now receiving oral chemotherapy (OC) as first-line treatment for cancer. Treatment with OC has resulted in reduced hospital costs, more autonomy for patients but with added responsibilities for patient self-management. Little is known about patient's knowledge following patient education to enable optimal adherence with OC. A mixed methods study was carried out using a self-report questionnaire to patients on OC for multiple myeloma (MM) followed by semi-structured interviews with patients at home. Analysis identifies high rates of adherence (92.2%) with OC for MM. However, statistically significant knowledge deficits were identified, which were related to patient ethnicity and to gender. There is the potential for non-intentional non-adherence with OC due to deficits in knowledge of OC. Support at home needs to include primary care practitioners such as GPs, practice nurses and pharmacists so that timely support is easily accessible especially in the early phase of treatment.
Learning individual motion preferences from audience feedback of motion sequences

A robot performs a sequence of motions to animate a given input, e.g., dancing to music or telling a story. Each input is pre-processed to determine labels, e.g., emotions of the music or words in the story. Each label corresponds to multiple motions, and each motion has multiple labels. Therefore, the robot can choose one sequence from multiple motion sequences to animate the input. We aim to choose the best sequence to animate based on the audience's preferences. The audience prefers some motions over others, and each motion has an initially unknown preference value. At the end of the motion sequence, the audience provides feedback which is the sum of the motions' preference values. However, the observation of the feedback is noisy due to the device used to capture the audience's feedback. To select the most preferred sequence, the robot has to determine the sequence to query the audience with, so as to learn the preference values of individual motions from noisy observations of the audience's feedback. By learning the individual motion preference values, the most preferred sequence can be determined. Moreover, the audience may get bored of watching the same single motion in multiple sequences and the preference value will degrade based on the number of times the motion is viewed. We contribute MAK (Multi-Armed bandit and Kalman filter) and show that MAK outperforms least squares regression in selecting the best sequence with lower degradation in our simulation experiments.
A Rehabilitation Program for Patients Recovering from Severe Stroke

ABSTRACT: Objective: The purpose of this study was to describe the outcomes of patients with a severe stroke admitted to a specialized “slow stream” rehabilitation program and to develop a model to predict discharge destination. Methods: Chart review of 196 consecutive non-ambulatory (“lower-band”) stroke patients admitted between 1996-2001, to a specialized in-patient rehabilitation unit designed to accommodate the needs of patients with profound disabilities, and who were considered inappropriate for conventional inpatient rehabilitation programs. Special features of this program included the availability of an independent living unit, therapies tailored to individual tolerance and the opportunity to remain on the unit for an extended period until such time that the patients' rehabilitation potential had been maximized. Results: Patients were admitted to the unit after a median of 49 days following stroke onset. Their median admission and discharge functional independence measure (FIMTM) scores were 46 and 70, respectively. The improvement in ability to perform self-care tasks was statistically significant (Z= -11.18, p<0.0001). By discharge, 54 patients (28%) were able to ambulate independently (with or without an assistive device), while 142 patients (72%) remained wheelchair dependent. Eighty-five patients (43%) returned to their own home upon rehabilitation discharge, while the remainder were admitted to nursing homes or hospitals closer to the patients' home. Admission FIM score, age, no previous history of stroke and male sex were the variables found to most strongly predict discharge home. Conclusions: Patients with severe strokes who received individualized care on a highly specialized stroke rehabilitation unit achieved impressive functional outcomes despite a lag of seven weeks post stroke before rehabilitation was initiated. Many patients were no longer wheelchair dependent and almost half returned home. Active rehabilitation should not be limited to “middle-band” stroke patients.
Diagnostic significance of DOG-1 and PKC-θ expression and c-Kit/PDGFRA mutations in gastrointestinal stromal tumours

Abstract Objective. To investigate discovered on gastrointestinal stromal tumor (GIST)-1 (DOG-1) and protein kinase C-θ (PKC-θ) expression in a series of GISTs and determine the sensitivity, specificity, and diagnostic value of these two antigens. Methods. Immnunohistochemistry (IHC) was used to detect CD117, DOG-1, PKC-θ, CD34, Ki-67, α-smooth muscle actin (SMA), S100, and Desmin expression in 147 GISTs and 51 non-GISTs. c-Kit gene (exons 9, 11, 13, and 17) and platelet-derived growth factor receptor-alpha (PDGFRA) gene (exons 12 and 18) mutations were also detected. Results. About 94.5% GISTs were CD117 positive, 96% were DOG-1 positive, and 90.5% were PKC-θ positive. DOG-1 had a specificity of 100%, while CD117 and PKC-θ had a specificity of 90% and 80%, respectively. There was no significant difference between DOG-1 and PKC-θ expressions when compared to CD117 expression. In 30 out of 42 (71.5%) GISTs, a c-Kit gene mutation was found, and in 3 out of 42 cases (7%), PDGFRA was mutated. Wild-type c-Kit/PDGFRA genes accounted for 21.5% (9/42). Most c-Kit gene mutations were found to be located at exon 11, mainly as in-frame deletions. Mutations in exon 9 were all missense mutations. Most PDGFRA gene mutations were found in exon 18, codon 842. c-Kit gene mutations in exons 13 and 17, and the PDGFRA gene mutation in exon 12 were not detected. Conclusions. Compared to CD117, DOG-1 is a biomarker with higher sensitivity and specificity. The combination of CD117 and DOG-1 can be used to improve the diagnosis of GIST. Although PKC-θ has a lower specificity than DOG-1, it can be a useful biomarker, especially in CD117− and/or DOG-1− cases.
Photoactivation Approaches Reveal a Role for Rab11 in FGFR4 Recycling and Signalling

Fibroblast growth factor receptor 4 (FGFR4) plays important roles during development and in the adult to maintain tissue homeostasis. Moreover, overexpression of FGFR4 or activating mutations in FGFR4 has been identified as tumour‐promoting events in several forms of cancer. Endocytosis is important for regulation of signalling receptors and we have previously shown that FGFR4 is mainly localized to transferrin‐positive structures after ligand‐induced endocytosis. Here, using a cell line with a defined pericentriolar endocytic recycling compartment, we show that FGFR4 accumulates in this compartment after endocytosis. Furthermore, using classical recycling assays and a new, photoactivatable FGFR4‐PA‐GFP fusion protein combined with live‐cell imaging, we demonstrate that recycling of FGFR4 is dependent on Rab11. Upon Rab11b depletion, FGFR4 is trapped in the pericentriolar recycling compartment and the total levels of FGFR4 in cells are increased. Moreover, fibroblast growth factor 1 (FGF1)‐induced autophosphorylation of FGFR4 as well as phosphorylation of phospholipase C (PLC)‐γ is prolonged in cells depleted of Rab11. Interestingly, the activation of mitogen‐activated protein kinase and AKT pathways were not prolonged but rather reduced in Rab11‐depleted cells, indicating that recycling of FGFR4 is important for the nature of its signalling output. Thus, Rab11‐dependent recycling of FGFR4 maintains proper levels of FGFR4 in cells and regulates FGF1‐induced FGFR4 signalling.
Modeling of protein binary complexes using structural mass spectrometry data

In this article, we describe a general approach to modeling the structure of binary protein complexes using structural mass spectrometry data combined with molecular docking. In the first step, hydroxyl radical mediated oxidative protein footprinting is used to identify residues that experience conformational reorganization due to binding or participate in the binding interface. In the second step, a three‐dimensional atomic structure of the complex is derived by computational modeling. Homology modeling approaches are used to define the structures of the individual proteins if footprinting detects significant conformational reorganization as a function of complex formation. A three‐dimensional model of the complex is constructed from these binary partners using the ClusPro program, which is composed of docking, energy filtering, and clustering steps. Footprinting data are used to incorporate constraints—positive and/or negative—in the docking step and are also used to decide the type of energy filter—electrostatics or desolvation—in the successive energy‐filtering step. By using this approach, we examine the structure of a number of binary complexes of monomeric actin and compare the results to crystallographic data. Based on docking alone, a number of competing models with widely varying structures are observed, one of which is likely to agree with crystallographic data. When the docking steps are guided by footprinting data, accurate models emerge as top scoring. We demonstrate this method with the actin/gelsolin segment‐1 complex. We also provide a structural model for the actin/cofilin complex using this approach which does not have a crystal or NMR structure.
Shedding of the soluble form of CD30 from the Hodgkin‐analogous cell line L540 is strongly inhibited by a new CD30‐specific antibody (Ki‐4)

The CD30‐activation marker was detected as the Hodgkin‐associated Ki‐I antigen and is regarded as a target for the treatment of Hodgkin patients with immunotoxins. The CD30 is released from tumor cells and this soluble CD30 (sCD30) is an indicator of the disease activity. Since the shedding of sCD30 may be influenced by antibodies, we produced 6 new CD30‐specific antibodies (Ki‐2 to Ki‐7) for the purpose of finding antibodies that might inhibit the formation of sCD30. Ki‐2 to Ki‐7 and the other anti‐CD30 antibodies Ki‐I, Ber‐H2, HeFi‐l, M44, M67, HRS‐I, HRS‐4 and CIO were employed for epitope mapping. The binding of a particular radio‐labeled anti‐CD30 antibody to Hodgkin's‐disease‐derived L540 cells was completed by addition of the various non‐labeled anti‐CD30 antibodies. Three non‐overlapping regions, expressing different antigen‐specific determinants, could be defined on the extracellular part of the CO30 molecule. Cluster A of determinants was recognized by Ki‐2, Ki‐4, Ki‐6 and Ki‐7, Ber‐H2, HRS‐I and HRS‐4, while cluster B was detected by Ki‐I, Ki‐S and M67. Cluster C, which probably contains the binding site for the CD30 ligand, was defined by Ki‐3, M44, HeFi‐l and CIO. Co‐culture experiments of LS40 cells with the various antibodies followed by the isolation of sCD30 from culture supernatant fluids revealed that the release of sCD30 was most strongly increased by Ki‐I and weakly enhanced by Ki‐2, Ki‐3, Ki‐5 and HeFi‐l, whereas it was almost completely inhibited by Ki‐4 and to a slightly lesser extent by Ber‐H2.