Miracle-dz/UniFAR-FTUs huggingface dataset:
A Novel Model System for Characterization of Phagosomal Maturation, Acidification, and Intracellular Collagen Degradation in Fibroblasts*

Intracellular collagen degradation by fibroblasts is an important but poorly understood pathway for the physiological remodeling of mature connective tissues. The objective of this study was to determine whether gingival fibroblasts that express endogenous α2β1 integrin, the collagen receptor, would exhibit the cellular machinery required for phagosomal maturation and collagen degradation. There was a time-dependent increase of collagen bead internalization and a time-dependent decrease of bead-associated α2β1 integrin after initial bead binding. β-Actin and gelsolin associated transiently with beads (0–30 min) followed by LAMP-2 (60–240 min) and cathepsin B (30–240 min). Cytochalasin D prevented phagosome formation and also prevented the sequential fusion of early endosomes with lysosomes. Collagen bead-associated pH was progressively reduced from 7.25 to 5.4, which was contemporaneous with progressive increases in degradation of bead-associated collagen (30–120 min). Concanamycin blocked acidification of phagolysosomes and collagen degradation but not phagosome maturation. Phagosomal acidification was partly dependent on elevated intracellular calcium. These studies demonstrate that the cellular machinery required for intracellular collagen degradation in fibroblasts closely resembles the vacuolar system in macrophages.
Role of HSP60 (HSPD1) in diabetes‐induced renal tubular dysfunction: regulation of intracellular protein aggregation, ATP production, and oxidative stress

Because underlying mechanisms of diabetic nephropathy/tubulopathy remained poorly understood, we aimed to define a key protein involving in hyperglycemia‐induced renal tubular dysfunction. All altered renal proteins identified from previous large‐scale proteome studies were subjected to global protein network analysis, which revealed heat shock protein 60 (HSP60, also known as HSPD1) as the central node of protein–protein interactions. Functional validation was performed using small interfering RNA (siRNA) to knock down HSP60 (siHSP60). At 48 h after exposure to high glucose (HG) (25 mM), Madin‐Darby canine kidney (MDCK) renal tubular cells transfected with controlled siRNA (siControl) had significantly increased level of HSP60 compared to normal glucose (NG) (5.5 mM), whereas siHSP60‐transfected cells showed a dramatically decreased HSP60 level. siHSP60 modestly increased intracellular protein aggregates in both NG and HG conditions. Luciferin–luciferase assay showed that HG modestly increased intracellular ATP, and siHSP60 further enhanced such an increase. OxyBlot assay showed significantly increased level of oxidized proteins in HG‐treated siControl‐transfected cells, whereas siHSP60 caused marked increase of oxidized proteins under the NG condition. However, the siHSP60‐induced accumulation of oxidized proteins was abolished by HG. In summary, our data demonstrated that HSP60 plays roles in regulation of intracellular protein aggregation, ATP production, and oxidative stress in renal tubular cells. Its involvement in HG‐induced tubular cell dysfunction was most likely via regulation of intracellular ATP production. —Aluksanasuwan, S. , Sueksakit, K. , Fong‐ngern, K. , Thongboonkerd, V. Role of HSP60 (HSPD1) in diabetes‐induced renal tubular dysfunction: regulation of intracellular protein aggregation, ATP production, and oxidative stress. FASEB J. 31, 2157–2167 (2017). www.fasebj. org
randomised controlled trial programme in less advanced COPD : a community-based COPD management Short-and long-term efficacy of a

http://thorax.bmj. com/content/65/1/7.full. html Updated information and services can be found at: These include: References http://thorax.bmj. com/content/65/1/7.full. html#ref-list-1 This article cites 30 articles, 17 of which can be accessed free at: service Email alerting box at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in the Notes
Impact of Out-of-Pocket Costs on Prescription Fills Among New Initiators of Biologic Therapies for Rheumatoid Arthritis

BACKGROUND: Biologic disease-modifying antirheumatic drug (DMARD) therapies are a mainstay of treatment for rheumatoid arthritis (RA), yet high member out-of-pocket (OOP) costs for such therapies may limit patient access to these therapies. OBJECTIVE: To understand whether there is a relationship between OOP costs and the initial fill and subsequent refills of biologic DMARD treatments for RA members. METHODS: Members of a national Medicare Advantage and Prescription Drug (MAPD) plan with an adjudicated (paid or reversed) claim for a biologic DMARD indicated for RA were identified from July 1, 2007, to December 31, 2012, and followed retrospectively. The first adjudicated claim date was the index date. Members were required to have 180 days of continuous enrollment pre- and post-index and ≥ 1 diagnosis for RA (ICD-9-CM: 714.0 or 714.2) during pre-index or ≤ 30 days post-index. Low-income subsidy and Medicaid-Medicare dual-eligible patients were excluded. The analysis used multivariate regression models to examine associations between initial prescription (Rx) abandonment rates and OOP costs and factors influencing the refill of a biologic DMARD therapy based on pharmacy claims. RESULTS: The final sample size included 864 MAPD members with an adjudicated claim for a biologic DMARD. The majority were female (77.4%) and mean age was 63.5 years (SD = 10.9). Most (78%) had conventional nonbiologic DMARD utilization during pre-index. The overall initial abandonment rate was 18.2% for biologic DMARDs, ranging from 1.3% for the lowest OOP cost group ($0-$250) to 32.7% for the highest OOP cost group (> $550; P < 0.0001 for Cochran-Armitage trend test). ORs for abandonment rose from 18.4 to 32.7 to 41.2 for OOP costs of $250.01-$400.00, $400.01-$550.00, and > $550.00 respectively, relative to OOP costs of ≤ $250.00 (all P < 0.0001). Meeting the catastrophic coverage limit and utilization of a specialty pharmacy for the index claim were both associated with a decreased likelihood of abandoning therapy (OR = 0.29 and OR = 0.14, respectively; both P < 0.05). Among the subset of 533 members with a paid claim, 82.4% had at least 1 refill post-index. The negative association between OOP cost and likelihood of refilling an Rx was highly significant (P < 0.0001). CONCLUSIONS: This study suggests that the higher the member OOP cost, the less likely an MAPD member is to initiate or refill a biologic DMARD therapy for RA. Further research is needed to understand reasons for initial Rx abandonment and lack of refills, including benefit design and adverse events.
A multidimensional decision-making model for internationalization of high-tech SMEs in transition economics

Until now, international entrepreneurship has mainly used stage theory, institutional theory, transaction cost economics and the resource-based view to explain or describe the internationalization of SMEs in transition economy context. Following recent literature we contend that these approaches are highlighting interesting elements of decision processes for internationalization, but are not yet enough managerial applicable because of the unidimensionality of these theories. We provide a model in four steps which enables multidimensional analyses of internationalization processes. In this the strengths and weaknesses in the strategic, economic, cultural and social network capital of the focal firm are assessed. Shortcomings in these capitals can be complemented by their partners to increase chances of successful internationalization. This article is a deductive study on three innovative Russian high-tech SMEs. The first case illustrates a clear fit with a potential partner, the second case describes a poor fit and in the third case the firm would not benefit from internationalization.
[Surgery versus radiotherapy in Ewing's sarcoma with good prognosis. Analysis of the CESS-86 data].

PURPOSE The evaluation of radiotherapy and surgery as exclusive local treatment in comparably selected subgroups of patients with Ewing's sarcoma on the basis of the CESS 86-data. PATIENTS AND METHODS In the German multicenter Ewing's sarcoma study CESS 86, treatment consisted of four 9-week-courses of VACA- or VAIA-chemotherapy plus local therapy. VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin) was given in low-risk extremity tumors with a tumor volume below 100 cm3. High-risk patients with central lesions or a tumor volume > 100 cm3 received VAIA (ifosfamide instead of cyclophosphamide). Local therapy started after one complete chemotherapy course in week 10. Based on an individual decision in each patient, local therapy was either radical surgery or resection plus postoperative irradiation with 45 Gy or definitive radiotherapy with 60 Gy. Because of poor results with radiotherapy in a preceding study, it was intended to restrict irradiation to patients with small lesions. RESULTS Hundred and seventy-seven protocol patients were recruited from January 1986 through June 1991 and 176 received local therapy: 39 underwent radical surgery, 44 received definitive radiotherapy and 93 were treated with resection and postoperative irradiation. The median tumor volume was higher in patients with radiotherapy as compared to combined local treatment or radical surgery, 156 cm3 versus 140 cm3 versus 102 cm3. The overall 5-year survival after radiotherapy and surgery was nearly identical, 63% versus 67% for the whole group 75% versus 65% in tumors < 100 cm3 volume and 65% versus 67% in tumors with 100 cm3 to 600 cm3 volume, respectively. CONCLUSIONS With regard to tumor volume, the most important single prognostic factor in Ewing's sarcoma, irradiated patients were poorer selected than surgically treated patients despite the fact that a selection of good-risk patients for radiotherapy was intended. The nearly identical survival figures after surgery and radiotherapy suggest that radiotherapy is as effective as surgery if selection of patients is comparable.
A Hybrid Conditions-Dependent Outage Model of a Transformer in Reliability Evaluation

Constant failure rate model used in the conventional reliability assessment of power systems cannot reflect the impacts of the various operating conditions such as transformer loading, ambient temperature, weather on component reliability. A hybrid conditions-dependent outage model (CDOM) of a transformer is proposed in this paper to include those impacts. The CDOM is the combination of three failure models: the aging failures due to the loss of mechanical strength of conductor insulation; the random failures considering weather conditions, and the outages caused by the direct trips of the overload protections. The component reliability using the proposed model has been tested under different operating conditions. The model is also applied in power system operational reliability assessment. The reliability indices using CDOM are compared with that using the condition-independent outage model. The reliability indices using the CDOMs of transformers can provide useful information for operators to understand possible system and component failure risk in real-time operation and to make important alleviation decisions.
Average membrane penetration depth of tryptophan residues of the nicotinic acetylcholine receptor by the parallax method.

The membrane penetration depths of tryptophan residues in the nicotinic acetylcholine receptor from Torpedo californica have been analyzed in reconstituted membranes containing purified receptor and defined lipids. Dioleoylphosphatidylcholine and three spin-labeled phosphatidylcholines with the nitroxide group at three different positions on the fatty acyl chain were used for reconstitution of the receptor. The spin-labeled phospholipids serve as quenchers of tryptophan fluorescence. Differential quenching of the intrinsic fluorescence of the acetylcholine receptor by the spin-labeled phospholipids has been utilized to analyze the average membrane penetration depth of tryptophans by the parallax method [Chattopadhyay, A. , & London, E. (1987) Biochemistry 26, 39-45]. Analyses of the quenching data indicate that the tryptophan residues on the average are at a shallow location (10.1 A from the center of the bilayer) in the membrane. In addition, the generally low levels of quenching imply that the majority of tryptophan residues are located in the putative extramembranous region of the receptor. These results are consistent with several proposed models for the tertiary structure of the acetylcholine receptor and are relevant to ongoing analyses of the overall conformation and orientation of the acetylcholine receptor in the membrane.
Electron microscopy and subunit-subunit interaction studies reveal a first architecture of COP9 signalosome.

The COP9 signalosome is involved in signal transduction, whereas the 26 S proteasome lid is a regulatory subcomplex of the 26 S proteasome responsible for degradation of ubiquitinated proteins. COP9 signalosome and lid possess significant sequence homologies among their eight core subunits and are likely derived from a common ancestor. Surprisingly, from our two-dimensional electron microscopy data, a common architectural plan for the two complexes could not be deduced. None-the-less, the two particles have structural features in common. Both COP9 signalosome and lid lack any symmetry in subunit arrangement and exhibit a central groove, possibly qualified for scaffolding functions.Filter-binding assays with recombinant COP9 signalosome components revealed a multitude of subunit-subunit interactions, supporting the asymmetrical appearance of the complex in electron microscopy. On the basis of two-dimensional images and subunit interaction studies, a first architectural model of COP9 signalosome was created. The fact that four distinct classes of particle views were identified and that only 50 % of the selected particles could be classified indicates a high degree of heterogeneity in electron microscopic images. Different orientations with respect to the viewing axis and conformational variety, presumably due to different grades of phosphorylation, are possible reasons for the heterogeneous appearance of the complex. Our biochemical data show that recombinant COP9 signalosome subunits 2 and 7 are phosphorylated by the associated kinase activity. The modification of COP9 signalosome subunit 2 might be essential for c-Jun phosphorylation. Dephosphorylation does not inactivate the associated kinase activity. Although substrate phosphorylation by COP9 signalosome is significantly decreased by lambda protein phosphatase treatment, "autophosphorylation" is increased.
IFNβ lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS

Objective: To 1)determine serum levels of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in patients with secondary progressive (SP) MS; 2)determine the relationship between these serum levels and MRI activity; and 3) evaluate the effect of interferon (IFN) therapy on these measures. Background: High serum levels of MMP-9 and low levels of TIMP-1 predict the appearance of new gadolinium-enhancing (Gd+) lesions in relapsing-remitting (RR) MS. Methods: Monthly Gd+ brain MRI and measures of serum MMP-2, MMP-9, TIMP-1, and TIMP-2 at 3-month intervals were performed for up to 3 years in 33 patients with SPMS participating in a phase III study of IFNβ-1b. Results: Patients who developed new Gd+ lesions had higher levels of MMP-9 than patients who did not develop Gd+ lesions (median 351 vs 226 ng/mL, p = 0.049). The ratio of MMP-9/TIMP-1 predicted new Gd+ lesion on the concurrent scan (OR = 2.23, 95% CI 0.99 to 4.99, p = 0.052) and on the following scan (OR = 2.16, 95% CI 1.01 to 4.63, p = 0.048), whereas levels of MMP-2/TIMP-2 did not. Median levels of TIMP-1 were higher and MMP-9 trended lower for IFNβ compared to placebo recipients (TIMP-1: 1,450 vs 1,185 ng/mL, p = 0.024; MMP-9: 225 vs 339 ng/mL, p = 0.081). IFNβ did not influence levels of MMP-2 and TIMP-2. Conclusion: The ratio of MMP-9/TIMP-1 may predict MRI activity in SPMS. The effect of IFNβ-1b in MS, as measured by reduction in new Gd+ lesions, may be partly explained by altering MMP-9/TIMP-1 ratio.
Socialized to Ruminate? Gender Role Mediates the Sex Difference in Rumination for Interpersonal Events

The marked sex difference in depression has been explained in part by the sex difference in rumination. However, we know little about why females are more likely than males to ruminate. One explanation is that greater feminine gender role identification may be associated with a greater tendency to ruminate. In Part 1 of this study, we examined gender role as a mediator of the sex difference in trait rumination for domain-specific stressors among 136 older adolescents (ages 14 to 20; 40% male). Although females were more likely than males to ruminate about all types of stressors, we found that femininity accounted for the sex difference in trait rumination about interpersonal, Coefficient = . 09, 95% CI (.01, .21), R2 = . 16, but not achievement stressors Coefficient = . 02, 95% CI (−.04, .14), R2 = . 10. In Part 2 of the study, we prospectively followed 107 of the initial 136 participants to track state rumination about specific interpersonal and achievement stressors. Using a weekly diary design, participant.
I-Vectors from DNN Senone Posteriors

Motivated by recent gains in speaker identification by incorporating senone posteriors from deep neural networks (DNNs) into i-vector extraction, we examine similar enhancements to speaker diarization with i-vector clustering. We examine two DNNs with different numbers of senone targets in combination with a diagonal or full covariance universal background model (UBM) in the context of the multilingual corpus CALLHOME. Results show that the larger DNN with a full covariance UBM gives the best performance. The improvements appear to have a strong dependence on number of speakers in a conversation, and a lesser dependence on language. Overall, when combined with resegmentation, the proposed system improves CALLHOME performance to 10.3% DER.
Proceedings of the 8th ACM SIGMOD workshop on Research issues in data mining and knowledge discovery, DMKD 2003, San Diego, California, USA, June 13, 2003

Continuous data streams arise naturally, for example, in the installations of large telecom and Internet service providers where detailed usage information (Call-Detail-Records, SNMP/RMON packet-flow data, etc.) from different parts of the underlying network needs to be continuously collected and analyzed for interesting trends. Such environments raise a critical need for effective stream-processing algorithms that can provide (typically, approximate) answers to data-analysis queries while utilizing only small space (to maintain concise stream synopses) and small processing time per stream item. In this talk, I will discuss the basic pseudo-random sketching mechanism for building stream synopses and our ongoing work that exploits sketch synopses to build an approximate SQL (multi) query processor. I will also describe our recent results on extending sketching to handle more complex forms of queries and streaming data (e.g., similarity joins over streams of XML trees), and try to identify some challenging open problems in the data-streaming area. DMKD03: 8th ACM SIGMOD Workshop on Research Issues in Data Mining and Knowledge Discovery, 2003 page 1 DMKD03: 8th ACM SIGMOD Workshop on Research Issues in Data Mining and Knowledge Discovery, 2003 page 2 A Symbolic Representation of Time Series, with Implications for Streaming Algorithms Jessica Lin Eamonn Keogh Stefano Lonardi Bill Chiu University of California Riverside Computer Science & Engineering Department Riverside, CA 92521, USA {jessica, eamonn, stelo, bill}@cs.ucr. edu
Active women before/after an intervention designed to restore menstrual function: resting metabolic rate and comparison of four methods to quantify energy expenditure and energy availability.

UNLABELLED It is hypothesized that exercise-related menstrual dysfunction (ExMD) results from low energy availability (EA), defined as energy intake (EI)--exercise energy expenditure (EEE). When EI is too low, resting metabolic rate (RMR) may be reduced to conserve energy. PURPOSE To measure changes in RMR and EA, using four methods to quantify EEE, before/after a 6-month diet intervention aimed at restoring menses in women with ExMD; eumenorrheic (Eumen) active controls (n = 9) were also measured. METHODS Active women with ExMD (n = 8) consumed +360 kcal/d (supplement) for 6 months; RMR was measured 2 times at 0 months/6 months. EI and total energy expenditure (TEE) were estimated using 7-day diet/activity records, with EA assessed using four methods to quantify EEE. RESULTS At baseline, groups did not differ for age, gynecological age, body weight, lean/fat mass, VO₂max, EI and EA, but mean TEE was higher in ExMD (58.3 ± 4.4 kcal/ kgFFM/d; Eumen = 50.6 ± 2.4; p < .001) and energy balance (EB) more negative (-10.3 ± 6.9 kcal/kgFFM/d; Eumen=-3.0 ± 9.7; p = .049). RMR was higher in ExMD (31.3 ± 1.8 kcal/kgFFM/d) vs. Eumen (29.1 ± 1.9; p < .02). The intervention increased weight (1.6 ± 2.0 kg; p = .029), but there were no significant changes in EA (0-month range = 28.2-36.7 kcal/kgFFM/d; 6-month range = 30.0-45.4; p > .05), EB (6 months = -0.7 ± 15.1 kcal/kgFFM/d) or RMR (0 months = 1515 ± 142; 6 months = 1522 ± 134 kcal/d). Assessment of EA varied dramatically (~30%) by method used. CONCLUSIONS For the ExMD group, EI and weight increased with +360 kcal/d for 6 months, but there were no significant changes in EB, EA or RMR. No threshold EA value was associated with ExMD. Future research should include TEE, EB and clearly quantifying EEE (e.g.,>4 MET) if EA is measured.
Identification of human immunodeficiency virus type 1 envelope genes recombinant between subtypes B and F in two epidemiologically linked individuals from Brazil

Sequence analysis of a human immunodeficiency virus type 1 env gene PCR amplified from a Brazilian woman's peripheral blood mononuclear cell DNA (sample RJIO1) showed that it was likely to have been derived from a double recombination event between human immunodeficiency virus type 1 subtypes B and F. The major portion of the gp120 coding sequence belonged to the B lineage, but a segment of the C2 to V3 region (approximately 135 nucleotides) clearly associated with sequences of the F lineage. The subtype F-like segment had 15 noncontiguous signature nucleotides in common with Brazilian subtype F sequences that were not found, or were rare, in subtype B sequences. In contrast, this same segment had only 3 signature nucleotides shared with subtype B sequences and not present in the Brazilian subtype F sequences. Phylogenetic analysis, amino acid signature pattern analysis, and the pattern of synonymous mutations all supported the hypothesis of a recombinational origin of the RJIO1 sequence. Related recombinant genes were also detected in peripheral blood mononuclear cell DNA obtained from the woman's recent sexual partner, indicating that the recombination event probably occurred at some previous time in the chain of virus transmission. Divergent viral sequences in the V3 region were found in the male sexual partner, while a relatively homogeneous viral population was detected in the woman, consistent with her recent infection.