Miracle-dz/UniFAR-FTUs huggingface dataset:
Cost-effectiveness of add-on treatments to metformin in a Swedish setting: liraglutide vs sulphonylurea or sitagplitin

Abstract Objective: To evaluate long-run cost-effectiveness in a Swedish setting for liraglutide compared with sulphonylureas (glimepiride) or sitagliptin, all as add-on to metformin for patients with type 2 diabetes insufficiently controlled with metformin in monotherapy. Methods: The IHE Cohort Model of Type 2 Diabetes was used to evaluate clinical and economic outcomes from a societal perspective. Model input data were obtained from two clinical trials, the Swedish National Diabetes Register and the literature. Cost data reflected year 2013 price level. The robustness of results was checked with one-way-sensitivity analysis and probability sensitivity analysis. Results: The cost per QALY gained for liraglutide (1.2 mg) compared to SU (glimepiride 4 mg), both as add-on to metformin, ranged from SEK 226,000 to SEK 255,000 in analyzed patient cohorts. The cost per QALY for liraglutide (1.2 mg) vs sitagliptin (100 mg) as second-line treatment was lower, ranging from SEK 149,000 to SEK 161,000. Costs of preventive treatment were driving costs, but there was also a cost offset from reduced costs of complications of ∼20%. Notable cost differences were found for nephropathy, stroke, and heart failure. The predicted life expectancy with liraglutide increased the cost of net consumption for liraglutide. Limitations: The analysis was an ex-ante analysis using model input data from clinical trials which may not reflect effectiveness in real-world clinical practice in broader patient populations. This limitation was explored in the sensitivity analysis. The lack of specific data on loss of production due to diabetes complications implied that these costs may be under-estimated. Conclusions: Treatment strategies with liraglutide 1.2 mg improved the expected quality-of-life and increased costs when compared to SU and to sitagliptin for second-line add-on treatments. The cost per QALY for liraglutide was in the range considered medium by Swedish authorities.
Sites of specific B cell activation in primary and secondary responses to T cell‐dependent and T cell‐independent antigens

Techniques which identify hapten‐specific B cells in tissues have been used to determine the sites of B cell activation in rat spleens in response to T cell‐dependent (TD) antigens and T cell‐independent type‐1 (TI‐1) antigens. Surface‐associated hapten binding by specific memory B cells and. B blasts was distinguished from the strong cytoplasmic hapten binding by specific plasma cells and plasmablasts. Blast cells in S phase were identified in tissue sections by staining cells which had been pulse labeled in vivo with 5‐bromo‐2′‐deoxyuridine.
Speech segmentation by statistical learning is supported by domain-general processes within working memory

The purpose of this study was to examine the extent to which working memory resources are recruited during statistical learning (SL). Participants were asked to identify novel words in an artificial speech stream where the transitional probabilities between syllables provided the only segmentation cue. Experiments 1 and 2 demonstrated that segmentation performance improved when the speech rate was slowed down, suggesting that SL is supported by some form of active processing or maintenance mechanism that operates more effectively under slower presentation rates. In Experiment 3 we investigated the nature of this mechanism by asking participants to perform a two-back task while listening to the speech stream. Half of the participants performed a two-back rhyme task designed to engage phonological processing, whereas the other half performed a comparable two-back task on un-nameable visual shapes. It was hypothesized that if SL is dependent only upon domain-specific processes (i.e., phonological rehearsal), the rhyme task should impair speech segmentation performance more than the shape task. However, the two loads were equally disruptive to learning, as they both eradicated the benefit provided by the slow rate. These results suggest that SL is supported by working-memory processes that rely on domain-general resources.
Effects of dopamine D-1 and D-2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat.

The effects of three dopamine D-1 receptor antagonists (SCH23390, SCH39166 and A69024) and three dopamine D-2 antagonists (raclopride, eticlopride and spiperone) on cocaine self-administration maintained under different schedules of reinforcement were examined in the rat. Intravenous cocaine self-administration was maintained under a fixed-ratio (FR) 5 schedule with a 20-sec timeout (TO) after each reinforcement or a FR 15 with a 2-min TO multiple schedule of cocaine (0.25 mg i.v.) and food (45 mg) reinforcement. With the exception of raclopride, all of the antagonists altered the self-administration of cocaine in a manner similar to decreasing the unit dose of cocaine under the schedule in effect, reflected by increased self-administration under the FR 5 TO 20-sec schedule and decreased self-administration under the FR 15 TO 2-min multiple schedule. Moreover, a low dose of either of the benzazepine dopamine D-1 antagonists SCH23390 or SCH39166, but not the other compounds, selectively reduced cocaine self-administration without altering responding for food under the multiple schedule. Conversely, a low dose of raclopride or A69024 selectively decreased food-reinforced responding without altering cocaine self-administration under the multiple schedule. These results suggest that benzazepine dopamine D-1 antagonists, at low doses, may attenuate the reinforcing properties of cocaine more selectively than other dopamine receptor antagonists. The results also demonstrate the advantages of using different schedules to investigate the effects of dopamine D-1 and D-2 antagonists on cocaine self-administration.
Induced l2 filtering of fuzzy stochastic systems with time-varying delays

This paper is concerned with the problem of induced l2 filter design for a class of discrete-time Takagi-Sugeno fuzzy Itô stochastic systems with time-varying delays. Attention is focused on the design of the desired filter to guarantee an induced l2 performance for the filtering error system. A new comparison model is proposed by employing a new approximation for the time-varying delay state, and then, sufficient conditions for the obtained filtering error system are derived by this comparison model. A desired filter is constructed by solving a convex optimization problem, which can be efficiently solved by standard numerical algorithms. Finally, simulation examples are provided to illustrate the effectiveness of the proposed approaches.
Regional Spatial Normalization: Toward an Optimal Target

Purpose The purpose of this work was to develop methods for defining, constructing, and evaluating a “minimal deformation target” (MDT) brain for multisubject studies based on analysis of the entire group. The goal is to provide a procedure that will create a standard, reproducible target brain image based on common features of a group of three-dimensional MR brain images. Method The average deformation and dispersion distance, derived from discrete three-dimensional deformation fields (DFs), are used to identify the best individual target (BIT) brain. This brain is assumed to be the one with the minimal deformation bias within a group of MR brain images. The BIT brain is determined as the one with the minimal target quality score, our cost function based on the deformation displacement and dispersion distance. The BIT brain is then transformed to the MDT brain using an average DF to create an optimized target brain. This analysis requires the calculation of a large number of DFs. To overcome this limitation, we developed an analysis method (the fast method) that reduces the task from order N2 complexity to one of order N, a tremendous advantage for large-N studies. Results Multiscale correlation analysis in a group of 20 subjects demonstrated the superiority of warping using the MDT target brain, made from the BIT brain, over several individual and MDT-transformed target brains also from the group. Conclusion Analysis of three-dimensional DF provides a means to quickly create a reproducible MDT target brain for any set of subjects. Warping to the MDT target was shown by an independent multiscale correlation method to produce superior results.
Estimation of the state of charge of Ni-MH battery pack based on artificial neural network

To track the state of charge (SOC) of Ni-MH battery pack at the hybrid electric vehicle, an artificial neural network (ANN) is designed. Current, voltage and the previous SOC are used to inputs of ANN, and output is SOC. The result show that, this artificial neural network can track the state of charge(SOC) of the batteries accurately, in the average tracking error less than 5%; the ANN is in low dependence on the initial SOC, and the output can be achieved target value only in 90 seconds.
Plateins: A Novel Family of Signal Peptide-Containing Articulins in Euplotid Ciliates1

Abstract In euplotid ciliates, the cortex is reinforced by alveolar plates—proteinaceous scales located within the membranous alveolar sacs, forming a monolayer just below the plasma membrane. This system appears to play a cytoskeletal role analogous to that provided by the fibrous epiplasm found beneath the cortical alveoli in other ciliates. In Euplotes aediculatus, the major alveolar plate proteins (termed α-, β-, and γ-plateins) have been identified. Using anti-platein antibodies, an expression library of Euplotes genes was screened, and a platein gene identified, cloned, and completely sequenced. Comparison of its derived amino acid sequence with microsequences obtained directly from purified plateins identified this gene as encoding one of the closely related β- or γ-plateins. The derived protein, of 644 amino acids (74.9 kDa), is very acidic (pI = 4.88). Microsequences from authentic α-platein were then used to design oligonucleotide primers, which yielded, via a PCR-based approach, the sequences of two α-platein genes from E. aediculatus. Even more acidic proteins, the derived α1- and α2-plateins contain 536 and 501 residues, respectively. Analyses of their amino acid sequences revealed the plateins to be members of the articulin superfamily of cytoskeletal proteins, first described in Euglena and now identified in the ciliate Pseudomicrothorax and in Plasmodium. The hallmark articulin repetitive motifs (based on degenerate valine- and proline-rich 12-mers) are present in all three plateins. In β/γ-platein this primary motif domain (27 repeats) is central in the molecule, whereas the primary repeats in the α-plateins lie near their C-termini. A cluster of proline-rich pentameric secondary repeats is found in the C-terminus of β/γ-platein, but near the N-terminus of α-plateins. All three plateins contain canonical N-terminal signal sequences, unique among known cytoskeletal proteins. The presence of start-transfer sequences correlates well with the final intra-alveolar location of these proteins. This feature, and significant differences from known articulins in amino acid usage and arrangement within the repeat domains, lead us to propose that the plateins comprise a new family of articulin-related proteins. Efforts to follow microscopically the assembly of plateins into new alveolar plates during pre-fission morphogenesis are underway.
Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto's thyroiditis.

CONTEXT Th17 lymphocytes play an important role in different chronic inflammatory and autoimmune conditions. AIM The aim of the study was to explore the status of Th17 cells in patients with autoimmune thyroid diseases (AITD). DESIGN We assessed the serum levels and in vitro synthesis of IL-17 and IL-22 and of different cytokines (IL-6, IL-15, and IL-23) involved in the differentiation of Th17 cells in the peripheral blood and thyroid glands of 26 patients with AITD, eight with Graves' disease, and 18 with Hashimoto's thyroiditis (HT) as well as 10 healthy controls. RESULTS We found enhanced levels of T cells synthesizing IL-17 and IL-22 in the peripheral blood from AITD patients, mainly in those with HT. In addition, a stronger expression of IL-17 and IL-22 and an enhanced number of IL-23R(+) cells was detected in thyroid glands from HT patients compared with Graves' disease or controls. Furthermore, increased concentrations of IL-6 and IL-15 were detected in sera from HT patients, whereas serum levels of IL-23 tended to be higher in these patients. Finally, an enhanced in vitro differentiation of T lymphocytes into Th17 cells induced by IL-23/IL-6 was observed in AITD patients. Accordingly, a strong induction of RORC2 gene was detected in lymphocytes from HT patients when stimulated with IL-23. CONCLUSION Our results indicate that there is an increased differentiation of Th17 lymphocytes and an enhanced synthesis of Th17 cytokines in AITD, mainly in HT. These phenomena may have an important role in the pathogenesis of thyroid autoimmunity.
The clinical and radiographic outcome of implants placed in the posterior maxilla with a guided flapless approach and immediately restored with a provisional rehabilitation: a randomized clinical trial.

OBJECTIVES To evaluate and compare the outcome of dental implants placed using a flapless protocol and immediate loading with a conventional protocol and loading after 6 weeks. MATERIALS AND METHODS Fourteen patients with bilateral maxillary edentulous areas were treated using Straumann SLA-implants. Using a randomized split-mouth design, implants were placed in one side of the maxilla using a stereolithographic surgical guide for flapless surgery and immediately loaded on temporary abutments with a bridge (test). Implants in the other side were placed using the conventional protocol and loaded after 6 weeks of healing (control). Clinical and radiographic evaluation of peri-implant tissues was performed at time of implant surgery, and after 1 week, 6 weeks, 3, 6, 12 and 18 months. RESULTS A total of 70 implants were placed (36 test and 34 control). One implant (test) was lost after 3 months, resulting in a survival rate of 97.3% for the test implants and 100% for the control implants. Marginal bone levels were not statistically significantly different between the test and control implants but at baseline the marginal bone level was significantly lower compared to the other evaluation periods (P < 0.05). The mean bone level for test and control implants was 1.95 mm ± 0.70 and 1.93 mm ± 0.42 after 18 months, respectively. There was a significant change in height of the attached mucosa at implants placed with a conventional flap between post-operative and 1 week and between 1 week and 6 weeks. Statistically significant differences were found between the test side and the control side for opinion about speech, function, aesthetics, self-confidence and overall appreciation the first 6 weeks. CONCLUSION Implants can successfully integrate in the posterior maxilla using a flapless approach with immediate loading similar to a conventional protocol. The mucosal tissues around implants placed with a conventional flap changed significantly compared with flapless placed implants.
Conditioned medium as a strategy for human stem cells chondrogenic differentiation

Paracrine signalling from chondrocytes has been reported to increase the synthesis and expression of cartilage extracellular matrix (ECM) by stem cells. The use of conditioned medium obtained from chondrocytes for stimulating stem cells chondrogenic differentiation may be a very interesting alternative for moving into the clinical application of these cells, as chondrocytes could be partially replaced by stem cells for this type of application. In the present study we aimed to achieve chondrogenic differentiation of two different sources of stem cells using conditioned medium, without adding growth factors. We tested both human bone marrow‐derived mesenchymal stem cells (hBSMCs) and human Wharton's jelly‐derived stem cells (hWJSCs). Conditioned medium obtained from a culture of human articular chondrocytes was used to feed the cells during the experiment. Cultures were performed in previously produced three‐dimensional (3D) scaffolds, composed of a blend of 50:50 chitosan:poly(butylene succinate). Both types of stem cells were able to undergo chondrogenic differentiation without the addition of growth factors. Cultures using hWJSCs showed significantly higher GAGs accumulation and expression of cartilage‐related genes (aggrecan, Sox9 and collagen type II) when compared to hBMSCs cultures. Conditioned medium obtained from articular chondrocytes induced the chondrogenic differentiation of MSCs and ECM formation. Obtained results showed that this new strategy is very interesting and should be further explored for clinical applications. Copyright © 2013 John Wiley & Sons, Ltd.
Asymptotic behaviour of critical controlled branching processes with random control functions

In this paper, we investigate the asymptotic behaviour of controlled branching processes with random control functions. In a critical case, we establish sufficient conditions for both their almost-sure extinction and for their nonextinction with a positive probability. For some suitably chosen norming constants, we also determine different kinds of limiting behaviour for this class of processes.
A Congestion Control Algorithm for Signalling Networks Based on a State Machine Controlled by Network Delays

Congestion control in Signaling System number 7 faces new challenges as mobile com-munication systems and Intelligent Networks grow rapidly. New services change traffic patterns, add to signalling network load, and raise demands on shorter service completion times. To handle new demands, the congestion control mechanisms must foresee an over-load situation, and respond to it so that the network can maintain high throughput. With the introduction of a state machine and a memory function for each signaling link it is possible to predict the completion time of a service session and to detect an emerging congestion. If the predicted completion time of a service session is too long, the session is annihilated. This is the foundation of a congestion control mechanism that reacts fast on information supplied by the network. The congestion control mechanism enables the network to main-tain a high throughput during overload.
SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1

SIRT1, a histone/protein deacetylase, and AMP-activated protein kinase (AMPK) are key enzymes responsible for longevity and energy homeostasis. We examined whether a mechanistic connection exists between these molecules that involves the major AMPK kinase LKB1. Initial studies demonstrated that LKB1 is acetylated in cultured (HEK293T) cells, mouse white adipose tissue, and rat liver. In the 293T cells, SIRT1 overexpression diminished lysine acetylation of LKB1 and concurrently increased its activity, cytoplasmic/nuclear ratio, and association with the LKB1 activator STRAD. In contrast, short hairpin RNA for SIRT1, where studied, had opposite effects on these parameters. Mass spectrometric analysis established that acetylation of LKB1 occurs on multiple, but specific, lysine residues; however, only mutation of lysine 48 to arginine, which mimics deacetylation, reproduced all of the effects of activated SIRT1. SIRT1 also affected downstream targets of LKB1. Thus its overexpression increased AMPK and acetyl-CoA carboxylase phosphorylation, and conversely, RNA interference-mediated SIRT1 knockdown reduced AMPK phosphorylation and that of another LKB1 target MARK1. Consistent with the results in cultured cells, total LKB1 lysine acetylation was decreased by 60% in the liver of 48-h starved rats compared with starved-refed rats, and this was associated with modest but significant increases in both LKB1 and AMPK activities. These results suggest that LKB1 deacetylation is regulated by SIRT1 and that this in turn influences its intracellular localization, association with STRAD, kinase activity, and ability to activate AMPK.
UmuDAb: An Error-Prone Polymerase Accessory Homolog Whose N-Terminal Domain Is Required for Repression of DNA Damage Inducible Gene Expression in Acinetobacter baylyi

In many bacteria, the DNA damage response induces genes (SOS genes) that were repressed by LexA. LexA represses transcription by binding to SOS promoters via a helix-turn-helix motif in its N-terminal domain (NTD). Upon DNA damage, LexA cleaves itself and allows induction of transcription. In Acinetobacter baumannii and Acinetobacter baylyi, multiple genes are induced by DNA damage, and although the Acinetobacter genus lacks LexA, a homolog of the error-prone polymerase subunit UmuD, called UmuDAb, regulates some DNA damage-induced genes. The mechanism of UmuDAb regulation has not been determined. We constructed UmuDAb mutant strains of A. baylyi to test whether UmuDAb mediates gene regulation through LexA-like repressor actions consisting of relief of repression through self-cleavage after DNA damage. Real-time quantitative PCR experiments in both a null umuDAb mutant and an NTD mutant showed that the DNA damage-inducible, UmuDAb-regulated gene ddrR was highly expressed even in the absence of DNA damage. Protein modeling identified a potential LexA-like helix-turn-helix structure in the UmuDAb NTD, which when disrupted, also relieved ddrR and umuDAb repression under non-inducing conditions. Mutations in a putative SOS box in the shared umuDAb-ddrR promoter region similarly relieved these genes’ repression under non-inducing conditions. Conversely, cells possessing a cleavage-deficient UmuDAb were unable to induce gene expression after MMC-mediated DNA damage. This evidence of a UmuDAb repressor mechanism was contrasted with the failure of umuDAb to complement an Escherichia coli umuD mutant for UmuD error-prone DNA replication activity. Similarly, A. baumannii null umuDAb mutant cells did not have a reduced UmuDˊ2UmuC-mediated mutation rate after DNA damage, suggesting that although this UmuDAb protein may have evolved from a umuDC operon in this genus, it now performs a LexA-like repressor function for a sub-set of DNA damage-induced genes.
Molecular mechanisms of hepatic metastasis in colorectal cancer

Colorectal cancer currently accounts for 11% of all cancers in the United States and is the second leading cause of cancer‐related death, with the majority of deaths attributable to hepatic metastases. Many new studies are elucidating the complex molecular factors involved in this event, which could be used to generate clinically applicable screening and therapeutic tools.