Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of Autoreactive B Cells by Endogenous TLR7 and TLR3 RNA Ligands*

Background: Low affinity autoreactive B cells are activated by co-engagement of the BCR and TLRs. Results: Endogenous RNAs that are associated with autoantigens are ligands for TLR7 and TLR3. Conclusion: Sequence and structure of RNA determines recognition by TLRs. Significance: B cells are activated by RNA delivered through the BCR, and the sequences of RNAs define their stimulatory capacity as TLR ligands. The key step in the activation of autoreactive B cells is the internalization of nucleic acid containing ligands and delivery of these ligands to the Toll-like Receptor (TLR) containing endolysosomal compartment. Ribonucleoproteins represent a large fraction of autoantigens in systemic autoimmune diseases. Here we demonstrate that many uridine-rich mammalian RNA sequences associated with common autoantigens effectively activate autoreactive B cells. Priming with type I IFN increased the magnitude of activation, and the range of which RNAs were stimulatory. A subset of RNAs that contain a high degree of self-complementarity also activated B cells through TLR3. For the RNA sequences that activated predominantly through TLR7, the activation is proportional to uridine-content, and more precisely defined by the frequency of specific uridine-containing motifs. These results identify parameters that define specific mammalian RNAs as ligands for TLRs.
Impact of Soft Tissue Heterogeneity on Augmented Reality for Liver Surgery

This paper presents a method for real-time augmented reality of internal liver structures during minimally invasive hepatic surgery. Vessels and tumors computed from pre-operative CT scans can be overlaid onto the laparoscopic view for surgery guidance. Compared to current methods, our method is able to locate the in-depth positions of the tumors based on partial three-dimensional liver tissue motion using a real-time biomechanical model. This model permits to properly handle the motion of internal structures even in the case of anisotropic or heterogeneous tissues, as it is the case for the liver and many anatomical structures. Experimentations conducted on phantom liver permits to measure the accuracy of the augmentation while real-time augmentation on in vivo human liver during real surgery shows the benefits of such an approach for minimally invasive surgery.
An experimental approach to generalized Wiener filtering in music source separation

Music source separation aims at decomposing music recordings into their constituent component signals. Many existing techniques are based on separating a time-frequency representation of the mixture signal by applying suitable modeling techniques in conjunction with generalized Wiener filtering. Recently, the term α-Wiener filtering was coined together with a theoretic foundation for the long-practiced use of magnitude spectrogram estimates in Wiener filtering. So far, optimal values for the magnitude exponent α have been empirically found in oracle experiments regarding the additivity of spectral magnitudes. In the first part of this paper, we extend these previous studies by examining further factors that affect the choice of α. In the second part, we investigate the role of α in Kernel Additive Modeling applied to Harmonic-Percussive Separation. Our results indicate that the parameter α may be understood as a kind of selectivity parameter, which should be chosen in a signal-adaptive fashion.
Effect of kidney tonifying prescriptions- Liu wei di huang Wan and Ba wei di huang Wan on insulin resistance

Metabolic syndrome (MetS) is a cluster of symptoms seen in type 2 diabetes mellitus, cardiovascular diseases, hypertension and obesity. Insulin resistance is a major component of MetS and is thus the key to cure and prevent any related illnesses. The treatment of type 2 diabetes mellitus in Traditional Chinese Medicine is focused on replenishing Yin (fluid) and evacuating fire (heat) from the body and, depending on the symptoms it can also be focused on replenishing the yang. We study how the Kidney tonifying preparations (Liuwei dihuang wanLW and Bawei dihuang wan-BW) affect osteocalcin levels to treat insulin resistance. We induced insulin resistance in Rats by a large dose of Dexamethasone 1 g/kg/alternate days (DXM) and simultaneously administered the LW low dose 1 g/kg, LW high dose 4 g/kg, BW low dose 1 g/kg, BW high dose 4 g/kg and Simvastatin 20 mg/kg (positive control). After a 2hr oral glucose tolerance test, blood was drawn for serum analysis of lipids, osteocalcin, adiponectin and leptin. Our results showed that LW and BW might act through increasing insulin sensitizing hormones- osteocalcin and adiponectin, and reducing hormones increased in obesity like leptin. The increase in insulin sensitizing hormones might be able to reduce the measures of insulin sensitivity. LW and BW might be unable to control lipid dysregulation in DXM induced insulin resistance.
Native purification of protein and RNA-protein complexes using a novel affinity procedure

Genetic studies in invertebrate model organisms such as Drosophila melanogaster have been a fundament of cell and developmental biology for more than one century. It is mainly the lack of an efficient purification strategy which has hampered biochemical and proteomic analyses of gene products. We describe a novel affinity-tag, termed TagIt-epitope specifically designed for affinity-purifications of multiprotein complexes from Drosophila. TagIt-fusion proteins can be efficiently purified using a monoclonal antibody and eluted under native conditions by competition with synthetic peptide encompassing the epitope. We demonstrate that this tag is suitable for the purification of proteinaceous assemblies such as the PRMT5-complex and RNA-protein complexes such as snoRNPs from Drosophila Schneider2 cells. Furthermore, we describe a novel approach by which this tag can be used to affinity-purify RNA-binding proteins from cell extracts. Therefore, the TagIt-technique or modifications thereof will be of great value in analyzing macromolecular complexes in Drosophila and also other invertebrates by biochemical means. In addition, RNA-peptide hybrid molecules may become a novel tool to purify RNA binding proteins.
Stimulus-Specific Adaptation in the Auditory Thalamus of the Anesthetized Rat

The specific adaptation of neuronal responses to a repeated stimulus (Stimulus-specific adaptation, SSA), which does not fully generalize to other stimuli, provides a mechanism for emphasizing rare and potentially interesting sensory events. Previous studies have demonstrated that neurons in the auditory cortex and inferior colliculus show SSA. However, the contribution of the medial geniculate body (MGB) and its main subdivisions to SSA and detection of rare sounds remains poorly characterized. We recorded from single neurons in the MGB of anaesthetized rats while presenting a sequence composed of a rare tone presented in the context of a common tone (oddball sequences). We demonstrate that a significant percentage of neurons in MGB adapt in a stimulus-specific manner. Neurons in the medial and dorsal subdivisions showed the strongest SSA, linking this property to the non-lemniscal pathway. Some neurons in the non-lemniscal regions showed strong SSA even under extreme testing conditions (e.g., a frequency interval of 0.14 octaves combined with a stimulus onset asynchrony of 2000 ms). Some of these neurons were able to discriminate between two very close frequencies (frequency interval of 0.057 octaves), revealing evidence of hyperacuity in neurons at a subcortical level. Thus, SSA is expressed strongly in the rat auditory thalamus and contribute significantly to auditory change detection.
Viewing Health Care Consolidation through the Lens of the Economics of Strategy

In January 2009, the Changes in Health Care Financing and Organization (HCFO) Initiative convened an invitational work group meeting as part of its program, 2009 Policy Reform: Implications of the Supply and Organization of the Delivery System on Health Care Reform, sponsored by the Robert Wood Johnson Foundation. The work group, co-chaired by Robert Berenson, M.D., and Harold Luft, Ph.D., commissioned several papers, including this one by David Dranove, Ph.D. Access the other commissioned briefs and reports at www.hcfo. org/ publications. For the past three decades, health care providers have hoped that consolidation would improve their competitive position. During the 1970s, for-profit systems acquired hundreds of mostly smaller, rural hospitals to help them cope with increasing regulatory complexity. Beginning in the 1980s and continuing almost unabated since then, urban hospitals have consolidated with erstwhile competitors in their local markets to improve their efficiency and enhance bargaining power. Not to be outdone, physicians have also partnered in local markets, with many single-specialty groups seeming to dominate the affected markets. Providers have also consolidated vertically. During the 1980s, hospitals and physicians formed physician-hospital organizations (PHO) to accept capitation from HMOs. In the 1990s, more fully integrated delivery systems (IDS) supplanted PHOs. While many IDSs still operate successfully, few industry observers discuss IDSs with the same enthusiasm that they did a decade ago.
Circadian Preference Modulates the Neural Substrate of Conflict Processing across the Day

Human morning and evening chronotypes differ in their preferred timing for sleep and wakefulness, as well as in optimal daytime periods to cope with cognitive challenges. Recent evidence suggests that these preferences are not a simple by-product of socio-professional timing constraints, but can be driven by inter-individual differences in the expression of circadian and homeostatic sleep-wake promoting signals. Chronotypes thus constitute a unique tool to access the interplay between those processes under normally entrained day-night conditions, and to investigate how they impinge onto higher cognitive control processes. Using functional magnetic resonance imaging (fMRI), we assessed the influence of chronotype and time-of-day on conflict processing-related cerebral activity throughout a normal waking day. Sixteen morning and 15 evening types were recorded at two individually adapted time points (1.5 versus 10.5 hours spent awake) while performing the Stroop paradigm. Results show that interference-related hemodynamic responses are maintained or even increased in evening types from the subjective morning to the subjective evening in a set of brain areas playing a pivotal role in successful inhibitory functioning, whereas they decreased in morning types under the same conditions. Furthermore, during the evening hours, activity in a posterior hypothalamic region putatively involved in sleep-wake regulation correlated in a chronotype-specific manner with slow wave activity at the beginning of the night, an index of accumulated homeostatic sleep pressure. These results shed light into the cerebral mechanisms underlying inter-individual differences of higher-order cognitive state maintenance under normally entrained day-night conditions.
Purified Human Pancreatic Duct Cell Culture Conditions Defined by Serum-Free High-Content Growth Factor Screening

The proliferation of pancreatic duct-like CK19+ cells has implications for multiple disease states including pancreatic cancer and diabetes mellitus. The in vitro study of this important cell type has been hampered by their limited expansion compared to fibroblast-like vimentin+ cells that overgrow primary cultures. We aimed to develop a screening platform for duct cell mitogens after depletion of the vimentin+ population. The CD90 cell surface marker was used to remove the vimentin+ cells from islet-depleted human pancreas cell cultures by magnetic-activated cell sorting. Cell sorting decreased CD90+ cell contamination of the cultures from 34±20% to 1.3±0.6%, yielding purified CK19+ cultures with epithelial morphology. A full-factorial experimental design was then applied to test the mitogenic effects of bFGF, EGF, HGF, KGF and VEGF. After 6 days in test conditions, the cells were labelled with BrdU, stained and analyzed by high-throughput imaging. This screening assay confirmed the expected mitogenic effects of bFGF, EGF, HGF and KGF on CK19+ cells and additionally revealed interactions between these factors and VEGF. A serum-free medium containing bFGF, EGF, HGF and KGF led to CK19+ cell expansion comparable to the addition of 10% serum. The methods developed in this work should advance pancreatic cancer and diabetes research by providing effective cell culture and high-throughput screening platforms to study purified primary pancreatic CK19+ cells.
The Age of the Inquiry: Learning and Blaming in Health and Social Care

Introduction: The inquiry as Janus, Nicky Stanley and Jill Manthorpe Part 1: Participating in inquiries 1. Mental health inquiries - 'Cui Bono? ', Herschel Prins 2. The family's perspective, Paul and Audrey Edwards 3. Staff and patient perspectives on the Fallon Inquiry into the Personality Disorder Service at Ashworth High Secure Hospital, Pete Melia Part 2: Inquiries into child abuse and deaths 4. The impact of child abuse inquiries since 1990, Eileen Munro 5. From Cornwall to Climbe: Inquiring into fatal child abuse, Peter Reder and Sylvia Duncan 6. The costs and benefits of the North Wales Tribunal Inquiry, Brian Corby Part 3: Inquiries into mental health homicides 7. Mental health inquiries, assertive outreach and compliance: Is there a relationship, Andrew McCulloch and Camilla Parker 8. Women and mental health inquiries, Nicky Stanley 9. Mental health inquiries 1985-2003, Dave Sheppard Part 4: Inquiries into the abuse of people with learning disabilities 10. Learning disability, abuse and inquiry, Rachel Fyson, Deborah Kitson and Alan Corbett 11. Abuse inquiries as learning tools for social care organisations, Paul Cambridge Part 5: Inquiries into the abuse and neglect of older people 12. Older people, institutional abuse and inquiries, Bridget Penhale and Jill Manthorpe 13. Inspections and inquiries, Roger Clough and Jill Manthorpe
Mobile dynamic content distribution networks

Mobile networks are becoming increasingly popular as means for distributing inform tion to large number of users. In comparison to wired networks, mobile networks distinguished by potentially much higher variability in demand due to user mobility. Most previous content techniques ssume static client demand distribution and, thus, may not perform well in mobile networks.This paper proposes and analyzes Mobile Dynamic Content Distribution Network model, which takes demand variations into account to decide whether to replicate content and whether to remove previously created replicas in order to minimize total network traffic. We develop two solutions to our model: an offline optimal, which provides an ideal lower-bound on the total traffic, and practical heuristic online algorithm, which uses demand forecasting to make replication decisions. We provide thorough evaluation of our solutions, comparing them against ACDN, the only previous dynamic content placement algorithm targeting bandwidth minimization that we are aware of. Our results show that our online algorithm significantly outperforms the ACDN one, reducing total network traffic by up to 85% in a number of experiments covering large system design space.
Trafficking of ThermoTRP Channels

ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to several pathological states. The surface expression of thermoTRPs is controlled by both, the constitutive and regulated vesicular trafficking. Modulation of receptor surface density during pathological processes is nowadays considered as an interesting therapeutic approach for management of diseases, such as chronic pain, in which an increased trafficking is associated with the pathological state. This review will focus on the recent advances trafficking of the thermoTRP channels, TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA1, into/from the plasma membrane. Particularly, regulated membrane insertion of thermoTRPs channels contributes to a fine tuning of final channel activity, and indeed, it has resulted in the development of novel therapeutic approaches with successful clinical results such as disruption of SNARE-dependent exocytosis by botulinum toxin or botulinomimetic peptides.
How Factors Involved in the Resolution of Crystal-Induced Inflammation Target IL-1β

One of the main clinical features characterizing crystal-induced inflammation is its spontaneous resolution. The aim of this review is to outline the various factors involved in the self-limiting course of crystal-induced inflammation focusing on their effect on IL-1β production. Endogenous molecules that are induced or locally recruited by the process itself, inhibitory proteins naturally present in the joint and exogenous dietary factors are discussed. Aside from the classical well-known molecules involved in the resolution of crystal-induced acute attack such as TGFβ, IL-10, IL-1Ra, and lipoproteins, particular attention is paid to recently uncovered mechanisms such as the aggregation of neutrophil extracellular traps, the release of ectosomes from neutrophil surface, and alpha-1-anti-trypsin-mediated IL-1 inhibition.
The thermodynamics of Kaluza–Klein black hole/bubble chains

A Killing bubble is a minimal surface that arises as the fixed surface of a spacelike Killing field. We compute the bubble contributions to the Smarr relations and the mass and tension first laws for spacetimes containing both black holes and Killing bubbles. The resulting relations display an interesting interchange symmetry between the properties of black hole horizons and those of KK bubbles. This interchange symmetry reflects the underlying relation between static bubbles and black holes under double analytic continuation of the time and Kaluza–Klein directions. The thermodynamics of bubbles involve a geometrical quantity that we call the bubble surface gravity, which we show has several properties in common with the black hole surface gravity.
Preexisting Insulin Autoantibodies Predict Efficacy of Otelixizumab in Preserving Residual β-Cell Function in Recent-Onset Type 1 Diabetes

OBJECTIVE Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose. RESEARCH DESIGN AND METHODS In the included patients (n = 40 otelixizumab, n = 40 placebo), β-cell function was assessed as area under the curve (AUC) C-peptide release during a hyperglycemic glucose clamp at baseline (median duration of insulin treatment: 6 days) and every 6 months until 18 months after randomization. (Auto)antibodies against insulin (I[A]A), GAD (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A) were determined on stored sera by liquid-phase radiobinding assay. RESULTS At baseline, only better preserved AUC C-peptide release and higher levels of IAA were associated with better preservation of β-cell function and lower insulin needs under anti-CD3 treatment. In multivariate analysis, IAA (P = 0.022) or the interaction of IAA and C-peptide (P = 0.013) independently predicted outcome together with treatment. During follow-up, good responders to anti-CD3 treatment (i.e., IAA+ participants with relatively preserved β-cell function [≥25% of healthy control subjects]) experienced a less pronounced insulin-induced rise in I(A)A and lower insulin needs. GADA, IA-2A, and ZnT8A levels were not influenced by anti-CD3 treatment, and their changes showed no relation to functional outcome. CONCLUSIONS There is important specificity of IAA among other diabetes autoantibodies to predict good therapeutic response of recent-onset type 1 diabetic patients to anti-CD3 treatment. If confirmed, future immune intervention trials in type 1 diabetes should consider both relatively preserved functional β-cell mass and presence of IAA as inclusion criteria.
Human fetal retinal pigment epithelial cells induce apoptosis in the T-cell line Jurkat.

PURPOSE To investigate the mechanism(s) involved in human fetal retinal pigment epithelium (HFRPE)-mediated T-cell death. METHODS Pure HFRPE cells were isolated and cultured. Normal and interferon (IFN)-gamma-activated HFRPE from early and late in vitro passages were incubated with cells from the human T-cell leukemia line Jurkat (Jkt). Cultures were pulsed with [3H]-thymidine to measure Jkt cell proliferation. Jkt cells were evaluated for apoptosis either by staining with an ethidium bromide/acridine orange mixture (AO/EB) or with Annexin V-phycoerythrin. The role of Fas ligand (FasL) molecule in HFRPE-mediated apoptosis was assessed by using a mutant Jkt cell line (DD3), which is deficient in Fas-mediated signaling. The involvement of the antiapoptotic human gene bcl-xL was determined by using Jkt cells that were stably transfected with bcl-x(L). The role of cell- cell contact in the induction of apoptosis was evaluated in a transwell system in the presence or absence of neutralizing antibodies against IFN-gamma and tumor necrosis factor (TNF)-alpha. RESULTS HFRPE cells inhibited the proliferation of Jkt cells by inducing apoptosis through a FasL-independent pathway. Passaging and IFN-gamma activation strengthened the inhibitory effect of HFRPE cells on the proliferation of Jkt cells. At lower HFRPE passages (P2), bcl-alphaL, overexpression rescued the HFRPE cell-mediated apoptosis. The separation of the cells by the transwell system did not affect the HFRPE cell-mediated suppression. This suppressive effect was not mediated by the secretion of IFN-gamma or TNF-alpha molecules. CONCLUSIONS HFRPE cells suppressed the proliferation of Jkt cells by inducing apoptosis. HFRPE cells induced a stronger inhibitory effect on Jkt cells at higher in vitro passages. The HFRPE-induced apoptosis was not mediated through the FasL/Fas pathway or through the secretion of the apoptosis-inducing cytokines IFN-gamma and TNF-alpha. The bcl-xL gene may play a role in preventing HFRPE cell-induced apoptosis in Jkt cells. These combined results suggest that the HFRPE-mediated suppression of primary T cells may also be mediated by the induction of apoptosis. Therefore, the retinal pigment epithelium may play a role in the induction of immune privilege in the subretinal space.