Miracle-dz/UniFAR-FTUs huggingface dataset:
Lysophosphatidic Acid Signals through Multiple Receptors in Osteoclasts to Elevate Cytosolic Calcium Concentration, Evoke Retraction, and Promote Cell Survival*

Lysophosphatidic acid (LPA) is a bioactive phospholipid whose functions are mediated by multiple G protein-coupled receptors. We have shown that osteoblasts produce LPA, raising the possibility that it mediates intercellular signaling among osteoblasts and osteoclasts. Here we investigated the expression, signaling and function of LPA receptors in osteoclasts. Focal application of LPA elicited transient increases in cytosolic calcium concentration ([Ca2+]i), with 50% of osteoclasts responding at ∼400 nm LPA. LPA-induced elevation of [Ca2+]i was blocked by pertussis toxin or the LPA1/3 receptor antagonist VPC-32183. LPA caused sustained retraction of osteoclast lamellipodia and disrupted peripheral actin belts. Retraction was insensitive to VPC-32183 or pertussis toxin, indicating involvement of a distinct signaling pathway. In this regard, inhibition of Rho-associated kinase stimulated respreading after LPA-induced retraction. Real-time reverse transcription-PCR revealed transcripts encoding LPA1 and to a lesser extent LPA2, LPA4, and LPA5 receptor subtypes. LPA induced nuclear translocation of NFATc1 and enhanced osteoclast survival, effects that were blocked by VPC-32183 or by a specific peptide inhibitor of NFAT activation. LPA slightly reduced the resorptive activity of osteoclasts in vitro. Thus, LPA binds to at least two receptor subtypes on osteoclasts: LPA1, which couples through Gi/o to elevate [Ca2+]i, activate NFATc1, and promote survival, and a second receptor that likely couples through G12/13 and Rho to evoke and maintain retraction through reorganization of the actin cytoskeleton. These findings reveal a signaling axis in bone through which LPA, produced by osteoblasts, acts on multiple receptor subtypes to induce pleiotropic effects on osteoclast activity and function.
Allergen immunotherapy for allergic respiratory diseases

Allergen specific immunotherapy involves the repeated administration of allergen products in order to induce clinical and immunologic tolerance to the offending allergen. Immunotherapy is the only etiology-based treatment that has the potential for disease modification, as reflected by longterm remission following its discontinuation and possibly prevention of disease progression and onset of new allergic sensitizations. Whereas subcutaneous immunotherapy is of proven value in allergic rhinitis and asthma there is a risk of untoward side effects including rarely anaphylaxis. Recently the sublingual route has emerged as an effective and safer alternative. Whereas the efficacy of SLIT in seasonal allergy is now well-documented in adults and children, the available data for perennial allergies and asthma is less reliable and particularly lacking in children. This review evaluates the efficacy, safety and longterm benefits of SCIT and SLIT and highlights new findings regarding mechanisms, potential biomarkers and recent novel approaches for allergen immunotherapy.
Effects of l-Alanyl-l-Glutamine Ingestion on One-Hour Run Performance

Objective: To examine the efficacy of l-alanyl-l-glutamine ingestion with a commercially available sports drink compared to the sports drink only on time to exhaustion and physiological measures during prolonged endurance exercise. Methods: Twelve endurance-trained men (23.5 ± 3.7 years; 175.5 ± 5.4 cm; 70.7 ± 7.6 kg) performed 4 trials, each consisting of a 1-hour treadmill run at 75% VO2peak followed by a run to exhaustion at 90% VO2peak. One trial consisted of no hydration (NHY), another required ingestion of only a sports drink (ED), and 2 trials required ingestion of a low dose (LD; 300 mg·500 ml−1) and high dose (HD) of l-alanyl-l-glutamine (1 g·500 ml−1) added to the sports drink. During the fluid ingestion trials, 250 ml was consumed every 15 minutes. Plasma glutamine, glucose, electrolytes, and osmolality were measured prior to the run (PRE) and at 30, 45, and 60 minutes. VO2, respiratory quotient (RQ), and heart rate (HR) were measured every 15 minutes. Results: Time to exhaustion was significantly longer during the LD and HD trials compared to NHY. No differences were noted in time to exhaustion between ED and NHY. Plasma glutamine concentrations were significantly elevated at 45 minutes in LD and HD trials and remained elevated at 60 minutes during HD. Sodium concentrations increased from the beginning of exercise and remained stable for the duration of the 1-hour run. At 60 minutes, plasma sodium was significantly lower in all trials compared to NHY. Conclusions: Results indicated that ingestion of the alanine-glutamine dipeptide at either the low or high dose significantly improved time to exhaustion during high-intensity exercise compared to a no-hydration trial.
Secure multi-party computation protocol using asymmetric encryption

Privacy preservation is very essential in various real life applications such as medical science and financial analysis. This paper focuses on implementation of an asymmetric secure multi-party computation protocol using anonymization and public-key encryption where all parties have access to trusted third party (TTP) who (1) doesn't add any contribution to computation (2) doesn't know who is the owner of the input received (3) has large number of resources (4) decryption key is known to trusted third party (TTP) to get the actual input for computation of final result. In this environment, concern is to design a protocol which deploys TTP for computation. It is proposed that the protocol is very proficient (in terms of secure computation and individual privacy) for the parties than the other available protocols. The solution incorporates protocol using asymmetric encryption scheme where any party can encrypt a message with the public key but decryption can be done by only the possessor of the decryption key (private key). As the protocol works on asymmetric encryption and packetization it ensures following: (1) Confidentiality (Anonymity) (2) Security (3) Privacy (Data).
Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST).

AIM To determine the relationship between resting heart rate (RHR) and adverse outcomes in coronary artery disease (CAD) patients treated for hypertension with different RHR-lowering strategies. METHODS AND RESULTS Time to adverse outcomes (death, non-fatal myocardial infarction, or non-fatal-stroke) and predictive values of baseline and follow-up RHR were assessed in INternational VErapamil-SR/trandolapril STudy (INVEST) patients randomized to either a verapamil-SR (Ve) or atenolol (At)-based strategy. Higher baseline and follow-up RHR were associated with increased adverse outcome risks, with a linear relationship for baseline RHR and J-shaped relationship for follow-up RHR. Although follow-up RHR was independently associated with adverse outcomes, it added less excess risk than baseline conditions such as heart failure and diabetes. The At strategy reduced RHR more than Ve (at 24 months, 69.2 vs. 72.8 beats/min; P < 0.001), yet adverse outcomes were similar [Ve 9.67% (rate 35/1000 patient-years) vs. At 9.88% (rate 36/1000 patient-years, confidence interval 0.90-1.06, P = 0.62)]. For the same RHR, men had a higher risk than women. CONCLUSION Among CAD patients with hypertension, RHR predicts adverse outcomes, and on-treatment RHR is more predictive than baseline RHR. A Ve strategy is less effective than an At strategy for lowering RHR but has a similar effect on adverse outcomes.
Incidence and risk factors of postoperative sore throat after endotracheal intubation in Korean patients

Objective To investigate the incidence of postoperative sore throat (POST) in Korean patients undergoing general anaesthesia with endotracheal intubation and to assess potential risk factors. Methods This prospective study enrolled patients who underwent all types of elective surgical procedures with endotracheal intubation and general anaesthesia. The patients were categorized into group S (those with a POST) or group N (those without a POST). The demographic, clinical and anaesthetic characteristics of each group were compared. Results This study enrolled 207 patients and the overall incidence of POST was 57.5% (n = 119). Univariate analysis revealed that significantly more patients in group S had a cough at emergence and hoarseness in the postanaesthetic care unit compared with group N. Receiver operating characteristic curve analysis showed that an intracuff pressure ≥17 cmH2O was associated with POST. Multivariate analysis identified an intracuff pressure ≥17 cmH2O and cough at emergence as risk factors for POST. At emergence, as the intracuff pressure over ≥17 cmH2O increased, the incidence of hoarseness increased. Conclusions An intracuff pressure ≥17 cmH2O and a cough at emergence were risk factors for POST in Korean patients. Intracuff monitoring during anaesthesia and a smooth emergence are needed to prevent POST.
Exploration of disease mechanism in acute kidney injury using a multiplex bead array assay: a nested case–control pilot study

Background: Acute kidney injury (AKI) following cardiac surgery with cardiopulmonary bypass (CPB) causes increased morbidity and mortality. Objective: To evaluate the plasma profile of biomarkers potentially involved in AKI development following CPB. Methods: In a nested case–control study, plasma levels of 27 biomarkers in 11 AKI cases were compared with 25 controls. Results: Pre-CPB, plasma levels of epidermal growth factor and macrophage inflammatory protein-1β, 2 h following CPB, soluble vascular cell adhesion molecule-1 (sVCAM-1), fractalkine and macrophage inflammatory protein-1α, and at later time points, sVCAM-1 and interleukin-6 were associated with AKI. Conclusion: Biomarkers associated with AKI following CPB may merit further study.
Crystal structure of 5-amino-5′-chloro-6-(4-chlorobenzoyl)-8-nitro-2,3-dihydro-1H-spiro[imidazo[1,2-a]pyridine-7,3′-indolin]-2′-one including an unknown solvent molecule

The asymmetric unit of the title compound, C21H15Cl2N5O4, contains two independent molecules (A and B) having similar conformations. The amine (NH2) group forms an intramolecular hydrogen bond with the benzoyl group, giving an S(6) ring motif in both molecules. The central six-membered rings adopt sofa conformations and the imidazole rings are planar (r.m.s deviations = 0.0150 and 0.0166 Å). The pyridine and imidazole rings are inclined to one another by 3.54 (1) and 3.03 (1)° in molecules A and B, respectively. In the crystal, molecules are linked by N—H⋯O hydrogen bonds, forming chains along the a axis which enclose R 2 2(16) ring motifs. The rings are linked by weak N—H⋯O and C—H⋯O hydrogen bonds and C—H⋯π interactions forming sheets lying parallel to (001). A region of disordered electron density, most probably disordered solvent molecules, occupying voids of ca 753 Å3 for an electron count of 260, was treated using the SQUEEZE routine in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148–155]. Their formula mass and unit-cell characteristics were not taken into account during refinement.
A KLF4–miRNA-206 Autoregulatory Feedback Loop Can Promote or Inhibit Protein Translation Depending upon Cell Context

ABSTRACT Krüppel-like factor 4 (KLF4), a transcription factor that regulates cell fate in a context-dependent fashion, is normally induced upon growth arrest or differentiation. In many cancer cells there is dysregulation, with increased expression in proliferating cells. To identify sequence elements that mediate KLF4 suppression in normal epithelial cells, we utilized a luciferase reporter and RK3E cells, which undergo a proliferation-differentiation switch to form an epithelial sheet. A translational control element (TCE) within the KLF4 3′-untranslated region interacted with microRNAs (miRs) 206 and 344-1 to promote or inhibit KLF4 expression, respectively, in proliferating epithelial cells. Overall, the TCE suppressed expression in proliferating primary human mammary epithelial cells, but this suppressive effect was attenuated in immortalized mammary epithelial MCF10A cells, in which Dicer1 and miR-206 promoted KLF4 expression and TCE reporter activity. In contrast to MCF10A cells, in breast cancer cells the activity of miR-206 was switched, and it repressed KLF4 expression and TCE reporter activity. As miR-206 levels were KLF4 dependent, the results identify a KLF4–miR-206 feedback pathway that oppositely affects protein translation in normal cells and cancer cells. In addition, the results indicate that two distinct miRs can have opposite and competing effects on translation in proliferating cells.
Predicting risk of upper gastrointestinal bleed and intracranial bleed with anticoagulants: cohort study to derive and validate the QBleed scores

Objective To develop and validate risk algorithms (QBleed) for estimating the absolute risk of upper gastrointestinal and intracranial bleed for patients with and without anticoagulation aged 21-99 years in primary care. Design Open cohort study using routinely collected data from general practice linked to hospital episode statistics data and mortality data during the five year study period between 1 January 2008 and 1 October 2013. Setting 565 general practices in England contributing to the national QResearch database to develop the algorithm and 188 different QResearch practices to validate the algorithm. All 753 general practices had data linked to hospital episode statistics and mortality data at individual patient level. Endpoint Gastrointestinal bleed and intracranial bleed recorded on either the linked mortality data or the linked hospital records. Participants We studied 4.4 million patients in the derivation cohort with 16.4 million person years of follow-up. During follow-up, 21 641 patients had an incident upper gastrointestinal bleed and 9040 had an intracranial bleed. For the validation cohort, we identified 1.4 million patients contributing over 4.9 million person years of follow-up. During follow-up, 6600 patients had an incident gastrointestinal bleed and 2820 had an intracranial bleed. We excluded patients without a valid Townsend score for deprivation and those prescribed anticoagulants in the 180 days before study entry. Risk factors Candidate variables recorded on the general practice computer system before entry to the cohort, including personal variables (age, sex, Townsend deprivation score, ethnicity), lifestyle variables (smoking, alcohol intake), chronic diseases, prescribed drugs, clinical values (body mass index, systolic blood pressure), and laboratory test results (haemoglobin, platelets). We also included previous bleed recorded before entry to the study. Results The final QBleed algorithms incorporated 21 variables. When applied to the validation cohort, the algorithms in women explained 40% of the variation for upper gastrointestinal bleed and 58% for intracranial bleed. The corresponding D statistics were 1.67 and 2.42. The receiver operating curve statistic values were 0.77 and 0.86. The sensitivity values for the top 10th of men and women at highest risk were 38% and 51%, respectively. There were similar results for men. Conclusion The QBleed algorithms provided valid measures of absolute risk of gastrointestinal and intracranial bleed in patients with and without anticoagulation as shown by the performance of the algorithms in a separate validation cohort. Further research is needed to evaluate the clinical outcomes and the cost effectiveness of using these algorithms in primary care.
Scalable Production of a Multifunctional Protein (TSG-6) That Aggregates with Itself and the CHO Cells That Synthesize It

TNF-α stimulated gene/protein 6 (TNFAIP6/TSG-6) is a multifunctional protein that has a number of potential therapeutic applications. Experiments and clinical trials with TSG-6, however, have been limited by the technical difficulties of producing the recombinant protein. We prepared stable clones of CHO cells that expressed recombinant human TSG-6 (rhTSG-6) as a secreted glycoprotein. Paradoxically, both cell number and protein production decreased dramatically when the clones were expanded. The decreases occurred because the protein aggregated the synthesizing CHO cells by binding to the brush border of hyaluronan that is found around many cultured cells. In addition, the rhTSG-6 readily self-aggregated. To address these problems, we added to the medium an inhibitor of hyaluronan synthesis and heparin to compete with the binding of TSG-6 to hyaluronan. Also, we optimized the composition of the culture medium, and transferred the CHO cells from a spinner culture system to a bioreactor that controlled pH and thereby decreased pH-dependent binding properties of the protein. With these and other improvements in the culture conditions, we obtained 57.0 mg ± 9.16 S.D. of rhTSG-6 in 5 or 6 liter of medium. The rhTSG-6 accounted for 18.0% ± 3.76 S.D. of the total protein in the medium. We then purified the protein with a Ni-chelate column that bound the His tag engineered into the C-terminus of the protein followed by an anion exchange column. The yield of the purified monomeric rhTSG-6 was 4.1 mg to 5.6 mg per liter of culture medium. After intravenous injection into mice, the protein had a longer plasma half-life than commercially available rhTSG-6 isolated from a mammalian cell lysate, apparently because it was recovered as a secreted glycoprotein. The bioactivity of the rhTSG-6 in suppressing inflammation was demonstrated in a murine model.
Soft-Tissue Blood Flow Following Reamed Versus Unreamed Locked Intramedullary Nailing: A Fractured Sheep Tibia Model

A study was performed to compare the effects of reamed versus unreamed locked intramedullary nailing on soft-tissue blood flow in a fractured sheep tibia model. After creation of a standardized short spiral fracture, each tibia was stabilized by insertion of a locked intramedullary nail. Ten animals were randomized into two groups: one that had reaming prior to nail insertion and one that did not. Blood flow was measured in real time, using laser Doppler flowmetry. Skin and muscle perfusion measurements were made at three locations (proximal diaphysis, fracture site, and distal diaphysis) and at five time intervals (postfracture; postnail insertion; and at 2-week, 6-week, and 12-week follow-ups). All animals were sacrificed at 12 weeks postoperatively. Muscle blood flow remained elevated longer in the reamed group than in the unreamed group, following completion of the procedure. Muscle perfusion was significantly greater in the reamed group than in the unreamed group (p < 0.033) and was significantly greater than skin perfusion at 2 weeks (p < 0.024). There was no difference in skin perfusion between the reamed and unreamed groups at any time interval. The study demonstrates that muscle perfusion is altered following reamed and unreamed intramedullary nailing. The findings demonstrate the change in blood flow in the surrounding soft-tissue envelope during the process of revascularization, following devascularization of a segment of tibial cortex by intramedullary nailing. Schemitsch EH, Kowalski MJ, Swiontkowski MF. Soft-tissue blood flow following reamed versus unreamed locked intramedullary nailing: a fractured sheep tibia model. Ann Plast Surg 1996;36:70-75
Estimating the Relation of Perception and Action During Interaction

We assume that for perception for manipulation the relevant structure lies in the combined S×A×t space, the space of changing sensor signals and actions. We also assume that if we can find the right structure we achieve robustness, resilience to noise and disturbances and generalization. If our hypothesis is right and S ×A× t is strongly structured, it should be possible to find this structure for a large class of manipulation tasks (tasks with smooth correlation between actions and changes in the sensor signal). In this work we propose a method to estimate on-line the structure of S×A×t in the form of a visuo-motor Jacobian. We show experimentally how the estimated Jacobian allows to solve perceptual tasks that can not be solved without knowledge of the robots actions. We also show how the Jacobian directly leads to a control law for simple manipulation tasks.
Metabolic fate of SCE-1365, a new broad-spectrum cephalosporin, after parenteral administration to rats and dogs

Disposition of [14C]SCE-1365 was studied in rats and dogs after intramuscular or intravenous injection. The plasma level of [14C]SCE-1365 peaked at 15 min after intramuscular administration and declined rapidly to give half-lives of 27 and 39 min, respectively, in rats and dogs. After intravenous dosage, half-lives were 22 and 32 min, respectively, in rats and dogs. In both animals, the plasma levels of 14C were made up largely of unchanged antibiotic. Binding to plasma protein was 91 and 31%, respectively, in rats and dogs. Tissue levels of [14C]SCE-1365 administered intramuscularly to rats peaked at 15 min and were highest in the kidney and lowest in the brain, with plasma, liver, lung, heart, intestinal wall, and adrenal gland occupying intermediary positions in the order listed. The concentration of [14C]SCE-1365 in erythrocytes was very low, as was the level of the antibiotic in rat fetuses. The milk of rats given [14C]SCE-1365 intramuscularly contained detectable levels of 14C. [14C]SCE-1365 was completely eliminated from the bodies of rats and dogs within 24 to 48 h. In both animals, a large amount of the dosed 14C was excreted in urine as unaltered antibiotic. The remainder was eliminated in the feces via bile. In rats, [14C]SCE-1365 was eliminated by both glomerular filtration (33%) and tubular secretion (67%). An active transport process appeared to be involved in biliary excretion in rats.
Genetic inducible fate mapping in mouse: Establishing genetic lineages and defining genetic neuroanatomy in the nervous system

A fascinating aspect of developmental biology is how organs are assembled in three dimensions over time. Fundamental to understanding organogenesis is the ability to determine when and where specific cell types are generated, the lineage of each cell, and how cells move to reside in their final position. Numerous methods have been developed to mark and follow the fate of cells in various model organisms used by developmental biologists, but most are not readily applicable to mouse embryos in utero because they involve physical marking of cells through injection of tracers. The advent of sophisticated transgenic and gene targeting techniques, combined with the use of site‐specific recombinases, has revolutionized fate mapping studies in mouse. Furthermore, using genetic fate mapping to mark cells has opened up the possibility of addressing fundamental questions that cannot be studied with traditional methods of fate mapping in other organisms. Specifically, genetic fate mapping allows both the relationship between embryonic gene expression and cell fate (genetic lineage) to be determined, as well as the link between gene expression domains and anatomy (genetic anatomy) to be established. In this review, we present the ever‐evolving development of genetic fate mapping techniques in mouse, especially the recent advance of Genetic Inducible Fate Mapping. We then review recent studies in the nervous system (focusing on the anterior hindbrain) as well as in the limb and with adult stem cells to highlight fundamental developmental processes that can be discovered using genetic fate mapping approaches. We end with a look toward the future at a powerful new approach that combines genetic fate mapping with cellular phenotyping alleles to study cell morphology, physiology, and function using examples from the nervous system. Developmental Dynamics 235:2376–2385, 2006. © 2006 Wiley‐Liss, Inc.