Miracle-dz/UniFAR-FTUs huggingface dataset:
Lipoprotein lipase and hepatic lipase mRNA tissue specific expression, developmental regulation, and evolution.

Lipoprotein lipase (LPL) and hepatic lipase (HL) enzyme activities were previously reported to be regulated during development, but the underlying molecular events are unknown. In addition, little is known about LPL evolution. We cloned and sequenced a complete mouse LPL cDNA. Comparison of sequences from mouse, human, bovine, and guinea pig cDNAs indicated that the rates of evolution of mouse, human, and bovine LPL are quite low, but guinea pig LPL has evolved several times faster than the others. 32P-Labeled mouse LPL and rat HL cDNAs were used to study lipase mRNA tissue distribution and developmental regulation in the rat. Northern gel analysis revealed the presence of a single 1.87 kb HL mRNA species in liver, but not in other tissues including adrenal and ovary. A single 4.0 kb LPL mRNA species was detected in epididymal fat, heart, psoas muscle, lactating mammary gland, adrenal, lung, and ovary, but not in adult kidney, liver, intestine, or brain. Quantitative slot-blot hybridization analysis demonstrated the following relative amounts of LPL mRNA in rat tissues: adipose, 100%; heart, 94%; adrenal, 6.6%; muscle, 3.8%; lung, 3.0%; kidney, 0%; adult liver, 0%. The same quantitative analysis was used to study lipase mRNA levels during development. There was little postnatal variation in LPL mRNA in adipose tissue; maximal levels were detected at the earliest time points studied for both inguinal and epididymal fat. In heart, however, LPL mRNA was detected at low levels 6 days before birth and increased 278-fold as the animals grew to adulthood. (ABSTRACT TRUNCATED AT 250 WORDS)
Chirp excitation of polydisperse microbubble populations for increasing sonoporation efficiency

The therapeutic application of microbubbles is a highly active area of research, since they can be used for drug or gene delivery. Phospholipid encapsulated microbubbles typically have a polydisperse size distribution over the 1-10 μm range and can be functionalised for molecular targeting as well as loaded with drug-carrying liposomes. The generation of shear stress on the cell membrane by microbubble oscillations is one mechanism that results in pore formation in the cell membrane. A microbubble oscillating at its resonant frequency would generate maximum shear stress on a membrane. However, due to the polydisperse nature of phospholipid microbubbles, a range of resonant frequencies would exist in a single population. Thus, the use of a linear modulated ultrasound pulse, or “chirp”, to excite a microbubble population could improve the sonoporation efficiency.
Blockade of the PI‐3K signalling pathway by the Aggregatibacter actinomycetemcomitans cytolethal distending toxin induces macrophages to synthesize and secrete pro‐inflammatory cytokines

The Aggregatibactor actinomycetemcomitans cytolethal distending toxin (Cdt) induces G2 arrest and apoptosis in lymphocytes; these toxic effects are due to the active subunit, CdtB, which functions as a phosphatidylinositol‐3,4,5‐triphosphate (PIP3) phosphatase. We now extend our investigation and demonstrate that Cdt is able to perturb human macrophage function. THP‐1‐ and monocyte‐derived macrophages were found not to be susceptible to Cdt‐induced apoptosis. Nonetheless, the toxin was capable of binding to macrophages and perturbing PI‐3K signalling resulting in decreased PIP3 levels and reduced phosphorylation of Akt and GSK3β; these changes were accompanied by concomitant alterations in kinase activity. Exposure of monocytes and macrophages to Cdt resulted in pro‐inflammatory cytokine production including increased expression and release of IL‐1β, TNFα and IL‐6. Furthermore, treatment of cells with either TLR‐2, ‐3 or ‐4 agonists in the presence of Cdt resulted in an augmented pro‐inflammatory response relative to agonist alone. GSK3β inhibitors blocked the Cdt‐induced pro‐inflammatory cytokine response suggesting a pivotal role for PI‐3K blockade, concomitant decrease in GSK3β phosphorylation and increased kinase activity. Collectively, these studies provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt‐producing organisms.
PHEROMONE SIGNALING IN THE FRUIT FLY DROSOPHILA MELANOGASTER

The fruit fly Drosophila melanogaster has been used as a model species in very diverse branches of science for more than 100 years. The genetic, molecular, and physiological tools that are available for this species offer unique opportunities for experiments that are currently not possible in other organisms. One important line of study in D. melanogaster has been how the chemosensory system of the fly converts information sampled from the outside world to representations in the central nervous system, and how this translates into specific behaviors. Insects rely on chemosensory cues for many aspects of their life, such as locating suitable mates, discovering the presence of a predator, or assessing the quality of a resource or an oviposition site. Communication between individuals of the same species is also often governed by pheromones; molecules that elicit a stereotypic reaction in a conspecific. These molecules can be perceived either by the olfactory system or by the gustatory system. The aim of this paper is to give an overview over what we know about how the chemosensory system of this fruit fly is organized, how odors are perceived and processed, and the identity and functional role of the pheromones that regulate its behavior.
The value of Modified Early Warning Score (MEWS) in surgical in-patients: a prospective observational study.

INTRODUCTION The Modified Early Warning Score (MEWS) is a simple, physiological score that may allow improvement in the quality and safety of management provided to surgical ward patients. The primary purpose is to prevent delay in intervention or transfer of critically ill patients. PATIENTS AND METHODS A total of 334 consecutive ward patients were prospectively studied. MEWS were recorded on all patients and the primary end-point was transfer to ITU or HDU. RESULTS Fifty-seven (17%) ward patients triggered the call-out algorithm by scoring four or more on MEWS. Emergency patients were more likely to trigger the system than elective patients. Sixteen (5% of the total) patients were admitted to the ITU or HDU. MEWS with a threshold of four or more was 75% sensitive and 83% specific for patients who required transfer to ITU or HDU. CONCLUSIONS The MEWS in association with a call-out algorithm is a useful and appropriate risk-management tool that should be implemented for all surgical in-patients.
Natural Immunity: A T‐Cell‐Independent Pathway of Macrophage Activation, Defined in the scid Mouse

In this review we summarize our studies on macrophage activation in mice with the scid mutation. Such mice exhibit, to a remarkable extent, a cellular system capable of activating macrophages. This pathway of macrophage activation defmes the cellular immune system operating presumably in its most primitive form without the modulation of B or T cells, i.e., without adaptive immunity. This T cell-independent mechanism of macrophage activation constitutes an important line of defense and protection against certain microbes in scid mice. It is likely that the T cell-independent pathway is also part of the normal response of mice with an intact immune system. Because it is not masked by the T-cell response, the JctV/mouse is an excellent model to defme the cellular and chemical components of the T cell-independent pathway. To date, we have defmed two cell types operating in this system, namely macrophages and natural killer (NK) cells, and three cytokines, interferon-y (IFNy), tumor necrosis factor (TNF) and interleukin-1 (IL-1). Our review summarizes our published results plus those of studies now in press or submitted (Bancroft et al. 1986,1987,1989a, 1989b, DeSchryver-Kecskemetietal. 1988, Wherry etal. 1991, Rogers et al. 1991, Bancroft & Webster 1991).
Modeling and Language Extensions

Answer set programming (ASP) has emerged as an approach to declarative problem solving based on the stable model semantics for logic programs. The basic idea is to represent a computational problem by a logic program, formulating constraints in terms of rules, such that its answer sets correspond to problem solutions. To this end, ASP combines an expressive language for high-level modeling with powerful low-level reasoning capacities, provided by off-the-shelf tools. Compact problem representations take advantage of genuine modeling features of ASP, including (first-order) variables, negation by default, and recursion. In this article, we demonstrate the ASP methodology on two example scenarios, illustrating basic as well as advanced modeling and solving concepts. We also discuss mechanisms to represent and implement extended kinds of preferences and optimization. An overview of further available extensions concludes the article.
Further evidence for an association between the Xbal polymorphism at the apolipoprotein B locus and lipoprotein level

Subjects with non‐familial hypercholesterolemia who were homozygous for absence of an Xbal restriction site in the apolipoprotein B gene (genotype X2X2) had significantly lower values of apolipoprotein B than those possessing the site. Our data are in agreement with those of Berg (1986) and Law et al. (1986) indicating that X2X2 homozygotes have lower levels of apolipoprotein B, total serum cholesterol, triglycerides and LDL cholesterol. The mechanism underlying this effect is unknown, but could reflect different LDL metabolism between subjects with different genotypes.
Wharf : Sharing Docker Images across Hosts from a Distributed Filesystem

Due to their portability and less overhead compared to traditional virtual machines, containers are becoming an attractive solution for running HPC workloads. Docker is a popular toolset which enables convenient provisioning and management of containers and their corresponding images. However, Docker does not natively support running on shared storage, a crucial requirement in large-scale HPC clusters which are often diskless or access data via a shared burst buffer layer. This lack of distributed storage support can lead to overhead when running containerized HPC applications. In this work, we explore how Docker images can be served efficiently from a shared distributed storage layer. We implement a distributed layer on top of Docker that allows multiple Docker daemons to access container images from a shared file system such as IBM Spectrum Scale or NFS. Our design is independent of the underlying storage layer and minimizes the synchronization overhead between different Docker daemons.
Finite Set Model Predictive Control of Interior PM Synchronous Motor Drives With an External Disturbance Rejection Technique

This paper designs a predictive speed controller of interior permanent-magnet synchronous motor (IPMSM) based on finite control set (FCS)–model predictive control (MPC). The proposed predictive speed controller has a cascade-free structure that comprises a single predictive control function for the speed and dq-axis stator currents. The future rotor speed and stator currents are predicted at each sampling interval. Then, the proposed predictive control function is evaluated to determine the optimal switching states for the IPMSM drive. In high-performance speed-controlled drive, the unknown load torque disturbance has to be suppressed. Therefore, the load torque disturbance estimator using the two-stage extended Kalman filter (TSEKF) is proposed to enhance the dynamic performance of the IPMSM drive. The proposed TSEKF simultaneously estimates the system states, which greatly improve the model prediction process. The proposed predictive speed control is simple and compact, which demonstrates a faster transient response and a robust feature to mechanical system parameter variations when compared with the conventional cascaded speed control under a wide speed range and load torque variations. The experimental results on a prototype IPMSM drive built on a Texas Instruments TMS320F28335 floating point digital signal processing (DSP) board are presented considering the constant torque and flux-weakening regions to confirm the feasibility of the proposed FCS-MPC scheme.
In-treatment reduced left atrial diameter during antihypertensive treatment is associated with reduced new-onset atrial fibrillation in hypertensive patients with left ventricular hypertrophy: The LIFE Study

Abstract Objective. It is unclear whether improvement of left atrial (LA) and ventricular (LV) structure results in reduction in new-onset atrial fibrillation (AF). The aim of the present study was to examine whether changes in-treatment LA diameter were related to changes in risk of new-onset AF. Methods. We followed 939 hypertensive patients with electrocardiographic LV hypertrophy randomized to atenolol or losartan-based regimens in the LIFE Study for a mean of 4.8 years with echocardiograms at enrolment and annually during treatment. Results. New-onset AF occurred in 46 patients (10.2/1000 patient-years of follow-up). At baseline, patients with new-onset AF were older, had higher systolic blood pressure and heart rate as well as higher prevalence of LA dilatation, but had similar prevalences of LV hypertrophy and mitral or aortic valve disease. In univariate Cox analysis baseline LA diameter (HR=4.67 per cm increase [95% CI 2.86–7.65], p<0.001) and LV mass index (HR=1.11 per 10 g/m2 increase [95% CI 1.02–1.22], p<0.05) both predicted new-onset AF. In multivariate analysis, increased baseline LA diameter increased the risk of new-onset AF (HR=5.16 per cm [95% CI 2.85–9.35], p<0.001) whereas reduction of in-treatment LA diameter reduced the risk (HR=0.21 per cm lower LA diameter during treatment [95% CI 0.14–0.32], p<0.001) with adjustment for in-treatment LV mass in-treatment systolic blood pressure, age and Framingham risk score. Conclusion. LA diameter at baseline and during antihypertensive treatment were equally strong predictors of new-onset AF independent of the level of arterial pressure, LV mass and other covariates. Prevention of AF during antihypertensive treatment may be improved by antihypertensive therapy that reduces LA size in addition to controlling blood pressure.
The In-Vitro Effect of Aqueous Leaf Extract of Basella Alba L. On Osmotic Fragility of Red Blood Cells in Hbss Subjects

The aqueous leaf extracts of Basella alba were investigated in the present study for their in-vitro effect on red blood cell fragility in clinically confirmed HbSS subjects. A total of 12 human subjects, six (6) male and six (6) female with HbSS were used for this study. In-vitro osmotic fragility was determined spectrophotometrically by obtaining optical density at wavelength of 540nm. 5-6 ml of blood was obtained from each subject and analyzed with the use of 15 centrifuge tubes, divided into 5 per group. The first group served as the control (without Basella alba), the second group contained low dose (0.2mg/ml) of Basella alba and the third group contained high dose (0.4mg/ml) of Basella alba in varying saline percentages of 0.0%, 0.3%, 0.6%, 0.9% and 1.2%. Hemolysis occurred at all saline percentages; however, low dose and high dose of aqueous extract of Basella alba reduced the percentage of hemolysis in all subjects, especially in the males. This suggests that there might be a possible synergistic activity between Basella alba and androgens, by which Basella alba reduces hemolysis of red blood cells, combined with its anti-anemic effect, thereby, maintaining the high red blood cell count seen in males. Thus, it is advised that Basella alba should be consumed regularly by sicklers, in order to help reduce the occurrence of hemolytic anemia.
Meeting the Challenges of Opioid-Induced Constipation in Chronic Pain Management – A Novel Approach

Opioid analgesics are the cornerstone of pain management for moderate-to-severe cancer pain and, increasingly, chronic noncancer pain. Despite proven analgesic efficacy, the use of opioids is commonly associated with frequently dose-limiting constipation that seriously impacts on patients’ quality of life. Agents currently used to manage opioid-induced constipation (OIC), such as laxatives, do not address the underlying opioid receptor-mediated cause of constipation and are often ineffective. A significant need therefore exists for more effective treatment options. A novel approach for selectively and locally antagonizing the gastrointestinal effects of opioids involves the coadministration of a μ-opioid receptor antagonist with negligible systemic availability, such as oral naloxone. Combination therapy with prolonged-release (PR) oxycodone plus PR naloxone has been shown to provide effective analgesia while preventing or reducing constipation. The current article highlights this novel strategy in its potential to significantly improve the quality of life of patients suffering from chronic pain, affording patients the benefit of full analgesia, without the burden of OIC.
Development and Applicability of Integrative Tumor Response Assays for Metastatic Colorectal Cancer.

AIM The present study investigated how well the results of integrative tumor-response assay (ITRA) compared to those of clinical response to chemotherapy in patients with metastatic colorectal cancer (CRC). PATIENTS AND METHODS A total of 129 patients with metastatic CRC were prospectively enrolled. ITRA consisted of two sequential histoculture drug-response assays (HDRAs). First-stage HDRAs were performed using 5-fluorouracil with leucovorin and oxaliplatin (FX), or with irinotecan (FR). Second-stage HDRAs (ITRA) were performed for cells surviving after the first-stage HDRA, using FX, FR, and their combinations with bevacizumab and cetuximab. RESULTS Among 129 patients, 42 (32.6%) completed second-line chemotherapy, results that correlated with those of ITRA. The accuracy of ITRA for predicting response to second-line chemotherapy was 61.9% (26/42), with a sensitivity of 44.4% (8/18) and a specificity of 75% (18/24). CONCLUSION Despite its relatively low accuracy, ITRA might be a useful technique for predicting therapeutic efficacy and selecting for appropriate first-line and second-line anticancer regimens for patients.
Analysis of Incision Sites Produced by Human Cell Extracts and Purified Proteins during Nucleotide Excision Repair of a 1,3-Intrastrand d(GpTpG)-Cisplatin Adduct (*)

Nucleotide excision repair by mammalian enzymes removes DNA damage as part of 30-mer oligonucleotides by incising phosphodiester bonds on either side of a lesion. We analyzed this dual incision reaction at a single 1,3-intrastrand d(GpTpG)-cisplatin cross-link in a closed circular duplex DNA substrate. Incisions were formed in the DNA with human cell extracts in which DNA repair synthesis was inhibited. The nicks were mapped by restriction fragment end labeling and primer extension analysis. Principal sites of cleavage were identified at the 9th phosphodiester bond 3′ to the lesion and at the 16th phosphodiester bond 5′ to the lesion. The predominant product was found to be a 26-mer platinated oligonucleotide by hybridization to a P-labeled complementary DNA probe. Oligonucleotides were formed at the same rate as the 3′ cleavage, suggesting that both incisions are made in a near-synchronous manner. There was, however, a low frequency of 5′ incisions in the absence of 3′ cleavage. The dual incision reaction was reconstituted using the purified mammalian proteins XPA, RPA, XPC, TFIIH, XPG, and a fraction containing ERCC1-XPF and IF7. All of these components were required in order to observe any cleavage.
The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins

Drug With a (Re)Purpose Thalidomide, once infamous for its deleterious effects on fetal development, has re-emerged as a drug of great interest because of its beneficial immunomodulatory effects. A derivative drug called lenalidomide significantly extends the survival of patients with multiple myeloma, but the molecular mechanisms underlying its efficacy remain unclear (see the Perspective by Stewart). Building on a previous observation that thalidomide binds to cereblon, a ubiquitin ligase, Lu et al. (p. 305, published online 28 November) and Krönke et al. (p. 301, published online 28 November) show that in the presence of lenalidomide, cereblon selectively targets two B cell transcription factors (Ikaros family members, IKZF1 and IKZF3) for degradation. In myeloma cell lines and patient cells, down-regulation of IKZF1 and IKZF3 was necessary and sufficient for the drug's anticancer activity. Thus, lenalidomide may act, at least in part, by “grepurposing” a ubiquitin ligase. A drug with potent activity in multiple myeloma patients acts by inducing degradation of two specific transcription factors. [Also see Perspective by Stewart] Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical mechanisms underlying their antitumor activity are unknown. Thalidomide was recently shown to bind to, and inhibit, the cereblon ubiquitin ligase. Cereblon loss in zebrafish causes fin defects reminiscent of the limb defects seen in children exposed to thalidomide in utero. Here we show that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide’s therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.
Adequacy of Initial Everolimus Dose, With and Without Calcineurin Inhibitors, in Kidney Transplant Recipients

Background: This study investigates the adequacy of initial everolimus (EVR) dose, with and without calcineurin inhibitors (CNI), in kidney transplant recipients. Methods: This retrospective cohort analysis involved data from 305 kidney transplant recipients participating in 3 randomized trials receiving reduced dose cyclosporin A (CsA) combined with EVR 0.75 mg BID (CSA/EVR0.75, N = 32) or 1.5 mg BID (CSA/EVR1.5, N = 31), reduced dose tacrolimus (TAC) combined with EVR 1.5 mg BID (TAC0.05/EVR1.5, N = 83), standard dose TAC combined with EVR 1.5 mg BID (TAC0.1/EVR1.5, N = 93), and EVR 1.5 mg BID (EVR1.5, N = 66) with TAC introduction after day 5. The adequacy of the initial EVR dose, based on EVR whole blood trough between 3 and 8 ng/mL, was compared using first EVR blood concentrations obtained at day 3 after transplantation. Results: Recipient age, proportion of patients with diabetes mellitus, and proportion of grafts from living donors were different among the groups. Dose-corrected EVR concentrations were higher in patients receiving CsA than in those receiving TAC or no calcineurin inhibitors (6.7 ± 5.9 versus 5.4 ± 2.2 versus 2.4 ± 0.8 versus 2.5 ± 0.9 versus 2.2 ± 0.7, P = 0.000). No differences were observed comparing dose adjusted EVR concentrations combined with TAC or alone (P = 0.073). The proportion of patients with EVR concentration below <3 ng/mL was lower when EVR was combined with CsA (25 versus 3 versus 43 versus 33 versus 50%, P = 0.000). Later introduction of TAC did not influence EVR concentrations. There were no differences in mean CsA concentrations comparing patients receiving EVR 0.75 or 1.5 mg BID (240 ± 143 versus 213 ± 105 ng/mL). On the other hand, mean TAC concentrations were higher according to the initial TAC dose regimen (6.4 ± 3.9 versus 9.8 ± 5.9 ng/mL). Conclusions: In de novo kidney transplant recipients, the choice of the initial dose of EVR should consider the type of calcineurin inhibitor to reach target EVR concentration within the first week in a higher proportion of patients, maximizing the efficacy/toxicity profile.