Miracle-dz/UniFAR-FTUs huggingface dataset:
The Reinforcing Efficacy of Psychostimulants in Rhesus Monkeys: The Role of Pharmacokinetics and Pharmacodynamics

This study was undertaken to investigate pharmacological variables that influence the reinforcing efficacy of psychostimulants. Rhesus monkeys (n = 9) responded under a within-session, exponentially increasing, progressive ratio schedule of cocaine reinforcement. Doses of cocaine, methylphenidate (MP), cocaine analogs [(±)-2β-propanoyl-3β-(2-naphthyl)-tropane (WF-23), HD-23; (±)-2β-propanoyl-3β-(2-isopropenyl)tropane (WF-60), HD-60; and 2β-propanoyl-3β-(4-tolyl)-tropane (HD-11, WF-11), and 2β-propanoyl-3β-(4-tolyl)-tropane (HD-11, WF-11), PTT], and MP analogs [(αR,2R)-α-(2-naphthalenyl)-2-piperidineacetic acid methyl ester, HDMP-28; and (αR,2S)-α-(2-naphthalenyl)-2-pyrrolideneacetic acid methyl ester, HDMP-29] that varied in their pharmacokinetic and pharmacodynamic properties were substituted for cocaine. These drugs were chosen according to their selectivity for dopamine transporters (DAT) and 5-hydroxytryptamine (serotonin) transporters (5-HTT) as assessed in rodents and their duration of action. In addition, data pertaining to the rate of onset at DAT were collected for the cocaine analogs using an ex vivo binding assay in rodent tissue. Finally, the pharmacodynamic profile of select drugs was confirmed in primate brain tissue. All drugs had reinforcing effects except HDMP-29. The rank ordering of the peak breaking points (BPs) was cocaine = MP = HDMP-28 ≥ HD-60 ≥ PTT ≥ HD-23 > HDMP-29. The time to peak DAT occupancy for the cocaine analogs was greater than 30 min. The potency to maintain peak BP was significantly correlated with DAT affinity. There was not a linear relationship between monoamine transporter affinity and reinforcing efficacy, but it appeared that in nonhuman primates there is a range of DAT affinity under which maximal responding is maintained. Interestingly, the 5-HTT-selective cocaine analog HD-60 functioned robustly as a reinforcer at several doses in all monkeys tested. These data question the dogma regarding the role of pharmacokinetic factors and the relative influence of DAT and 5-HTT in stimulant reinforcement.
Genetic variance components estimation for binary traits using multiple related individuals

Understanding and modeling genetic or nongenetic factors that influence susceptibility to complex traits has been the focus of many genetic studies. Large pedigrees with known complex structure may be advantageous in epidemiological studies since they can significantly increase the number of factors whose influence on the trait can be estimated. We propose a likelihood approach, developed in the context of generalized linear mixed models, for modeling dichotomous traits based on data from hundreds of individuals all of whom are potentially correlated through either a known pedigree or an estimated covariance matrix. Our approach is based on a hierarchical model where we first assess the probability of each individual having the trait and then formulate a likelihood assuming conditional independence of individuals. The advantage of our formulation is that it easily incorporates information from pertinent covariates as fixed effects and at the same time takes into account the correlation between individuals that share genetic background or other random effects. The high dimensionality of the integration involved in the likelihood prohibits exact computations. Instead, an automated Monte Carlo expectation maximization algorithm is employed for obtaining the maximum likelihood estimates of the model parameters. Through a simulation study we demonstrate that our method can provide reliable estimates of the model parameters when the sample size is close to 500. Implementation of our method to data from a pedigree of 491 Hutterites evaluated for Type 2 diabetes (T2D) reveal evidence of a strong genetic component to T2D risk, particularly for younger and leaner cases. Genet. Epidemiol. 2011. © 2011 Wiley‐Liss, Inc. 35:291‐302, 2011
Distribution of glucose-6-phosphate dehydrogenase phenotypes in Jamaica.

Interest in the distribution of glucose-6-phosphate dehydrogenase (G6PD; E.C.1.1.1.49, D-glucose-6-phosphate:NADP oxidoreductase) phenotypes has stemmed not only from the anthropological and genetic data which may be derived from such studies, but also from the demonstration of the relationship between G6PD variants and the different clinical syndromes which may be recognized in patients with G6PD deficiency. There is very little information about this aspect of red cell metabolism in Jamaica, even though the majority of the population is derived from West Africa where the incidence of G6PD deficiency is high. We report here the results of a survey in Kingston, the capital of Jamaica.
Guanabenz-mediated Inactivation and Enhanced Proteolytic Degradation of Neuronal Nitric-oxide Synthase*

Guanabenz, a metabolism-based irreversible inactivator of neuronal nitric-oxide synthase (nNOS) in vitro, causes the loss of immunodetectable nNOS in vivo. This process is selective in that the slowly reversible inhibitor N G-nitro-l-arginine did not decrease the levels of nNOS in vivo. To better understand the mechanism for the loss of nNOS protein in vivo, we have investigated the effects of guanabenz andN G-nitro-l-arginine in HEK 293 cells stably transfected with the enzyme. We show here that guanabenz, but not N G-nitro-l-arginine, caused the inactivation and loss of nNOS protein in the HEK 293 cells. In studies with cycloheximide or in pulse-chase experiments with [35S]methionine, we demonstrate that the loss of nNOS was due in large part to enhanced proteolysis of the protein with the half-life decreasing by one-half from 20 to 10 h. Other metabolism-based irreversible inactivators to nNOS,N G-methyl-l-arginine, andN 5-(1-iminoethyl)-l-ornithine, but not the reversible inhibitor 7-nitroindazole (7-NI), caused a similar decrease in the half-life of nNOS. Proteasomal inhibitors, lactacystin, Cbz-leucine-leucine-leucinal, andN-acetyl-leucine-leucine-norleucinal, but not the lysosomal protease inhibitor leupeptin, were found to effectively inhibit the proteolytic degradation of nNOS. Thus we have shown for the first time that the irreversible inactivators of nNOS, perhaps through covalent alteration of the enzyme, enhance the proteolytic turnover of the enzyme by a mechanism involving the proteasome.
Legion: Expressing locality and independence with logical regions

Modern parallel architectures have both heterogeneous processors and deep, complex memory hierarchies. We present Legion, a programming model and runtime system for achieving high performance on these machines. Legion is organized around logical regions, which express both locality and independence of program data, and tasks, functions that perform computations on regions. We describe a runtime system that dynamically extracts parallelism from Legion programs, using a distributed, parallel scheduling algorithm that identifies both independent tasks and nested parallelism. Legion also enables explicit, programmer controlled movement of data through the memory hierarchy and placement of tasks based on locality information via a novel mapping interface. We evaluate our Legion implementation on three applications: fluid-flow on a regular grid, a three-level AMR code solving a heat diffusion equation, and a circuit simulation.
Varicella zoster virus infection of the pharynx and larynx with multiple cranial neuropathies

Varicella zoster virus (VZV) infection of the head and neck region may present with various clinical symptoms, involving different entities and different routes of viral spreading. We present a case of VZV infection of the pharynx and larynx with multiple cranial nerve (CN) neuropathies (CN VII, VIII, IX, and X) of a 52‐year‐old woman who complained of the sudden onset of hoarseness, odynophagia, dysphagia, and hearing loss in the left ear, followed by left‐side facial weakness lasting for 1 week. Endoscopic examination revealed multiple mucosal erosions over the oropharynx, with extension upward to the nasopharynx and downward to the mucosa overlying the epiglottis, arytenoid, and vocal cord. All of these lesions tended to lateralize to the left side, suggesting a VZV infection diagnosis; this was confirmed by polymerase chain reaction on eruptional exudates, as well as serologic examination.
Photostimulation activates restorable fragmentation of single mitochondrion by initiating oxide flashes

Mitochondrial research is important to ageing, apoptosis, and mitochondrial diseases. In previous works, mitochondria are usually stimulated indirectly by proapoptotic drugs to study mitochondrial development, which is in lack of controllability, or spatial and temporal resolution. These chemicals or even gene techniques regulating mitochondrial dynamics may also activate other inter- or intra-cellular processes simultaneously. Here we demonstrate a photostimulation method on single-mitochondrion level by tightly-focused femtosecond laser that can precisely activate restorable fragmentation of mitochondria which soon recover their original tubular structure after tens of seconds. In this process, series of mitochondrial reactive oxygen species (mROS) flashes are observed and found very critical to mitochondrial fragmentation. Meanwhile, transient openings of mitochondrial permeability transition pores (mPTP), suggested by oscillations of mitochondrial membrane potential, contribute to the scavenging of redundant mROS and recovery of fragmented mitochondria. Those results demonstrate photostimulation as an active, precise and controllable method for the study of mitochondrial oxidative and morphological dynamics or related fields.
Cow postpartum uterine infection : A review of risk factors , prevention and the overall impact

Accepted: 02/06/2014 Abstract Several physiological changes occur in the cow’s ut erus soon after calving. These changes are significant if a cow is to recover and come back into season, ready to conceive, thus any factors th at interfare with the normal functioning of the uterus and other associat ed structures will affect overall reproductive performance. Research has show n variations in the prevalence of uterine infection between different c ountries due to several factors such as general environment, nutrition, cal ving season and breed. Infections such as puerperal metritis and endometri tis are often caused by pathogens such as Actinomyces pyogenes, Fusobacterium necroforum and Bacteroides spp, which can cause significant damage to the uterine endometrial tissue. Such infections require prompt diagnosis and attention in order to prevent their detrimental effect. Resea rch has also documented other factors that may contribute to the incidence of infection of the uterus after calving. They include age, parity, poor nutri tion, dystocia and retained foetal membranes (RFMs). Prevention of uterine infe ction should therefore focus on the causal factors, applying the best mana gement practises in order to minimise their overall impact. Further studies i nto improved genetics focusing on reproductive immunology would be someth ing that is worthwhile in the 21 century.
Feature selection and transduction for prediction of molecular bioactivity for drug design

MOTIVATION In drug discovery a key task is to identify characteristics that separate active (binding) compounds from inactive (non-binding) ones. An automated prediction system can help reduce resources necessary to carry out this task. RESULTS Two methods for prediction of molecular bioactivity for drug design are introduced and shown to perform well in a data set previously studied as part of the KDD (Knowledge Discovery and Data Mining) Cup 2001. The data is characterized by very few positive examples, a very large number of features (describing three-dimensional properties of the molecules) and rather different distributions between training and test data. Two techniques are introduced specifically to tackle these problems: a feature selection method for unbalanced data and a classifier which adapts to the distribution of the the unlabeled test data (a so-called transductive method). We show both techniques improve identification performance and in conjunction provide an improvement over using only one of the techniques. Our results suggest the importance of taking into account the characteristics in this data which may also be relevant in other problems of a similar type.
On Over-Relaxed Proximal Point Algorithms for Generalized Nonlinear Operator Equation with (A,η,m)-Monotonicity Framework

In this paper, a new class of over-relaxed proximal point algorithms for solving nonlinear operator equations with (A,η,m)-monotonicity framework in Hilbert spaces is introduced and studied. Further, by using the generalized resolvent operator technique associated with the (A,η,m)-monotone operators, the approximation solvability of the operator equation problems and the convergence of iterative sequences generated by the algorithm are discussed. Our results improve and generalize the corresponding results in the literature.
A Decade of DTI in Traumatic Brain Injury: 10 Years and 100 Articles Later

SUMMARY: The past decade has seen an increase in the number of articles reporting the use of DTI to detect brain abnormalities in patients with traumatic brain injury. DTI is well-suited to the interrogation of white matter microstructure, the most important location of pathology in TBI. Additionally, studies in animal models have demonstrated the correlation of DTI findings and TBI pathology. One hundred articles met the inclusion criteria for this quantitative literature review. Despite significant variability in sample characteristics, technical aspects of imaging, and analysis approaches, the consensus is that DTI effectively differentiates patients with TBI and controls, regardless of the severity and timeframe following injury. Furthermore, many have established a relationship between DTI measures and TBI outcomes. However, the heterogeneity of specific outcome measures used limits interpretation of the literature. Similarly, few longitudinal studies have been performed, limiting inferences regarding the long-term predictive utility of DTI. Larger longitudinal studies, using standardized imaging, analysis approaches, and outcome measures will help realize the promise of DTI as a prognostic tool in the care of patients with TBI.
Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system

The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor α and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.
Deconstruction, G_2 Holonomy, and Doublet-Triplet Splitting

We describe a mechanism for using discrete symmetries to solve the doublet-triplet splitting problem of four-dimensional supersymmetric GUT's. We present two versions of the mechanism, one via ``deconstruction,'' and one in terms of M-theory compactification to four dimensions on a manifold of G_2 holonomy.
Production of sausage

PURPOSE: To provide low salt and/or low phosphate and/or low fat and/or high moisture sausage by processing and heating later meat batter under specified hydrostatic pressure. CONSTITUTION: A casing is filled with the meat batter prepared from meat, additive fat, ice and nitrite curing salt, processed under hydrostatic pressure from 500 to 400 bars and heated later. The low salt, low phosphate, low fat and/or high moisture sausage, with which the hardness of texture is enough and heating yield is satisfactory, can be provided. COPYRIGHT: (C)1995,JPO
Membrane Type 1 Matrix Metalloproteinase Digests Interstitial Collagens and Other Extracellular Matrix Macromolecules*

Membrane type 1 matrix metalloproteinase (MT1-MMP) is expressed on cancer cell membranes and activates the zymogen of MMP-2 (gelatinase A). We have recently isolated MT1-MMP complexed with tissue inhibitor of metalloproteinases 2 (TIMP-2) and demonstrated that MT1-MMP exhibits gelatinolytic activity by gelatin zymography (Imai, K., Ohuchi, E., Aoki, T., Nomura, H., Fujii, Y., Sato, H., Seiki, M., and Okada, Y. (1996) Cancer Res. 56, 2707-2710). In the present study, we have further purified to homogeneity a deletion mutant of MT1-MMP lacking the transmembrane domain (ΔMT1) and native MT1-MMP secreted from a human breast carcinoma cell line (MDA-MB-231 cells) and examined their substrate specificities. Both proteinases are active, without any treatment for activation, and digest type I (guinea pig), II (bovine), and III (human) collagens into characteristic 3/4 and 1/4 fragments. The cleavage sites of type I collagen are the Gly775-Ile776 bond for α1(I) chains and the Gly775-Leu776 and Gly781-Ile782 bonds for α2(I) chains. ΔMT1 hydrolyzes type I collagen 6.5- or 4-fold more preferentially than type II or III collagen, whereas MMP-1 (tissue collagenase) digests type III collagen more efficiently than the other two collagens. Quantitative analyses of the activity of ΔMT1 and MMP-1 indicate that ΔMT1 is 5-7.1-fold less efficient at cleaving type I collagen. On the other hand, gelatinolytic activity of ΔMT1 is 8-fold higher than that of MMP-1. ΔMT1 also digests cartilage proteoglycan, fibronectin, vitronectin and laminin-1 as well as α1-proteinase inhibitor and α2-macroglobulin. The activity of ΔMT1 on type I collagen is synergistically increased with co-incubation with MMP-2. These results indicate that MT1-MMP is an extracellular matrix-degrading enzyme sharing the substrate specificity with interstitial collagenases, and suggest that MT1-MMP plays a dual role in pathophysiological digestion of extracellular matrix through direct cleavage of the substrates and activation of proMMP-2.
Effect of Substrate Temperature on Structural and Optical Properties of Au/SiO2 Nanocomposite Films Prepared by RF Magnetron Sputtering

Silica films containing gold nanoparticles were grown by magnetron radio frequency (rf) sputtering technique under various deposition conditions. The structural and optical properties of the composite films deposited at 400℃ substrate temperature were compared with those deposited at room temperature. Effect of substrate temperature of AuNPs on micro structural properties of the Au/SiO2nanocomposite films, such as size, dislocation density (δ), strain (e) and lattice distortion (LD) have been investigated. The face-centered cubic crystalline structure of Au nanoparticles inclusion in the amorphous silica dielectric matrix was confirmed using X-ray diffraction. The average grain size of AuNPs has been found in the range of 0.56 - 0.60 nm and 1.15 - 1.23 nm at 3 × 10﹣3 mbar and 2 × 10﹣3mbar argon pressure respectively. The δ, e, LD values change inversely with the increasing of the substrate temperatures. These composites exhibit the optical features of a semiconductor with direct band gap. The band gap energy of 3.85 eV and 4.1 eV achieved for gold nanoparticles when the substrate temperatures increases from 25℃ to 400℃. A peak wavelength of the surface plasmon resonance band absorption (SPR) characteristic of gold nanoparticle was found around 500 nm for the sample deposited at 2 × 10﹣3 mbar and at 400℃ substrate temperature.
RAS isoforms and mutations in cancer at a glance

ABSTRACT RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP–GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. However, despite more than three decades of intense effort, no anti-RAS therapies have reached clinical application. Contributing to this failure has been an underestimation of the complexities of RAS. First, there is now appreciation that the four human RAS proteins are not functionally identical. Second, with >130 different missense mutations found in cancer, there is an emerging view that there are mutation-specific consequences on RAS structure, biochemistry and biology, and mutation-selective therapeutic strategies are needed. In this Cell Science at a Glance article and accompanying poster, we provide a snapshot of the differences between RAS isoforms and mutations, as well as the current status of anti-RAS drug-discovery efforts. Summary: In this Cell Science at a Glance article, we discuss the distinct roles of and properties of RAS isoforms and mutations in cancer – matters that are current foci of ongoing research studies.
Lethal and Sublethal Effects of Avermectin/Milbemycin Parasiticides on the African Malaria Vector, Anopheles arabiensis

ABSTRACT Four cattle parasiticides of the avermectin/milbemycin class were examined for lethal and sublethal effects on the zoophilic, African malaria vector Anopheles arabiensis. Ivermectin, moxidectin, doramectin, and eprinomectin were mixed with bovine blood and provided to laboratoryreared An. arabiensis in a membrane feeder. Ivermectin and eprinomectin were lethal to An. arabiensis at low concentrations (LC50s of 7.9 ppb and 8.5 ppb, respectively). While the lethality of doramectin (LC50 of 23.9 ppb), was less than that of ivermectin and eprinomectin, it markedly reduced egg development. The concentration of moxidectin required to reduce survivorship and egg production in An. arabiensis was >100 fold greater than for ivermectin or eprinomectin. Moxidectin was weak in its actions against An. arabiensis relative to the other three chemicals. These results suggest that cattle treated with ivermectin or eprinomectin in the prescribed range of low dosages as parasiticides have blood toxic to zoophilic malaria vectors. Regionally coordinated, seasonal treatment of cattle could suppress An. arabiensis populations, thereby reducing malaria transmission. Doramectin (although less toxic) would have population level effects on egg production if used in this manner.
Static scheduling for out-of-order instruction issue processors

Superscalar processors strive to increase the number of instructions issued in each processor cycle. Compilers therefore need to expose as much Instruction Level Parallelism (ILP) as possible by using increasingly complex code optimisations. However, the knowledge base of instruction scheduling is focused on in-order instruction issue. It has previously been determined that aggressive static instruction scheduling impedes the speedup achieved by out-of-order instruction issue given an ideal environment. This paper examines how the scheduling process impairs the performance of out-of-order instruction issue. The use of Boolean guards, function in-lining, register renaming and percolation both between basic blocks and around loop back edges is evaluated. The results show that removing Boolean guards and severely limiting percolation while retaining function in-lining produces an improvement over unscheduled benchmarks.