Miracle-dz/UniFAR-FTUs huggingface dataset:
Acute amphetamine down‐regulates RGS4 mRNA and protein expression in rat forebrain: distinct roles of D1 and D2 dopamine receptors

Administration of psychostimulants modulates mRNA of several regulators of guanine nucleotide‐binding protein signaling (RGSs) proteins in the brain. In the present study, the regulation of amphetamine‐induced decrease of RGS4 expression in the rat forebrain was evaluated. RGS4 mRNA was reduced by amphetamine in an inverse, dose‐dependent manner. The lowest dose (2.5 mg/kg) decreased RGS4 mRNA in caudate putamen for up to 6 h after injection whereas the decrease in several frontal cortical areas was detected at 3 h only. Analysis of RGS4 immunoreactivity by western blotting revealed a decrease 3 h after amphetamine solely in the caudate putamen. Systemic administration of D1 (SCH23390) or D2 (eticlopride) receptor antagonists blocked amphetamine‐induced locomotion but amphetamine augmented both the SCH23390‐induced increase and the eticlopride‐induced decrease in RGS4 mRNA in the caudate putamen. Further, the down‐regulation of RGS4 immunoreactivity by eticlopride was robust whereas the effect of SCH23390 was blunted as compared with its effect on mRNA. These data suggest that, by decreasing RGS4 expression in the caudate putamen via D1 receptors, acute amphetamine could disinhibit RGS4‐sensitive guanine nucleotide‐binding protein α‐subunit i‐ and/or q‐coupled signaling pathways and favor mechanisms that counterbalance D1 receptor stimulation.
Unified approach to the analysis of genetic variation in serotonergic pathways.

Serotonin is a key neurotransmitter in the central nervous system, and dysregulation of serotonergic pathways has been implicated in the pathogenesis of many complex psychiatric diseases. Polymorphisms of many of the genes involved in serotonin biosynthesis, catabolism, and response have been reported, suggesting that genetic variability may underlie the development of diseases such as schizophrenia, obsessive compulsive disorder, and suicide. A number of single-gene polymorphisms in serotonergic pathways have been examined in these and other diseases, but to date results from this candidate gene approach have been disappointing. Although this may be because the detection of a small effect may require the analysis of large numbers of patients and controls, an alternative explanation is that the clinical importance of a single subtle genetic variant may be overlooked unless other functionally related genes are studied in tandem. To facilitate an integrated analysis, we have developed a PCR-SSP-based assay that permits the simultaneous genotyping of 13 single nucleotide polymorphisms in 9 serotonergic genes under identical conditions. These genes include tryptophan hydroxylase, tryptophan dioxygenase, monoamine oxidase A, and the serotonin receptors 5HT1A, 5HT1D-alpha, 5HT1D-beta, 5HT2A, 5HT2C, and 5HT5A. Using this technology, we have genotyped 100 Caucasoid control individuals and demonstrate that this approach is reliable, quick, cheap, and easy to interpret. We anticipate that this will facilitate the analysis of the genetic basis of susceptibility and phenotypic variability of a number of complex psychiatric diseases. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:621-627, 1999.
Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia

Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone marrow samples from 133 consecutive patients with acute myeloid leukemia and 198 controls for variations in TERT and TERC genes. An additional 89 patients from a second cohort, selected based on cytogenetic status, and 528 controls were further examined for mutations. A third cohort of 372 patients and 384 controls were specifically tested for one TERT gene variant. In the first cohort, 11 patients carried missense TERT gene variants that were not present in controls (P < 0.0001); in the second cohort, TERT mutations were associated with trisomy 8 and inversion 16. Mutation germ-line origin was demonstrated in 5 patients from whom other tissues were available. Analysis of all 3 cohorts (n = 594) for the most common gene variant (A1062T) indicated a prevalence 3 times higher in patients than in controls (n = 1,110; P = 0.0009). Introduction of TERT mutants into telomerase-deficient cells resulted in loss of enzymatic activity by haploinsufficiency. Inherited mutations in TERT that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability.
Personalized cell-mediated immunotherapy and vaccination: combating detrimental uprisings of malignancies

A large number of researchers worldwide have conducted various investigations to advance the cell-based immunotherapies and to examine their clinical benefits as an ultimate prevention and/or treatment modalities against life-threatening malignancies. This dominion needs integration of science and technology to change the face of treatment of diseases towards much more personalized medicines. It is now plausible to reprogram the human cells for the prevention and treatment of diseases through various mechanisms such as modulation of immune system, nonetheless we should understand the complexity of biological functions of the cells in a holistic way to be able to manipulate the central dogma of the life to prevent any inadvertent mistake. We should, if not must, comprehend the interrelations of the cellular components (e.g., transport machineries) in the developmental processes of diseases. Still, we do not have a complete image of life, perhaps as expressive barcodes, and many pieces are missing. While completing this puzzle to picture the whole image and examine new treatment modalities, we should take extra caution upon unknown/little-known biological phenomena because trifling modulation/ alteration in the complex systems of the life may result in tremendous impacts. In short, it seems we need to consider malignancies as complex systems and treat them in a holistic manner by targeting its hallmarks. Taken all, the immune system reinforcement would be one of the main foundations in combating detrimental malignancy uprising.
Towards a theoretical clarification of biomimetics using conceptual tools from engineering design

Many successful examples of biomimetic products are available, and most research efforts in this emerging field are directed towards the development of specific applications. The theoretical and conceptual underpinnings of the knowledge transfer between biologists, engineers and architects are, however, poorly investigated. The present article addresses this gap. We use a ‘technomorphic’ approach, i.e. the application of conceptual tools derived from engineering design, to better understand the processes operating during a typical biomimetic research project. This helps to elucidate the formal connections between functions, working principles and constructions (in a broad sense)—because the ‘form-function-relationship’ is a recurring issue in biology and engineering. The presented schema also serves as a conceptual framework that can be implemented for future biomimetic projects. The concepts of ‘function’ and ‘working principle’ are identified as the core elements in the biomimetic knowledge transfer towards applications. This schema not only facilitates the development of a common language in the emerging science of biomimetics, but also promotes the interdisciplinary dialogue among its subdisciplines.
Novel Pseudomonas aeruginosa Quorum-Sensing Inhibitors Identified in an Ultra-High-Throughput Screen

ABSTRACT The opportunistic pathogen Pseudomonas aeruginosa has two complete acyl-homoserine lactone (acyl-HSL) signaling systems, LasR-LasI and RhlR-RhlI. LasI catalyzes the synthesis of N-3-oxododecanoyl homoserine lactone (3OC12-HSL), and LasR is a transcription factor that requires 3OC12-HSL as a ligand. RhlI catalyzes the synthesis of N-butanoyl homoserine lactone (C4), and RhlR is a transcription factor that responds to C4. LasR and RhlR control the transcription of hundreds of P. aeruginosa genes, many of which are critical virulence determinants, and LasR is required for RhlR function. We developed an ultra-high-throughput cell-based assay to screen a library of approximately 200,000 compounds for inhibitors of LasR-dependent gene expression. Although the library contained a large variety of chemical structures, the two best inhibitors resembled the acyl-homoserine lactone molecule that normally binds to LasR. One compound, a tetrazole with a 12-carbon alkyl tail designated PD12, had a 50% inhibitory concentration (IC50) of 30 nM. The second compound, V-06-018, had an IC50 of 10 μM and is a phenyl ring with a 12-carbon alkyl tail. A microarray analysis showed that both compounds were general inhibitors of quorum sensing, i.e., the expression levels of most LasR-dependent genes were affected. Both compounds also inhibited the production of two quorum-sensing-dependent virulence factors, elastase and pyocyanin. These compounds should be useful for studies of LasR-dependent gene regulation and might serve as scaffolds for the identification of new quorum-sensing modulators.
Meiotic inhibition of bovine oocytes in medium supplemented with a serum replacer and hormones: effects on meiosis progression and developmental capacity

Summary Aiming to improve the developmental competence of bovine oocytes during meiotic block, this study evaluated the effects of a serum replacer (Knockout SR®) and hormones (gonadotropins and estradiol) supplementation of prematuration medium (TCM119 with 0.5 mM IBMX [IBMX group] or 25 μM roscovitine [ROSC group]) on the kinetics of oocyte nuclear maturation and embryo development. Most IBMX and ROSC oocytes prematured for 8 h culture remained in the GV stage (70.3% and 73.1%, respectively; p > 0.05) similar to Control 8 h (63.5%) and to control immature oocytes (Control 0 h, 92.5%). After prematuration for 16 h, no oocytes remained in the GV stage at similar rates to those recently aspirated (p < 0.05); GV rates in ROSC (32.4%) were higher (p < 0.05) than in the Control 16 h group (8.6%), but similar (p > 0.05) to IBMX (9.7%). After in vitro maturation (IMV) for 24 h, metaphase II (MII) rates for oocytes prematured during 8 h were similar (p > 0.05) between control and treatments (65.0–71.7%). Similarly, MII rates oocytes prematured during 16 h were similar (p > 0.05) between all groups (45.9–60.4%). Cleavage rates (67.8–78.2%), embryonic development in day-7 (25.0–35.6%) and hatching rates in day-8 (2.5–11.3%) oocytes blocked during 8 h were similar for all groups (p > 0.05). Results indicate that addition of Knockout SR® and hormones to meiotic block culture with IBMX and roscovitine negatively affected meiotic arrest, but did not impair oocyte nuclear maturation and acquisition of developmental competence.
Enhanced fertility prediction of cryopreserved boar spermatozoa using novel sperm function assessment

Due to reduced fertility, cryopreserved semen is seldom used for commercial porcine artificial insemination (AI). Predicting the fertility of individual frozen ejaculates for selection of higher quality semen prior to AI would increase overall success. Our objective was to test novel and traditional laboratory analyses to identify characteristics of cryopreserved spermatozoa that are related to boar fertility. Traditional post‐thaw analyses of motility, viability, and acrosome integrity were performed on each ejaculate. In vitro fertilization, cleavage, and blastocyst development were also determined. Finally, spermatozoa–oviduct binding and competitive zona‐binding assays were applied to assess sperm adhesion to these two matrices. Fertility of the same ejaculates subjected to laboratory assays was determined for each boar by multi‐sire AI and defined as (i) the mean percentage of the litter sired and (ii) the mean number of piglets sired in each litter. Means of each laboratory evaluation were calculated for each boar and those values were applied to multiple linear regression analyses to determine which sperm traits could collectively estimate fertility in the simplest model. The regression model to predict the percent of litter sired by each boar was highly effective (p < 0.001, r2 = 0.87) and included five traits; acrosome‐compromised spermatozoa, percent live spermatozoa (0 and 60 min post‐thaw), percent total motility, and the number of zona‐bound spermatozoa. A second model to predict the number of piglets sired by boar was also effective (p < 0.05, r2 = 0.57). These models indicate that the fertility of cryopreserved boar spermatozoa can be predicted effectively by including traditional and novel laboratory assays that consider functions of spermatozoa.
Disturbance rejection control for Markov jump systems with nonhomogeneous processes

This paper studies the problem of disturbance rejection controller design for a class of nonhomogeneous Markov jump systems, in which the nonhomogeneous Markov jump process is described as a polytope set. To compensate the disturbance, a disturbance observer is considered, and based on which the state-feedback control law is designed. Under the designed controller, a sufficient condition is presented to ensure that the resulting closed-loop system is stochastically stable and a prescribed H∞ performance index is satisfied. Finally, a simulation example is given to illustrate the effectiveness of the developed techniques proposed.
Embedding Color Watermarks Into Halftoning Images Using Minimum-Distance Binary Patterns

This paper presents a half toning-based watermarking method. This method enables the embedding of a color image into a binary black-and-white halftone, while maintaining the image quality. The proposed technique is capable of embedding watermarks of three color channels into a binary halftone. To achieve high quality halftones, the method maps colors to halftone channels with homogeneous dot patterns which in turn use different binary texture orientations to carry the watermark. They are obtained by solving a minimization problem in which the objective function is the binary distance between the original binary halftone and the available patterns. To restore the color information, we scan the printed halftone image and compute the inverse information (considering the dot pattern). Using the mapped information, we restore the original color channels from the halftone images using a high-quality inverse half toning algorithm. Experimental results show that the method produces restorations with a superior quality than other methods found in the literature and increases the embedding capacity.
Hypothalamic gonadotropin-releasing hormone gene expression during rat estrous cycle.

Expression of gonadotropin-releasing hormone (GnRH) gene in the hypothalamus of female rats was studied by the quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. During the estrous cycle, the GnRH mRNA level did not change from diestrus I to II, and then increased with a peak at 1100 h on proestrus. In the afternoon of proestrus, GnRH mRNA decreased rapidly with a nadir at 1600 h, and thereafter increased again and reached a peak at 1100 h on estrus. Since hypothalamic GnRH mRNA was found to be increased by subcutaneous implantation of estradiol-containing silastic tubing in ovariectomized rats, the peak of GnRH gene expression in the proestrous morning might be due to an increase in circulating estrogen in this phase of the estrous cycle. The surge of luteinizing hormone in the proestrous afternoon and the subsequent increase in GnRH mRNA were completely blocked by the injection of MK801, an antagonist for NMDA receptors, suggesting that the excitation of GnRH neurons leads to an increase in GnRH gene expression. This was further supported by the in vitro observation that high K(+)-induced membrane depolarization markedly increased GnRH mRNA in hypothalamic slices. This increase in GnRH mRNA due to neuronal excitation does not seem to require newly synthesized proteins because anisomycin, a protein synthesis inhibitor at the level of translation, did not affect GnRH gene expression. These results suggest that the hypothalamic GnRH mRNA level reached two peaks during the rat estrous cycle, i.e., in proestrous morning and estrous morning, and that estrogen and GnRH neuronal excitation play pivotal roles in regulating GnRH gene expression.
An actomyosin contractile mechanism for erythrocyte shape transformations

The membrane skeleton of the human erythrocyte consists of many short actin filaments that are multiply cross‐linked by long, flexible spectrin molecules into a continuous network in the plane of the membrane. The mechanical properties expected for this spectrin‐actin network can account for the tensile strength of the erythrocyte membrane and for the remarkable deformability of the cells, yet not for their characteristic biconcave shape. Recently, an authentic vertebrate myosin as well as a non‐muscle form of tropomyosin have been identified and purified from erythrocytes. The myosin is present with respect to the actin in an amount comparable to actin‐myosin ratios in other non‐muscle cells, and there is enough tropomyosin to almost completely coat all of the short actin filaments in the membrane skeleton. The implications of these unexpected discoveries for the molecular organization of the cytoskeleton are discussed, and a mechanism is proposed by which myosin could interact with the membrane‐associated actin filaments to influence erythrocyte shape and membrane properties.
Effect of a community intervention on patient delay and emergency medical service use in acute coronary heart disease: The Rapid Early Action for Coronary Treatment (REACT) Trial.

CONTEXT Delayed access to medical care in patients with acute myocardial infarction (AMI) is common and increases myocardial damage and mortality. OBJECTIVE To evaluate a community intervention to reduce patient delay from symptom onset to hospital presentation and increase emergency medical service (EMS) use. DESIGN AND SETTING The Rapid Early Action for Coronary Treatment Trial, a randomized trial conducted from 1995 to 1997 in 20 US cities (10 matched pairs; population range, 55,777-238,912) in 10 states. PARTICIPANTS A total of 59,944 adults aged 30 years or older presenting to hospital emergency departments (EDs) with chest pain, of whom 20,364 met the primary population criteria of suspected acute coronary heart disease on admission and were discharged with a coronary heart disease-related diagnosis. INTERVENTION One city in each pair was randomly assigned to an 18-month intervention that targeted mass media, community organizations, and professional, public, and patient education to increase appropriate patient actions for AMI symptoms (primary population, n=10,563). The other city in each pair was randomly assigned to reference status (primary population, n=9801). MAIN OUTCOME MEASURES Time from symptom onset to ED arrival and EMS use, compared between intervention and reference city pairs. RESULTS General population surveys provided evidence of increased public awareness and knowledge of program messages. Patient delay from symptom onset to hospital arrival at baseline (median, 140 minutes) was identical in the intervention and reference communities. Delay time decreased in intervention communities by -4.7% per year (95% confidence interval [CI], -8.6% to -0.6%), but the change did not differ significantly from that observed in reference communities (-6. 8% per year; 95% CI, -14.5% to 1.6%; P=.54). EMS use by the primary study population increased significantly in intervention communities compared with reference communities, with a net effect of 20% (95% CI, 7%-34%; P<.005). Total numbers of ED presentations for chest pain and patients with chest pain discharged from the ED, as well as EMS use among patients with chest pain released from the ED, did not change significantly. CONCLUSIONS In this study, despite an 18-month intervention, time from symptom onset to hospital arrival for patients with chest pain did not change differentially between groups, although increased appropriate EMS use occurred in intervention communities. New strategies are needed if delay time from symptom onset to hospital presentation is to be decreased further in patients with suspected AMI. JAMA. 2000;284:60-67
Enhanced Controlled Transdermal Delivery of Ambroxol from the EVA Matrix

To avoid the systemic adverse effects that might occur after oral administration, transdermal delivery of ambroxol was studied as a method for maintaining proper blood levels for an extended period. Release of ambroxol according to concentration and temperature was determined, and permeation of drug through rat skin was studied using two chamber-diffusion cells. The solubility according to PEG 400 volume fraction was highest at 40% PEG 400. The rate of drug release from the EVA matrix increased with increased temperature and drug loading doses. A linear relationship existed between the release rate and the square root of loading rate. The activation energy (Ea) was measured from the slope of the plot of log P versus 1000/T and was found to be 10.71, 10.39, 10.33 and 9.87 kcal/mol for 2, 3, 4 and 5% loading dose from the EVA matrix, respectively. To increase the permeation rate of ambroxol across rat skin from the EVA matrix, various penetration enhancers such as fatty acids (saturated, unsaturated), propylene glycols, glycerides, pyrrolidones, and non-ionic surfactants were used. The enhancing effects of the incorporated enhancers on the skin permeation of ambroxol were evaluated using Franz diffusion cells fitted with intact excised rat skin at 37° using 40% PEG 400 solution as a receptor medium. Among the enhancers used, polyoxyethylene-2-oleyl ether increased the permeation rate by 4.25-fold. In conclusion, EVA matrix containing plasticizer and permeation enhancer could be developed for enhanced transdermal delivery of ambroxol.
Role of IL-22– and TNF-α–Producing Th22 Cells in Uveitis Patients with Behçet’s Disease

Behçet’s disease is a systemic inflammatory disorder with recurrent episodes of oral ulceration, skin lesions, genital ulceration, and intraocular inflammation (uveitis). The intraocular inflammation is strictly associated with Th effector cells. IL-22 is a member of the IL-10 cytokine family that is involved in inflammatory processes. Recently, Th22 cells were identified as a Th cell population that produces IL-22 and TNF-α and are distinct from Th1, Th2, and Th17 cells. In this study, we established Th22-type T cell clones from ocular samples taken from Behçet’s disease patients with active uveitis. These clones produced large amounts of IL-22 and TNF-α but not the Th1 cytokine IFN-γ and the Th17 cytokine IL-17. CD4+ T cells from the peripheral blood of Behçet’s disease patients differentiated into Th22 cells in the presence of IL-6 and TNF-α in vitro. The polarized Th22 cell lines produced large amounts of IL-22, and the polarized Th1 and Th17 cells also produced IL-22. In the presence of anti–TNF-α– and anti–IL-6–blocking Abs, Behçet’s disease Th22-type T cells failed to produce IL-22. In addition, infliximab-pretreated Th22 cells and Th22-type ocular T cells produced less IL-22 and TNF-α. Moreover, IL-22–producing T cells were isolated from mice with experimental autoimmune uveitis, an animal model of Behçet’s disease, and the intraocular T cells from uveitis models produced large amounts of IL-22 in the presence of retinal Ags. Our results suggest that inflammatory cytokines IL-22 and TNF-α may play a key role in the ocular immune response in Behçet’s disease.