Miracle-dz/UniFAR-FTUs huggingface dataset:
Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies

Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, meprobamate, a controlled substance that produces sedation via GABAA receptors (GABAARs). Given the structural similarities between carisoprodol and meprobamate, we used electrophysiological and behavioral approaches to investigate whether carisoprodol directly affects GABAAR function. In whole-cell patch-clamp studies, carisoprodol allosterically modulated and directly activated human α1β2γ2 GABAAR function in a barbiturate-like manner. At millimolar concentrations, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric ρ1 GABA or glycine α1 receptors. In the absence of GABA, carisoprodol produced picrotoxin-sensitive, inward currents that were significantly larger than those produced by meprobamate, suggesting carisoprodol may directly produce GABAergic effects in vivo. When administered to mice via intraperitoneal or oral routes, carisoprodol elicited locomotor depression within 8 to 12 min after injection. Intraperitoneal administration of meprobamate depressed locomotor activity in the same time frame. In drug discrimination studies with carisoprodol-trained rats, the GABAergic ligands pentobarbital, chlordiazepoxide, and meprobamate each substituted for carisoprodol in a dose-dependent manner. In accordance with findings in vitro, the discriminative stimulus effects of carisoprodol were antagonized by a barbiturate antagonist, bemegride, but not by the benzodiazepine site antagonist, flumazenil. The results of our studies in vivo and in vitro collectively suggest the barbiturate-like effects of carisoprodol may not be due solely to its metabolite, meprobamate. Furthermore, the functional traits we have identified probably contribute to the abuse potential of carisoprodol.
The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma

Deletion of CDKN2A (p16) or amplification of CCND1 (cyclin D1) occurs commonly in head and neck squamous cell carcinoma (HNSCC) and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. Here, we report the antiproliferative activity of LY2835219, a selective CDK4/6 inhibitor through inhibition of CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induction of cell cycle arrest in HNSCC cells. In addition, we demonstrated the antitumor effects of HNSCC xenografts to LY2835219 in vivo. Given the limited effect in HNSCC as a single-agent treatment with LY2835219, a combinational strategy is required to enhance antitumor activity. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. Taken together, our findings suggest that a combinational treatment with LY2835219 and mTOR inhibitor is a promising therapeutic approach for HNSCC.
Incidence of Gardnerella vaginalis, Candida sp and human papilloma virus in cytological smears.

CONTEXT In spite of the wide-ranging literature on the microbiology of normal and abnormal flora of the vagina, there are few studies on the relationship between human papilloma virus (HPV) and other vaginal microorganisms. OBJECTIVE To analyze the frequency of infection by human papilloma virus (HPV) and other agents like Candida sp. , Gardnerella vaginalis and Trichomonas vaginalis in cytological smears. DESIGN STUDY Retrospective study SETTING A public tertiary referral center. SAMPLE An analysis of 17,391 cytologies from outpatients seen between January 1997 and August 1998. The control group was made up of patients in the same age group and same period with no cytological evidence of HPV infection. Patients with a diagnosis of cervical intraepithelial neoplasia (CIN) II or III were excluded from this analysis. MAIN MEASUREMENTS The diagnosis of HPV infection was made in accordance with the criteria of Schneider et al. and the diagnosis of Gardnerella vaginalis was made with a finding of clue cells. RESULTS 390 (2. 24%) had alterations consistent with infection by HPV, sometimes associated with CIN I. The results showed that Gardnerella vaginalis was the most frequent agent in women with HPV infection (23.6% versus 17.4%; P <0.05), while in the control group the most frequent agent was Candida sp. (23.9% versus 13.8%; p <0.001). CONCLUSION In spite of this study being based solely on cytological criteria, in which specific HPV and Gardnerella diagnostic tests were not used, the cytological smear is widely used in clinical practice and the data presented in this investigation show that there is an association between Gardnerella vaginalis and HPV infection. It remains to be established whether the microorganisms favor each other.
The cognitive network model of creativity: a new causal model of creativity and a new brainstorming technique

Creativity is a vital component of problem solving, yet despite decades of creativity research, many of the techniques for increasing creative production still lack compelling theoretical and causal foundations. This paper defines a Cognitive Network Model, a causal model of creative solution generation for problem solving domains. This model is grounded in mechanisms of human cognition which are hypothesized to exist within all individuals, regardless of their intelligence level, socio-economic status, or other variable, personal attributes. Guided by the model, we outline a new Group Support System (GSS) based technique called directed brainstorming. We propose the Cognitive Network Model is useful for explaining the effectiveness of existing creativity techniques, and may represent a basis from which new techniques and technologies for enhancing the creative output of problem-solvers can be developed.
The Nurse-Nurse Collaboration Scale

Objective: To develop and examine the reliability and validity of a new instrument, the nurse-nurse collaboration (NNC) scale. Background: Nurse-nurse collaboration (NNC) is recommended to reduce medical errors and improve patient care and nurses' job satisfaction. While instruments are available to measure nurse-physician collaboration, an instrument to measure NNC was not available in the literature. Because collaboration is necessary for optimal patient care, a valid and reliable instrument would make it possible to measure the level of collaboration among nurses. Methods: A comprehensive literature review was conducted to develop a definition and define relevant domains of NNC and identify instruments with acceptable psychometrics that included items measuring NNC. Instrument items to develop the Nurse-Nurse Collaboration Scale (NNC Scale) were adapted from previously published tools or developed based on domains identified in the literature. Five domains were identified: problem solving, communication, coordination, shared process, and professionalism. Psychometric testing of the NNC Scale included pilot testing for content and construct validity and field testing among 76 staff nurses working in 4 ICUs in a large tertiary-care academic medical center in the northeast United States. Psychometric tests assessing reliability and convergent validity correlations were conducted. Results: The overall Cronbach &agr; for the scale was . 89. Convergent validity correlations, however, were low to moderate, indicating minimal shared variance among the subscales. Therefore, the instrument did not measure a global concept but rather 5 separate domains of collaboration. Internal consistency testing of the 5 subscales produced acceptable results ranging from . 66 to . 91. Conclusion: The NNC Scale demonstrated acceptable reliability and validity for measuring the level of NNC in intensive care nurses. Further psychometric testing and a factor analysis with a larger-sample, more diverse groups of nurses are necessary to further characterize the generalizability of the NNC Scale.
Escherichia coli Twin Arginine (Tat) Mutant Translocases Possessing Relaxed Signal Peptide Recognition Specificities*

The twin arginine (Tat) secretion pathway allows the translocation of folded proteins across the cytoplasmic membrane of bacteria. Tat-specific signal peptides contain a characteristic amino acid motif ((S/T)RRXFLK) including two highly conserved consecutive arginine residues that are thought to be involved in the recognition of the signal peptides by the Tat translocase. Here, we have analyzed the specificity of Tat signal peptide recognition by using a genetic approach. Replacement of the two arginine residues in a Tat-specific precursor protein by lysine-glutamine resulted in an export-defective mutant precursor that was no longer accepted by the wild-type translocase. Selection for restored export allowed for the isolation of Tat translocases possessing single mutations in either the amino-terminal domain of TatB or the first cytosolic domain of TatC. The mutant Tat translocases still efficiently accepted the unaltered precursor protein, indicating that the substrate specificity of the translocases was not strictly changed; rather, the translocases showed an increased tolerance toward variations of the amino acids occupying the positions of the twin arginine residues in the consensus motif of a Tat signal peptide.
Synthesis of multi-functional large pore mesoporous silica nanoparticles as gene carriers

The development of functional nanocarriers that can enhance the cellular delivery of a variety of nucleic acid agents is important in many biomedical applications such as siRNA therapy. We report the synthesis of large pore mesoporous silica nanoparticles (LPMSN) loaded with iron oxide and covalently modified by polyethyleneimine (denoted PEI-Fe-LPMSN) as carriers for gene delivery. The LPMSN have a particle size of ∼200 nm and a large pore size of 11 nm. The large pore size is essential for the formation of large iron oxide nanoparticles to increase the magnetic properties and the adsorption capacity of siRNA molecules. The magnetic property facilitates the cellular uptake of nanocarriers under an external magnetic field. PEI is covalently grafted on the silica surface to enhance the nanocarriers’ affinity against siRNA molecules and to improve gene silencing performance. The PEI-Fe-LPMSN delivered siRNA–PLK1 effectively into osteosarcoma cancer cells, leading to cell viability inhibition of 80%, higher compared to the 50% reduction when the same dose of siRNA was delivered by a commercial product, oligofectamine.
The role of interpretation in the internationalization of smaller Brazilian firms

This study considers how decision-makers in smaller firms interpret the means and conditions of internationalization, and how different modes of interpretation are likely to inform action choices in this process. Drawing on 58 qualitative interviews with the leaders of Brazilian small and medium-sized enterprises (SMEs) in the clothing industry located in the state of Parana, the results support the contention that different understandings given to the means/conditions of internationalization are associated with different action choices. More specifically, the results indicate that: (a) interpretation changes the criteria and parameters by which rational choices on internationalization are made; (b) a comprehensive explanation of internationalization on the basis of situational characteristics is likely to be inconclusive without taking into account decision-makers' interpretations; (c) particular meanings given to internationalization are likely to inform choice in different ways, (d) managers act on the basis of their inter-subjectively negotiated, shared and sustained reality; and (e) investigative proximity with practitioners is pivotal in order to comprehensively account for their interpretations.
D-4F increases microRNA-124a and reduces neuroinflammation in diabetic stroke rats

D-4F is an apolipoprotein-A1 mimetic peptide that promotes anti-inflammatory effects. MicroRNA-124 is the most abundant brain-specific microRNA and has anti-inflammatory effects. In this study, we investigated the therapeutic efficacy and mechanisms of D-4F treatment of stroke in type one diabetes mellitus (T1DM) rats. Male Wistar rats were induced with T1DM, subjected to embolic middle cerebral artery occlusion and treated with PBS or D-4F (1 mg/kg i.p.) at 2, 24 and 48 hours after stroke (n=8/group). A battery of function tests, brain blood barrier (BBB) integrity, white matter changes and microRNA expression were evaluated in vivo and in vitro. D-4F treatment in T1DM-stroke rats significantly improves functional outcome, decreases BBB leakage, increases tight junction protein expression, decreases white matter damage and inflammatory factor expression, while increasing anti-inflammatory M2 macrophage polarization in the ischemic brain. D-4F significantly increases microRNA-124a expression, and decreases matrix metalloproteinase-9, tumor necrosis factor-α and toll-like receptor-4 gene expression in the ischemic brain, and in primary cortical neuronal and microglial cultures. Inhibition of microRNA-124 in cultured primary cortical neurons and microglia attenuates D-4F induced anti-inflammatory effects and M2 macrophage polarization. D-4F treatment of T1DM-stroke increases microRNA-124 expression, promotes anti-inflammatory effects and M2 macrophage polarization, which may contribute to D-4F-induced improvement in neurological function, and BBB and white matter integrity.
Factor Analysis of the Caregiver Quality of Life Index-Cancer (CQOLC) Scale for Chinese Cancer Caregivers: A Preliminary Reliability and Validity Study of the CQOLC-Chinese Version

The English version of the Caregiver Quality of Life Index-Cancer (CQOLC) was translated into simplified Chinese (CQOLC-C), following cultural translation, back-translation and pretest steps. Three hundred and sixty one cancer caregivers participated in this study. Cronbach’s alpha was used to assess CQOLC-C reliability. Exploratory factor analyses (EFA) was used to generate two models of the measure’s factor structure, and confirmatory factor analyses (CFA) were used to test each model, such that the best model to explain the latent structure of the CQOLC-C was identified. EFA using different factor extraction methods yielded two models including four and eight factors. According to the CFA results, model 2 was better fit for the original study data, based on the RMSEA criterion [0.058(90% CI = 0.051-0.065)], χ2 (531) = 853.92, p < 0.0001; CFI (0.96), NNFI (0.96), IFI (0.97), and NFI (0.92). We also examined the effect of removing three items on the CQOLC-C factor structure and discuss the resulting differences from other versions. These results indicate that the CQOLC-C’s factor structure does not fully fit the original theorized model. This study provides preliminary support for further use of the CQOLC-C. However, the present work provides only partial support for the relevance and construct validity of the scale for Chinese caregivers.
Rapid cold hardening improves recovery of ion homeostasis and chill coma recovery time in the migratory locust, Locusta migratoria

SUMMARY Chill tolerance of insects is defined as the ability to tolerate low temperature under circumstances not involving freezing of intracellular or extracellular fluids. For many insects chill tolerance is crucial for their ability to persist in cold environments and mounting evidence indicates that chill tolerance is associated with the ability to maintain ion and water homeostasis, thereby ensuring muscular function and preventing chill injury at low temperature. The present study describes the relationship between muscle and haemolymph ion homeostasis and time to regain posture following cold shock (CS, 2 h at −4°C) in the chill-susceptible locust Locusta migratoria. This relationship was examined in animals with and without a prior rapid cold-hardening treatment (RCH, 2 h at 0°C) to investigate the physiological underpinnings of RCH. CS elicited a doubling of haemolymph [K+] and this disturbance was greater in locusts pre-exposed to RCH. Recovery of ion homeostasis was, however, markedly faster in RCH-treated animals, which correlated well with whole-organism performance as hardened individuals regained posture faster than non-hardened individuals following CS. The present study indicates that loss and recovery of muscular function are associated with the resting membrane potential of excitable membranes as attested by the changes in the equilibrium potential for K+ (EK) following CS. Both hardened and non-hardened animals regained movement once K+ homeostasis had recovered to a fixed level (EK≈−41 mV). RCH is therefore not associated with altered sensitivity to ion disturbance but instead is correlated to a faster recovery of haemolymph [K+].
Selective inhibition of herpes simplex virus by 5-amino-2,5-dideoxy-5-iodouridine

5-Amino-2,5-dideoxy-5-iodouridine, a nel thymidine analogue, is a potent inhibitor of herpes simplex virus type 1 replication. In contrast to most other nucleoside analogues which possess antiviral activity, 5-amino-2,5-dideoxy-5-iodouridine exhibits little, if any, cellular toxicity. Preliminary evidence suggests that 5-amino-2,5-dideoxy-5-iodouridine selectively inhibits viral-specific DNA synthesis.
HyperForm balloon remodeling in the endovascular treatment of anterior cerebral, middle cerebral, and anterior communicating artery aneurysms: clinical and angiographic follow-up results in 800 consecutive patients.

OBJECT The purpose of this paper was to present the safety, efficacy, and clinical/angiographic follow-up results of HyperForm balloon-assisted endosaccular coil occlusion of distal anterior circulation bifurcation aneurysms. METHODS Over a 7-year period, the authors treated 864 middle cerebral artery, distal anterior cerebral artery bifurcation, and anterior communicating artery aneurysms by means of coil embolization with HyperForm balloon assistance in 800 patients. In 37 aneurysms, 2 HyperForm balloons were used simultaneously for remodeling. RESULTS The overall mortality rate was 7.1%, including 1.4% procedural mortality. Various neurological deficits were present at discharge in 8.9% of the patients, and 4.4% had permanent disabling morbidity 6 months posttreatment (modified Rankin Scale score ≥ 2). Thromboembolic complications developed during the treatment of 15 aneurysms (1.7%) causing morbidity or mortality in 10 cases (1.3%). There were 14 intraoperative perforations (1.6%). In all 14 cases, the HyperForm balloon saved patients from severe bleeding. The perforation led to morbidity or mortality in 3 cases (0.4%); there were no negative consequences in 11. There were 726 patients with 757 aneurysms (87.6%) available for follow-up. Control angiograms were obtained at 6 months in 386 patients, at 1 year in 267, and at 2 years in 104, revealing an 82% complete obliteration rate according to the most recent follow-up angiograms. CONCLUSIONS The satisfactory results obtained in this experience demonstrate that HyperForm balloon remodeling provides strong benefits for the endovascular management of middle cerebral, anterior cerebral, and anterior communicating artery aneurysms without increasing the risk of treatment. Not only does this technique allow for the safe treatment of these aneurysms, but it also expands the indications of endovascular treatment to include aneurysms that otherwise cannot be treated with simple coil embolization.
How affected is oxygen metabolism in DWI lesions?

Objective: To use back-to-back diffusion-weighted imaging (DWI) and PET to obtain quantitative measures of the cerebral metabolic rate of oxygen (CMRO2) within DWI lesions, and to assess the perfusion-metabolism coupling status by measuring the cerebral blood flow and the oxygen extraction fraction within DWI lesions. Methods: Six prospectively recruited acute carotid-territory stroke patients completed the imaging protocol, which was commenced 7 to 21 hours from onset and combined DWI derived from state-of-the-art diffusion tensor imaging sequencing using a 3-T magnet and fully quantitative 15O-PET. The PET variables were obtained in individual DWI lesions in each patient. Results: Across patients, the CMRO2 was reduced in the DWI lesion relative to mirror (mean reduction 39.5%; p = 0.028). Examining individual DWI lesions, however, revealed considerable variability in the extent of this CMRO2 reduction. The flow–metabolism coupling pattern underlying the DWI lesion was also variable, including ongoing ischemia, mild oligemia, and partial or complete reperfusion. Discussion: Diffusion-weighted imaging (DWI) lesions generally reflect substantial disruption of energy metabolism. However, the degree of metabolic disruption is variable, indicating DWI lesions may not always represent irreversibly damaged tissue. Finally, because DWI lesions can persist despite reperfusion, assessment of perfusion is necessary for interpretation of DWI changes in acute stroke.
SENSAT-a practical tool for estimation of the IC layout sensitivity to spot defects

A practical interactive tool, SENSAT, is presented for IC layout optimization based on the concept of sensitive area. Since reduction of the layout sensitivity to shorts may increase its sensitivity to opens and vice versa, a practical tool must determine sensitive areas for both. The main function of SENSAT is to extract and display the sensitive areas in the IC masks. Crucial algorithms in SENSAT are the algorithms which determine shapes of the sensitive areas for shorts and opens in the actual layout. In this work we focus our attention on the sensitive area for opens. We demonstrate that in the case of arbitrary mask geometry there are qualitative differences between the concepts of the sensitive areas for shorts and for opens, and a more complex algorithm is needed to find the sensitive areas for opens. We propose such an algorithm. This algorithm has been implemented in SENSAT together with a known algorithm which determines the sensitive areas for shorts. A practical example of optimization of an analog CMOS cell layout shows how our tool can be used to reduce the sensitivity of a layout to spot defects. <<ETX>>
HSA21 Single-Minded 2 (Sim2) Binding Sites Co-Localize with Super-Enhancers and Pioneer Transcription Factors in Pluripotent Mouse ES Cells

The HSA21 encoded Single-minded 2 (SIM2) transcription factor has key neurological functions and is a good candidate to be involved in the cognitive impairment of Down syndrome. We aimed to explore the functional capacity of SIM2 by mapping its DNA binding sites in mouse embryonic stem cells. ChIP-sequencing revealed 1229 high-confidence SIM2-binding sites. Analysis of the SIM2 target genes confirmed the importance of SIM2 in developmental and neuronal processes and indicated that SIM2 may be a master transcription regulator. Indeed, SIM2 DNA binding sites share sequence specificity and overlapping domains of occupancy with master transcription factors such as SOX2, OCT4 (Pou5f1), NANOG or KLF4. The association between SIM2 and these pioneer factors is supported by co-immunoprecipitation of SIM2 with SOX2, OCT4, NANOG or KLF4. Furthermore, the binding of SIM2 marks a particular sub-category of enhancers known as super-enhancers. These regions are characterized by typical DNA modifications and Mediator co-occupancy (MED1 and MED12). Altogether, we provide evidence that SIM2 binds a specific set of enhancer elements thus explaining how SIM2 can regulate its gene network in neuronal features.