Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluation of the neuroprotective effect of dextromethorphan in the acute phase of ischaemic stroke

Introduction Stroke is the second leading cause of death in the world. However, there is still no approved neuroprotective drug for acute ischaemic stroke. To clarify the neuroprotective efficacy and safety of dextromethorphan in stroke, the following study was carried out. Material and methods Forty patients with acute stroke causing moderate deficit were randomized to be treated with either dextromethorphan 300 mg per day or placebo for 5 days. Plasma level of dextromethorphan and its active metabolite was not evaluated in this study. The NIHSS score was calculated on day 5 and the Barthel activities of daily living index and Rankin score were checked after 3 months by a blinded investigator. Collected data were analysed using the t-test and χ2 test. Results In the dextromethorphan-treated group, the mean NIHSS score was 16.8 ±3.9 at baseline, and was 14.2 ±4.8 for the placebo-treated group (p = 0.069). At day 5, there was also no significant difference regarding NIHSS score (p = 0.167). At the 3-month follow-up, there was no significant difference regarding Barthel scale and Rankin score between the dextromethorphan and placebo groups. Conclusions The results of our study suggest that although low-dose and short-term oral administration of dextromethorphan seems to be not neuroprotective, it does not worsen either patients’ condition or NIHSS score. Moreover, patients treated with dextromethorphan showed a significant reduction in seizures (complication after stroke), but had increased chance of MI and renal failure by almost 5% when compared to the placebo-treated groups. More prolonged studies with a higher number of cases are recommended.
In silico Experimentation of Glioma Microenvironment Development and Anti-tumor Therapy

Tumor cells do not develop in isolation, but co-evolve with stromal cells and tumor-associated immune cells in a tumor microenvironment mediated by an array of soluble factors, forming a complex intercellular signaling network. Herein, we report an unbiased, generic model to integrate prior biochemical data and the constructed brain tumor microenvironment in silico as characterized by an intercellular signaling network comprising 5 types of cells, 15 cytokines, and 69 signaling pathways. The results show that glioma develops through three distinct phases: pre-tumor, rapid expansion, and saturation. We designed a microglia depletion therapy and observed significant benefit for virtual patients treated at the early stages but strikingly no therapeutic efficacy at all when therapy was given at a slightly later stage. Cytokine combination therapy exhibits more focused and enhanced therapeutic response even when microglia depletion therapy already fails. It was further revealed that the optimal combination depends on the molecular profile of individual patients, suggesting the need for patient stratification and personalized treatment. These results, obtained solely by observing the in silico dynamics of the glioma microenvironment with no fitting to experimental/clinical data, reflect many characteristics of human glioma development and imply new venues for treating tumors via selective targeting of microenvironmental components.
Stochastic variational learning in recurrent spiking networks

The ability to learn and perform statistical inference with biologically plausible recurrent networks of spiking neurons is an important step toward understanding perception and reasoning. Here we derive and investigate a new learning rule for recurrent spiking networks with hidden neurons, combining principles from variational learning and reinforcement learning. Our network defines a generative model over spike train histories and the derived learning rule has the form of a local Spike Timing Dependent Plasticity rule modulated by global factors (neuromodulators) conveying information about “novelty” on a statistically rigorous ground. Simulations show that our model is able to learn both stationary and non-stationary patterns of spike trains. We also propose one experiment that could potentially be performed with animals in order to test the dynamics of the predicted novelty signal.
The influence of secondary phase carbide particles on the passivity behaviour of NiTi shape memory alloys

The current investigation aims at studying the passivity behaviour of NiTi shape memory alloys with different levels of secondary phase titanium carbide (TiC) particles in an electrolyte of 0.9% sodium chloride at 37 °C. The influence of carbides and thermo‐mechanical treatment/cold working on the passivity breakdown is highlighted. The polarisation studies on the as‐cast and cold worked NiTi with high (0.05 wt%) and low (0.005 wt%) carbon levels show a significant difference in oxide stability. The alloy with extremely low carbon content shows a higher breakdown potential. Higher carbon levels result in higher density of larger TiC and these carbide/matrix interfaces are more susceptible to pitting. The qualitative behaviour of passive layer formed at 0.5 V on the cold worked NiTi alloy with different carbon levels was ascertained by electrochemical impedance spectroscopy (EIS). The oxide on the NiTi alloy with high (0.05 wt%) carbon levels showed lower resistance and poor stability at this condition.
Dopamine Neuron Stimulating Actions of a GDNF Propeptide

Background Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), have shown great promise for protection and restoration of damaged or dying dopamine neurons in animal models and in some Parkinson's disease (PD) clinical trials. However, the delivery of neurotrophic factors to the brain is difficult due to their large size and poor bio-distribution. In addition, developing more efficacious trophic factors is hampered by the difficulty of synthesis and structural modification. Small molecules with neurotrophic actions that are easy to synthesize and modify to improve bioavailability are needed. Methods and Findings Here we present the neurobiological actions of dopamine neuron stimulating peptide-11 (DNSP-11), an 11-mer peptide from the proGDNF domain. In vitro, DNSP-11 supports the survival of fetal mesencephalic neurons, increasing both the number of surviving cells and neuritic outgrowth. In MN9D cells, DNSP-11 protects against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced cell death, significantly decreasing TUNEL-positive cells and levels of caspase-3 activity. In vivo, a single injection of DNSP-11 into the normal adult rat substantia nigra is taken up rapidly into neurons and increases resting levels of dopamine and its metabolites for up to 28 days. Of particular note, DNSP-11 significantly improves apomorphine-induced rotational behavior, and increases dopamine and dopamine metabolite tissue levels in the substantia nigra in a rat model of PD. Unlike GDNF, DNSP-11 was found to block staurosporine- and gramicidin-induced cytotoxicity in nutrient-deprived dopaminergic B65 cells, and its neuroprotective effects included preventing the release of cytochrome c from mitochondria. Conclusions Collectively, these data support that DNSP-11 exhibits potent neurotrophic actions analogous to GDNF, making it a viable candidate for a PD therapeutic. However, it likely signals through pathways that do not directly involve the GFRα1 receptor.
Cancerous epithelial cell lines shed extracellular vesicles with a bimodal size distribution that is sensitive to glutamine inhibition

Extracellular shed vesicles (ESVs) facilitate a unique mode of cell–cell communication wherein vesicle uptake can induce a change in the recipient cellʼs state. Despite the intensity of ESV research, currently reported data represent the bulk characterization of concentrated vesicle samples with little attention paid to heterogeneity. ESV populations likely represent diversity in mechanisms of formation, cargo and size. To better understand ESV subpopulations and the signaling cascades implicated in their formation, we characterize ESV size distributions to identify subpopulations in normal and cancerous epithelial cells. We have discovered that cancer cells exhibit bimodal ESV distributions, one small-diameter and another large-diameter population, suggesting that two mechanisms may govern ESV formation, an exosome population and a cancer-specific microvesicle population. Altered glutamine metabolism in cancer is thought to fuel cancer growth but may also support metastatic niche formation through microvesicle production. We describe the role of a glutaminase inhibitor, compound 968, in ESV production. We have discovered that inhibiting glutamine metabolism significantly impairs large-diameter microvesicle production in cancer cells.
Persistent Cognitive Dysfunctions in Bipolar I Disorder and Schizophrenic Patients: A 3-Year Follow-Up Study

Background: Neurocognitive impairment has consistently been considered a central and stable feature in schizophrenia. As this possibility has been far less studied in bipolar disorder, we aimed to prospectively investigate the stability and specificity of cognitive performance in bipolar disorder compared to schizophrenia. Methods: Fifteen DSM-IV bipolar type I patients and 15 schizophrenic patients were assessed twice with a comprehensive neuropsychological battery and the Positive and Negative Syndrome Scale over a 3-year follow-up. The cognitive performance of the groups was compared at baseline and 3 years later as a mean with that of 26 healthy volunteers. Endpoint and baseline assessments were also compared for each patient group in order to evaluate the stability of cognitive impairment. Results: At both time points, bipolar and schizophrenic patients showed significant deficits on most of the cognitive tasks compared to healthy subjects. Overall, the cross-sectional cognitive profile was similar for both patient groups. Moreover, after controlling for age and length of illness, the two groups’ cognitive function did not differ over time in any test. With the exception of the Stroop color-word interference task, performance at baseline for each test but neither length of illness nor diagnostic category predicted the endpoint performance. Conclusion: This preliminary study suggests that cognitive impairment is also mainly stable over time in bipolar I disorder and thus not specific to schizophrenia.
Phytochemicals Approach for Developing Cancer Immunotherapeutics

Phytochemicals or their derived compounds are being increasingly recognized as potentially potent complementary treatments for cancer. Among them, some phytochemicals are being actively evaluated for use as adjuvants in anticancer therapies. For instance, shikonin and hypericin were found to induce immunogenic cell death of specific cancer cells, and this effect was able to further activate the recognition activity of tumor cells by the host immune system. On the other hand, some derivatives of phytochemicals, such as dihydrobenzofuran lignan (Q2-3) have been found to induce the secretion of an endogenous anticancer factor, namely IL-25, from non-malignant cells. These findings suggest that phytochemicals or their derivatives confer a spectrum of different pharmacological activities, which contrasts with the current cytotoxic anticancer drugs commonly used in clinics. In this review, we have collected together pertinent information from recent studies about the biochemical and cellular mechanisms through which specific phytochemicals regulate target immune systems in defined tumor microenvironments. We have further highlighted the potential application of these immunotherapeutic modifiers in cell-based cancer vaccine systems. This knowledge provides useful technological support and know how for future applications of phytochemicals in cancer immunotherapy.
Neuropsychological Characteristics of Children with Mixed Autism and ADHD

Clinical heterogeneity is a well-established characteristic of autism spectrum disorder (ASD). While the comorbidity of ASD and ADHD is well known in clinical practice, relatively little research has examined the neuropsychological profile of children with ASD + ADHD. Our study showed significant differences in the neuropsychological characteristics of children with ASD + ADHD compared to those with ASD only. Children with ASD + ADHD showed higher symptoms of anxiety, worse working memory, and less empathy, as measured by the “Reading the Mind in the Eyes. ” This suggests that having ADHD brings further challenges to individuals with ASD and may negatively impact their management and outcome. Our findings may have implications for clinical assessment as well as for intervention.
Activity and Phylogenetic Diversity of Bacterial Cells with High and Low Nucleic Acid Content and Electron Transport System Activity in an Upwelling Ecosystem

ABSTRACT We evaluated whether bacteria with higher cell-specific nucleic acid content (HNA) or an active electron transport system, i.e., positive for reduction of 5-cyano-2,3-ditolyl tetrazolium chloride (CTC), were responsible for the bulk of bacterioplankton metabolic activity. We also examined whether the phylogenetic diversity of HNA and CTC-positive cells differed from the diversity of Bacteria with low nucleic acid content (LNA). Bacterial assemblages were sampled both in eutrophic shelf waters and in mesotrophic offshore waters in the Oregon coastal upwelling region. Cytometrically sorted HNA, LNA, and CTC-positive cells were assayed for their cell-specific [3H]leucine incorporation rates. Phylogenetic diversity in sorted non-radioactively labeled samples was assayed using denaturing gradient gel electrophoresis (DGGE) of PCR-amplified 16S rRNA genes. Cell-specific rates of leucine incorporation of HNA and CTC-positive cells were on average only slightly greater than the cell-specific rates of LNA cells. HNA cells accounted for most bacterioplankton substrate incorporation due to high abundances, while the low abundances of CTC-positive cells resulted in only a small contribution by these cells to total bacterial activity. The proportion of the total bacterial leucine incorporation attributable to LNA cells was higher in offshore regions than in shelf waters. Sequence data obtained from DGGE bands showed broadly similar phylogenetic diversity across HNA, LNA, and CTC-positive cells, with between-sample and between-region variability in the distribution of phylotypes. Our results suggest that LNA bacteria are not substantially different from HNA bacteria in either cell-specific rates of substrate incorporation or phylogenetic composition and that they can be significant contributors to bacterial metabolism in the sea.
Characteristic formulae for fixed-point semantics: a general framework

The concurrency theory literature offers a wealth of examples of characteristic-formula constructions for various behavioural relations over finite labelled transition systems and Kripke structures that are defined in terms of fixed points of suitable functions. Such constructions and their proofs of correctness have been developed independently, but have a common underlying structure. This paper provides a general view of characteristic formulae that are expressed in terms of logics that have a facility for the recursive definition of formulae. We show how several examples of characteristic-formula constructions in the literature can be recovered as instances of the proposed general framework, and how the framework can be used to yield novel constructions. The paper also offers general results pertaining to the definition of co-characteristic formulae and of characteristic formulae expressed in terms of infinitary modal logics.
SNARE Protein Syntaxin-1 Colocalizes Closely with NMDA Receptor Subunit NR2B in Postsynaptic Spines in the Hippocampus

Syntaxins are a family of membrane-integrated proteins that are instrumental in exocytosis of vesicles. Syntaxin-1 is an essential component of the presynaptic exocytotic fusion machinery in the brain and interacts with several other proteins. Syntaxin-1 forms a four-helical bundle complex with proteins SNAP-25 and VAMP2 that drives fusion of vesicles with the plasma membrane in the active zone (AZ). Little is known, however, about the ultrastructural localization of syntaxin-1 at the synapse. We have analyzed the intrasynaptic expression of syntaxin-1 in glutamatergic hippocampal synapses in detail by using quantitative postembedding immunogold labeling. Syntaxin-1 was present in highest concentrations at the presynaptic AZ, supporting its role in transmitter release. Presynaptic plasma membrane lateral to the AZ, as well as presynaptic cytoplasmic (PreCy) vesicles were also labeled. However, syntaxin-1 was also significantly expressed in postsynaptic spines, where it was localized at the postsynaptic density (PSD), at postsynaptic lateral membranes and in postsynaptic cytoplasm. Postsynaptically, syntaxin-1 colocalized in the nanometer range with the N-methyl-D-aspartate (NMDA) receptor subunit NR2B, but only weakly with the AMPA receptor subunits GluA2/3. This observation points to the possibility that syntaxin-1 may be involved with NR2B vesicular trafficking from cytoplasmic stores to the postsynaptic plasma membrane, thus facilitating synaptic plasticity. Confocal immunofluorescence double labeling with PSD-95 and ultrastructural fractionation of synaptosomes also confirm localization of syntaxin-1 at the PSD.
Surveillance of outpatient antibiotic consumption in Spain according to sales data and reimbursement data.

OBJECTIVES National data on antibiotic consumption are needed in order to interpret trends in antibiotic resistance. We compared antibiotic prescription reimbursement data and sales data in Spain. METHODS Data covering the years 2002, 2004 and 2005 were examined. Reimbursement data for ambulatory care were provided by the Spanish Agency for Medicines and Healthcare Products and sales data by International Medical Statistics Health. Quantities were standardized using the defined daily dose per 1000 inhabitants per day (DID) in accordance with the anatomical therapeutic classification. RESULTS Sales data increased from 26.33 DID in 2002 to 28.12 DID in 2004 and 28.93 DID in 2005. Estimates based on equivalent reimbursement data were ~30% lower and increased from 18.01 DID in 2002 to 18.48 DID in 2004 and 19.29 DID in 2005. The differences were greatest for amoxicillin, amoxicillin/clavulanic acid, clarithromycin and cefuroxime. CONCLUSIONS Antibiotic consumption as estimated from reimbursement data is substantially less than that from sales data. This finding has major implications for national surveillance of antibiotic consumption.
Experimental study of horizontal flame spread over rigid polyurethane foam on a plateau: effects of sample width and ambient pressure

The effects of sample width and ambient pressure on horizontal flame spread over horizontal rigid polyurethane foams are experimentally studied. A series of comparative experiments are conducted at two places with different altitudes in China. The sample surface temperature, spread rate, and height of flame are measured over a range of sample widths from 4 to 16 cm. Experimental results show that the horizontal flame spread rate decreases as the sample width increases in a negative power law at both two altitudes and the flame spread rate in the Hefei plain (at an altitude of 30 m) is larger than that on the Tibetan plateau (at an altitude of 3658 m) of the same width. The horizontal flame spread mechanism on the rigid polyurethane foam is analyzed qualitatively in comparison with the results of the flame spread rate of expanded polystyrene foams. The relationship between the dimensionless flame height (Hf/W) and the sample width (W) is obtained by using Froude number similarity. It is found based on the experimental data under two different ambient pressures that the average value of the exponent of the ambient pressure in the power law for the horizontal flame spread rate is about 1.9, which is in good agreement with the theoretical value 2.0. Copyright © 2014 John Wiley & Sons, Ltd.
Dysregulation of olfactory receptor neuron lineage in schizophrenia.

BACKGROUND Growing evidence implicates abnormal neurodevelopment in schizophrenia. While neuron birth and differentiation is largely completed by the end of gestation, the olfactory epithelium (OE) is a unique part of the central nervous system that undergoes regeneration throughout life, thus offering an opportunity to investigate cellular and molecular events of neurogenesis and development postmortem. We hypothesized that OE neurons exhibit deviant progress through neurodevelopment in schizophrenia characterized by an increase in immature neurons. METHODS Olfactory epithelium was removed at autopsy from 13 prospectively assessed elderly subjects who had schizophrenia and 10 nonpsychiatric control subjects. Sections were immunolabeled with antibodies that distinguish OE neurons in different stages of development, including basal cells (low-affinity nerve growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated protein 43 [GAP43]), and mature olfactory receptor neurons (olfactory marker protein). Absolute and relative densities of each cell type were determined. RESULTS We observed a significantly lower density of p75NGFR basal cells (37%) in schizophrenia and increases in GAP43 + postmitotic immature neurons (316%) and ratios of GAP43 + postmitotic immature neurons to p75NGFR + cells (665%) and olfactory marker protein + mature neurons to p75NGFR + basal cells (328%). Neuroleptic-free schizophrenia subjects exhibited the highest GAP43 + postmitotic immature neuron values. CONCLUSIONS Abnormal densities and ratios of OE neurons at different stages of development indicate dysregulation of OE neuronal lineage in schizophrenia. This could be because of intrinsic factors controlling differentiation or an inability to gain trophic support from axonal targets in the olfactory bulb. While caution is necessary in extrapolating developmental findings in mature OE to early brain development, similarities in molecular events suggest that such studies may be instructive.
Effect of protease therapy on cytokine secretion by peripheral blood mononuclear cells (PBMC) from HIV‐infected subjects

The viral load reduction seen in patients with late stage HIV infection treated with the protease inhibitor, ritonavir, is accompanied by increases in the in vitro proliferative responses generated by PBMC. The present study was undertaken to investigate which lymphocyte subsets generated these responses and the effects of therapy on cytokine production. Lymphoproliferation following phytohaemagglutinin (PHA) stimulation was studied by thymidine incorporation, and production of IL‐2, interferon‐gamma (IFN‐γ) and IL‐4 was assessed by ELISA in 12 patients receiving ritonavir and seven receiving placebo in the context of randomized, blinded clinical trials. CD4+ cell‐depleted and CD8+ cell‐depleted subsets were obtained from PBMC by immunomagnetic bead depletion. At week 4 of therapy a two‐fold or greater increase in proliferative responses was observed in 9/12 subjects receiving therapy, compared with 0/7 receiving placebo. Similarly there was a significant increase in IL‐2 and IFN‐γ production of 2.7‐fold (P = 0.02) and 1.7‐fold (P = 0.03), respectively, in the treatment group compared with those receiving placebo. No change in IL‐4 production was observed. Despite these increases, cytokine responses post‐therapy were still reduced compared with both healthy controls and asymptomatic HIV‐infected subjects. Increases in proliferative response and IL‐2 production were greater in the CD8+ cell‐depleted population than in the CD4+ cell‐depleted population, whereas increases in IFN‐γ production were derived from the CD4+ cell‐depleted population.