Miracle-dz/UniFAR-FTUs huggingface dataset:
From neuroanatomy to gene therapy: searching for new ways to manipulate the supraspinal endogenous pain modulatory system

The endogenous pain modulatory system is a complex network of brain areas that control nociceptive transmission at the spinal cord by inhibitory and facilitatory actions. The balance between these actions ensures effective modulation of acute pain, while during chronic pain the pronociceptive effects appear to prevail. The mechanisms underlying this imbalance were studied as to the role of two medullary components of the pain modulatory system: the dorsal reticular nucleus and the caudal ventrolateral medulla, which function primarily as pronociceptive and antinociceptive centres, respectively. Both areas are connected with the spinal dorsal horn by closed reciprocal loops. In the spino‐dorsal reticular nucleus loop, the ascending branch is strongly inhibited by spinal GABAergic neurons, which may act as a buffering system of the dorsal reticular nucleus‐centred amplifying effect. In the spino‐caudal ventrolateral medulla loop, the ascending branch is under potent excitation of substance P (SP) released from primary afferents, which is likely to trigger the intense descending inhibition detected in acute pain. During chronic pain, the activity in the lateral reticular formation of the caudal ventrolateral medulla changes, so that the action of the caudal ventrolateral medulla upon SP‐responsive spinal neurons shifts from inhibitory to excitatory. The mechanisms of this modulatory shift are unknown but probably relate to the decresed expression of µ‐opioid, δ‐opioid and GABAB receptors. Normalizing receptor expression in the caudal ventrolateral medulla or controlling noci‐evoked activity at the dorsal reticular nucleus or caudal ventrolateral medulla by interfering with neurotransmitter release is now possible by the use of gene therapy, an approach that stands out as a unique tool to manipulate the supraspinal endogenous pain control system.
Thin film growth of aromatic rod-like molecules on graphene

Research on graphene (Gr) is a vastly expanding field due to its potential for technological applications. Its close structural and chemical relationship to conjugated organic molecules makes it a superior candidate as a transparent electrode material in organic electronics and optoelectronics. The growth of organic thin films—intensively investigated in the past few decades—has demonstrated the complexity in growth and nucleation processes arising from the anisotropy and spatial extension of the molecular building blocks. Choosing the small, conjugated rod-like molecules para-hexaphenyl and pentacene as model representatives for small organic molecules, we review recent findings in organic thin film growth on a variety of Gr substrates. Special attention is paid to the differences in the resulting growth arising from the various methods of Gr fabrication and support that affect both the Gr–molecule interfacing and the involved molecular diffusion processes.
Functional brain imaging in glucocerebrosidase mutation carriers with and without Parkinsonism

Mutations in the glucocerebrosidase gene (GBA) increase the risk for Parkinson's disease and are also associated with an earlier onset of the disease and an akinetic parkinsonian phenotype. To investigate the underlying pathogenesis of this condition, we assessed cerebral metabolism using positron emission tomography (PET) in GBA mutation carriers with and without parkinsonism. [18F]‐fluorodeoxyglucose (FDG)‐PET using a three‐dimensional stereotactic surface projection analysis was used to measure the cerebral metabolic rates of glucose (CMRGlc) in a patient with parkinsonism and Gaucher disease (GD) and five subjects with a heterozygous GBA mutation, including three patients with parkinsonism and three asymptomatic carriers in comparison to 10 healthy controls in the same age range. Dopaminergic neuronal activity was investigated using [11C] CFT‐ and [11C] raclopride‐PET. All GBA mutation carriers displayed a significant CMRGlc decrease in the supplemental motor area (SMA). The carriers with parkinsonism showed additional hypometabolism in the parietooccipital cortices. The CFT and raclopride PET images in the asymptomatic carriers demonstrated the CFT binding to be within normal values in the putamen and a significant increase was observed in the caudate nucleus while raclopride binding in the striatum was in the normal range. An advanced parkinsonian carrier showed decreased CFT binding and increased raclopride binding in the striatum. The decreased CMRGlc in the SMA was characteristic of the GBA mutation carriers. The hypometabolism in the SMA may, therefore, be involved in the clinical characteristics of parkinsonism associated with GBA mutations when the carriers manifest parkinsonism. © 2010 Movement Disorder Society
Regulation of Tiam1 Nucleotide Exchange Activity by Pleckstrin Domain Binding Ligands*

Rho family GTPases play roles in cytoskeletal organization and cellular transformation. Tiam1 is a member of the Dbl family of guanine nucleotide exchange factors that activate Rho family GTPases. These exchange factors have in common a catalytic Dbl homology and adjacent pleckstrin homology domain. Previous structural studies suggest that the pleckstrin domain, a putative phosphoinositide-binding site, may serve a regulatory function. We identified ascorbyl stearate as a compound that binds to the pleckstrin domain of p120 Ras GTPase-activating protein. Furthermore, ascorbyl stearate appears to be a general pleckstrin domain ligand, perhaps by mimicking an endogenous amphiphilic ligand. Tiam1 nucleotide exchange activity was greatly stimulated by ascorbyl stearate. Certain phosphoinositides also stimulated Tiam1 activity but were less potent than ascorbyl stearate. Tiam1 contains an additional N-terminal pleckstrin domain, but only the C-terminal pleckstrin domain was required for activation. Our results suggest that the pleckstrin domains of Dbl-type proteins may not only be involved in subcellular localization but may also directly regulate the nucleotide exchange activity of an associated Dbl homology domain. In addition, this paper introduces ascorbyl stearate as a pleckstrin domain ligand that can modulate the activity of certain pleckstrin domain-containing proteins.
Demonstration of a safe & precise planetary landing system on-board a terrestrial rocket

The Autonomous Landing and Hazard Avoidance Technology (ALHAT) Project is a multiyear NASA technology development effort focused on A(utonomous)-GNC and sensor technology to enable safe and precise planetary landings. The culmination of this project work involves field testing of the developed technology in a relevant terrestrial environment. These tests will demonstrate the capability of the ALHAT AGNC and sensor system, raising the Technology Readiness Level (TRL), in preparation for a next generation planetary lander. With this system, a next generation lander will be capable of safe and precise landings regardless of local lighting conditions. At least two independent terrestrial rocket systems will be utilized for demonstration of aspects of the ALHAT system. This paper discusses the use of the commercial Masten Space Systems terrestrial rocket for ALHAT demonstration purposes. This demonstration is being performed through the NASA Flight Opportunities program. This Terrestrial Test Rocket (TTR) will have the ALHAT AGNC software and hardware system integrated with Masten as a secondary, independent GNC system that will fly the vehicle closed-loop through highly dynamic lunar- and Mars-like approach and landing trajectories. With the AGNC system demonstrated, advanced ALHAT sensor systems will then be incorporated with the TTR, enabling autonomous hazard detection and avoidance in conjunction with a highly precise landing. Details of the hardware and software integration process with Masten are discussed along with performance results from recent tests.
RIP-140 interacts with multiple nuclear receptors by means of two distinct sites

We have characterized two distinct binding sites, called site 1 and site 2, in the nuclear protein RIP-140 which interact with the ligand binding domain of the estrogen receptor both in solution and when the receptor is bound to DNA. Both sites are capable of independently interacting with other nuclear receptors, including the thyroid hormone and retinoic acid receptors, but they are not identical since the interaction with retinoid X receptor is mediated primarily by site 1. The interaction is enhanced by agonists but not by antagonists, and the in vitro binding activities to a number of mutant receptors correlate with their abilities to stimulate transcription in vivo. When RIP-140 is fused to heterologous DNA binding domains, it is able to stimulate the transcription of reporter genes in both yeast and mammalian cells. Thus, RIP-140 is likely to function as a bridging protein between receptors and the basal transcription machinery and thereby stimulate the transcription of target genes.
Self-efficacy: a useful construct to promote physical activity in people with stable chronic heart failure.

AIM To explore the conceptual underpinnings of self-efficacy to address the barriers to participating in physical activity and propose a model of intervention. BACKGROUND The benefits of physical activity in reducing cardiovascular risk have led to evidence-based recommendations for patients with heart disease, including those with chronic heart failure. However, adherence to best practice recommendations is often suboptimal, particularly in those individuals who experience high symptom burden and feel less confident to undertake physical activity. Self-efficacy is the degree of confidence an individual has in his/her ability to perform behaviour under several specific circumstances. Four factors influence an individual's level of self-efficacy: (1) past performance, (2) vicarious experience, (3) verbal persuasion and (4) physiological arousal. DESIGN Discursive. METHODS Using the method of a discursive paper, this article seeks to explore the conceptual underpinnings of self-efficacy to address the barriers to participating in physical activity and proposes a model of intervention, the Home-Heart-Walk, to promote physical activity and monitor functional status. CONCLUSIONS Implementing effective interventions to promote physical activities require appreciation of factors impacting on behaviour change. Addressing concepts relating to self-efficacy in physical activity interventions may promote participation and adherence in the longer term. RELEVANCE TO CLINICAL PRACTICE The increasing burden of chronic disease and the emphasis on self-management strategies underscore the importance of promoting adherence to recommendations, such as physical activity.
A novel structure for multilevel converters

In this paper a new structure for asymmetric multilevel converters is presented. The new topology is consisting of N series-connected of two interconnected multilevel converters per phase. The presented circuit is an optimized multilevel converter with minimum DC voltage sources and switches. The investigated topology can generate a large number of levels (odd and even) without increasing the number of switches and DC voltage sources. For this structure a new algorithm for calculating the levels of DC voltage sources is proposed. Also a complete analysis is given for calculating the harmonic distortion and THD. The proposed converter has higher efficiency because the number of switches is reduced and the devices which can be switched at low frequency. Then for showing the ability of the proposed converter, we use this converter as the core of a DVR, which is based on this converter. This DVR has been modeled and the simulation results show that the DVR can solve power quality problems such as: voltage sag, voltage swell, unbalanced and distorted voltages
Drug Transport into the Mammalian Brain: The Nasal Pathway and its Specific Metabolic Barrier

It is generally accepted that the rate of entry into and distribution of drugs and other xenobiotics within the central nervous system (CNS) depends on the particular anatomy of the brain microvessels forming the blood-brain barrier (BBB), and of the choroid plexus forming the blood-cerebrospinal fluid barrier (CSF), which possess tight junctions preventing the passage of most polar substances. Drug entry to the CNS also depends on the physicochemical properties of the substances, which can be metabolised during this transport to pharmacologically inactive, non-penetrating polar products. Finally, the entry of drugs may be prevented by multiple complex specialized carriers, which are able to catalyse the active transport of numerous drugs and xenobiotics out of the CNS. Nasal delivery is currently considered as an efficient tool for systemic administration of drugs that are poorly absorbed via the oral route, and increasing evidence suggests that numerous drugs and potentially toxic xenobiotics can reach the CNS by this route. This short review summarizes recent knowledge on factors controlling the nasal pathway, focusing on drug metabolising enzymes in olfactory mucosa, olfactory bulb and brain, which should constitute a CNS metabolic barrier.
Serum IGF‐I and IGFBP‐3 concentrations do not accurately predict growth hormone deficiency in children with brain tumours

The growth hormone (GH)‐dependent growth factors insulin‐like growth factor‐I (IGF‐I) and IGF‐binding protein‐3 (IGFBP‐3) may be superior to provocative GH testing in diagnosing GH deficiency (GHD) in children. In adults with brain tumours (BT) and GHD, however, provocative GH testing more accurately reflects GHD than either IGF‐I or IGFBP‐3. We assessed growth factor levels in children with GHD due to BT with respect to brain tumour type, pubertal stage, growth velocity, bone age delay, and body mass index (BMI).
BINDING OF [99mTc]CHONDROITIN SULFATE TO SCAVENGER RECEPTORS ON HUMAN CHONDROCYTES AS COMPARED TO BINDING OF OXIDIZED [125I]LDL ON HUMAN MACROPHAGES

ABSTRACT Chondroitin sulfate (CS) used for treatment of osteoarthritis exerts distinct effects on human articular chondrocytes in vitro. We performed a binding analysis with 99mTc-labeled CS (Condrosulf, a commercial CS preparation containing calcium stearate) and cultured human chondrocytes in order to evaluate the presence of specific receptors. Saturation binding at 37°C for 2 h revealed the presence of high-affinity binding sites for CS with a Kd of 2.3 × 10−9 mol/L and a Bmax of 5.0 × 108. Extensive dialysis of Chondrosulf led to a decrease of the binding affinity by 52.5 ± 19.5% and of the number of CS binding sites/cell by 62.0 ± 14.0%, demonstrating that the additive present in the Condrosulf preparation enhances CS binding. The nature of the binding site is not yet known but evidence exists in the literature that the scavenger receptor CD36, thoroughly investigated on macrophages, is also found on chondrocytes and might be involved in CS binding. Therefore, we undertook a comparative binding study with human monocytes and labelled LDL and oxidized LDL, the latter being a postulated atherogenic agent in atherosclerosis. For [125I]-LDL binding we found a Kd of 0.45 × 10−8 mol/L and a Bmax of 0.14 × 106 on quiescent monocytes and for [125I]-(ox)LDL binding a Kd of 1.8 × 10−8 mol/L and a Bmax of 1.3 × 106 using LPS-activated monocytes. These data are comparable to the binding affinity found for lipoprotein–proteoglycan-complexes and hence are an indication but not a proof that CD36 is involved in CS binding to human chondrocytes.
Novel biomarkers of androgen deficiency from seminal plasma profiling using high-resolution mass spectrometry.

CONTEXT The seminal plasma is made of secretions from the testis, the epididymis, and the male accessory glands, which are dependent on the presence of androgenic stimuli. OBJECTIVE The objective of this study was to identify new seminal biomarkers for secundary male hypogonadism using proteomic profiling. DESIGN Seminal plasma samples from patients affected by secundary hypogonadism and normogonadal controls were analyzed by an LTQ Orbitrap XL hybrid mass spectrometer and data were evaluated using bioinformatic tools. SETTING The study was performed at a clinical research center. SUBJECTS Twenty male patients, aged 25-55 years, affected by secundary hypogonadic were studied. Ten patients were reevaluated after 6 months of T replacement therapy (TRT). Ten normogonadic men were enrolled as a control group. INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURES The list of absent proteins in the samples of hypogonadic patients and identified after TRT was studied. Bioinformatic tools were used to functionally annotate the panel of androgen-dependent proteins. The interaction network of the differentially expressed proteins was built in silico, including the androgen receptor. RESULTS A lower number of proteins was identified in hypogonadic patients compared with normogonadal men. Among the 61 proteins identified in normogonadal men, 33 proteins were absent in hypogonadic patients. Fourteen of 33 absent proteins were identified in seminal samples after 6 months of TRT. Functional annotation analysis revealed that binding and enzymatic activities are mainly deficient in male hypogonadism. Seven of 14 differentially expressed proteins can fall into one large protein-protein interaction network, which directly involves the androgen receptor. CONCLUSION A high resolution mass spectrometry-based proteomic approach was first used to describe the alterations of seminal seminal proteome in secundary male hypogonadism. These proteins represent putative physiological in vivo targets for androgen deficiency.
8-Amino-Adenosine Activates p53-Independent Cell Death of Metastatic Breast Cancers

8-Amino-adenosine (8-NH2-Ado) is a ribose sugar nucleoside analogue that reduces cellular ATP levels and inhibits mRNA synthesis. Estrogen receptor-negative (ER−) metastatic breast cancers often contain mutant p53; therefore, we asked if 8-NH2-Ado could kill breast cancer cells without activating the p53-pathway. Regardless of the breast cancer subtype tested or the p53 status of the cells, 8-NH2-Ado was more cytotoxic than either gemcitabine or etoposide. 8-NH2-Ado treatment inhibited cell proliferation, activated cell death, and did not activate transcription of the p53 target gene p21 or increase protein levels of either p53 or p21. This occurred in the estrogen receptor-positive (ER+) MCF-7 cells that express wild-type p53, the ER+ T47-D cells that express mutant p53, and the ER− MDA-MB-468 cells or MDA-MB-231 cells that both express mutant p53. 8-NH2-Ado induced apoptotic death of MCF-7 cells and apoptosis was not inhibited by knockdown of functional p53. Moreover, the pan-caspase inhibitor Z-VAD blocked the 8-NH2-Ado–induced MCF-7 cell death. Interestingly, 8-NH2-Ado caused the MDA-MB-231 cells to detach from the plate with only limited evidence of apoptotic cell death markers and the cell death was not inhibited by Z-VAD. Inhibition of MDA-MB-231 cell autophagy, by reduction of ATG7 or 3-methyladenine treatment, did not block this 8-NH2-Ado–mediated cytotoxicity. Importantly 8-NH2-Ado was highly cytotoxic to triple-negative breast cancer cells and worked through a pathway that did not require wild-type p53 for cytoxicity. Therefore, 8-NH2-Ado should be considered for the treatment of triple-negative breast cancers that are chemotherapy resistant. Mol Cancer Ther; 11(11); 2495–504. ©2012 AACR.
Reverse transcription-polymerase chain reaction in the diagnosis of Helicobacter pylori infection in Finnish children.

BACKGROUND The purpose of this study was to design a simplified polymerase chain reaction (PCR) technique for the detection of Helicobacter pylori and to compare it with conventional diagnostic methods-culture and histology of gastric biopsy specimens. In addition, the capability of this technique to detect H. pylori in the gastric mucosal biopsies of originally H. pylori-negative children with gastritis or recurrent abdominal pain was investigated. METHODS Reverse transcriptase polymerase chain reaction (RT-PCR) using polymerase from Thermus thermophilus was applied to detect H. pylori 16S rRNA. Twenty-five children H. pylori-positive by culture and/or histology were used as positive control subjects. Sixteen healthy H. pylori-negative children served as negative control subjects. Biopsy specimens from gastric antrum and corpus from 81 children were examined by RT-PCR. Altogether, 30 had histologic gastritis and 51 had nonspecific abdominal pain only, with no disease in histologic specimens. Histology and culture of H. pylori were negative in both patient groups. RESULTS Reverse transcription-polymerase chain reaction detected 24 of 25 tissue-positive and 0 of 16 tissue-negative cases, indicating 96% sensitivity and 100% specificity for the test. None of the culturally and histologically H. pylori-negative samples showed H. pylori colonization when analyzed by RT-PCR. CONCLUSIONS RT-PCR using Thermus thermophilus polymerase is a fast and simple means of detecting H. pylori in gastric biopsy specimens. It is at least as specific and sensitive as conventional methods. In pediatric patients it may be necessary to take more than two biopsy specimens to increase sensitivity in cases of local or patchy colonization.
Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat

Depression and anxiety are the prevalent nonmotor symptoms that worsen quality of life for Parkinson's disease (PD) patients. Although dopamine (DA) cell loss is a commonly proposed mechanism, the reported efficacy of DA replacement therapy with L-DOPA on affective symptoms is inconsistent. To delineate the effects of DA denervation and chronic L-DOPA treatment on affective behaviors, male Sprague–Dawley rats received unilateral 6-hydroxydopamine or sham lesions and were treated daily with L-DOPA (12 mg/kg+benserazide, 15 mg/kg, subcutaneously) or vehicle (0.9% NaCl, 0.1% ascorbic acid) for 28 days before commencing investigations into anxiety (locomotor chambers, social interaction) and depression-like behaviors (forced swim test) during the OFF phase of L-DOPA. One hour after the final treatments, rats were killed and striatum, prefrontal cortex, hippocampus, and amygdala were analyzed through high-performance liquid chromatography for monoamine levels. In locomotor chambers and social interaction, DA lesions exerted mild anxiogenic effects. Surprisingly, chronic L-DOPA treatment did not improve these effects. Although DA lesion reduced climbing behaviors on day 2 of exposure to the forced swim test, chronic L-DOPA treatment did not reverse these effects. Neurochemically, L-DOPA treatment in hemiparkinsonian rats reduced norepinephrine levels in the prefrontal cortex, striatum, and hippocampus. Collectively, these data suggest that chronic L-DOPA therapy in severely DA-lesioned rats does not improve nonmotor symptoms and may impair nondopaminergic processes, indicating that long-term L-DOPA therapy does not exert necessary neuroplastic changes for improving affect.