Miracle-dz/UniFAR-FTUs huggingface dataset:
Phosphorus magnetic resonance spectroscopy 2 h after perinatal cerebral hypoxia‐ischemia prognosticates outcome in the newborn piglet

Phosphorus magnetic resonance spectroscopy (31P MRS) often reveals apparently normal brain metabolism in the first hours after intrapartum hypoxia‐ischemia (HI) at a time when conventional clinical assessment of injury severity is problematic. We aimed to elucidate very‐early, injury‐severity biomarkers. Twenty‐seven newborn piglets underwent cerebral HI: 31P‐MRS measures ∼2 h after HI were compared between injury groups defined by secondary‐energy‐failure severity as quantified by the minimum nucleotide triphosphate (NTP) observed after 6 h. For severe and moderate injury versus baseline, [Pi]/[total exchangeable high‐energy phosphate pool (EPP)] was increased (p < 0.001 and < 0.02, respectively), and [NTP]/[EPP] decreased (p < 0.03 and < 0.006, respectively): severe‐injury [Pi]/[EPP] was also increased versus mild injury (p < 0.04). Mild‐injury [phosphocreatine]/[EPP] was increased (p < 0.004). Severe‐injury intracellular pH was alkaline versus baseline (p < 0.002). For severe and moderate injury [total Mg]/[ATP] (p < 0.0002 and < 0.02, respectively) and [free Mg] (p < 0.0001 and < 0.02, respectively) were increased versus baseline. [Pi]/[EPP], [phosphocreatine]/[Pi] and [NTP]/[EPP] correlated linearly with injury severity (p < 0.005, < 0.005 and < 0.02, respectively). Increased [Pi]/[EPP], intracellular pH and intracellular Mg ∼2 h after intrapartum HI may prognosticate severe injury, whereas increased [phosphocreatine]/[EPP] may suggest mild damage. In vivo31P MRS may have potential to provide very‐early prognosis in neonatal encephalopathy.
ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood–brain barrier

We have established the expression patterns of the genes encoding ATP‐binding cassette (ABC) transporters and cytochromes P450 (CYPs) at the adult human blood–brain barrier (BBB) using isolated brain microvessels and cortex biopsies from patients with epilepsia or glioma. Microves synaptophysin (neurons) and neuron‐glial antigen 2 (NG2) (pericytes). ABCG2 [breast cancer resistance protein (BCRP)] and ABCB1 (MDR1) were the main ABC transporter genes expressed in microvessels, with 20 times more ABCG2 and 25 times more ABCB1 in microvessels than in the cortex. The CYP1B1 isoform represented over 80% of all the CYPs genes detected in microvessels. There were 14 times more CYP1B1 in microvessels than in the cortex, showing that CYP1B1 is mainly expressed at the BBB. p‐glycoprotein (ABCB1), BCRP (ABCG2) and CYP1B1 proteins were found in microvessels by western blotting. The expression of genes encoding three transcription factors [pregnane xenobiotic receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AhR)] was also investigated. The AhR gene, involved in the regulation of CYP1B1 expression, was highly expressed in brain microvessels, whereas PXR and CAR genes were almost undetected. This detailed pattern of ABC and CYPs gene expression at the human BBB provides useful information for understanding how their substrates enter the brain.
Chronic voluntary ethanol intake hypersensitizes 5‐HT1A autoreceptors in C57BL/6J mice

Alcoholism is a complex disorder involving, among others, the serotoninergic (5‐HT) system, mainly regulated by 5‐HT1A autoreceptors in the dorsal raphe nucleus. 5‐HT1A autoreceptor desensitization induced by chronic 5‐HT reuptake inactivation has been associated with a decrease in ethanol intake in mice. We investigated here whether, conversely, chronic ethanol intake could induce 5‐HT1A autoreceptor supersensitivity, thereby contributing to the maintenance of high ethanol consumption. C57BL/6J mice were subjected to a progressive ethanol intake procedure in a free‐choice paradigm (3–10% ethanol versus tap water; 21 days) and 5‐HT1A autoreceptor functional state was assessed using different approaches. Acute administration of the 5‐HT1A receptor agonist ipsapirone decreased the rate of tryptophan hydroxylation in striatum, and this effect was significantly larger (+75%) in mice that drank ethanol than in those drinking water. Furthermore, ethanol intake produced both an increased potency (+45%) of ipsapirone to inhibit the firing of 5‐HT neurons, and a raise (+35%) in 5‐HT1A autoreceptor‐mediated stimulation of [35S]GTP‐γ‐S binding in the dorsal raphe nucleus. These data showed that chronic voluntary ethanol intake in C57BL/6J mice induced 5‐HT1A autoreceptor supersensitivity, at the origin of a 5‐HT neurotransmission deficit, which might be causally related to the addictive effects of ethanol intake.
Differential effects of 24‐hydroxycholesterol and 27‐hydroxycholesterol on tyrosine hydroxylase and α‐synuclein in human neuroblastoma SH‐SY5Y cells

Evidence suggests that environmental and dietary factors may contribute to the pathogenesis of Parkinson’s disease (PD). High dietary intake of cholesterol is such a factor that has been shown to increase or decrease the risk of PD. However, because circulating cholesterol does not cross the blood–brain barrier, the mechanisms linking dietary cholesterol to the pathogenesis of PD remain to be understood. In contrast to cholesterol, the oxidized cholesterol metabolites (oxysterols), 24S‐hydroxycholesterol (24‐OHC) and 27‐hydroxycholesterol (27‐OHC), can cross the blood–brain barrier and may place the brain at risk of degeneration. In this study, we incubated the human neuroblastoma SH‐SY5Y cells for 24 h with 24‐OHC, 27‐OHC, or a mixture of 24‐OHC plus 27‐OHC, and have determined effects on tyrosine hydroxylase (the rate‐limiting enzyme in dopamine synthesis) levels, α‐synuclein levels, and apoptosis. We demonstrate that while 24‐OHC increases the levels of tyrosine hydroxylase, 27‐OHC increases levels of α‐synuclein, and induces apoptosis. Our findings show for the first time that oxysterols trigger changes in levels of proteins that are associated with the pathogenesis of PD. As steady state levels of 24‐OHC and 27‐OHC are tightly regulated in the brain, disturbances in these levels may contribute to the pathogenesis of PD.
Biodegradable shape memory nanocomposites with thermal and magnetic field responsiveness

Thermal and magnetic field responsive biodegradable shape memory polymer nanocomposite was prepared with Fe3O4 nanoparticles and poly(L-lactides) (PLLA). The magnetic Fe3O4 nanoparticles with an average size of 9 nm were initially synthesized by co-precipitation method and then followed by surface modification using oleic acid. The TEM and SEM results show that the surface modified Fe3O4 nanoparticles can evenly disperse in chloroform and PLLA polymer matrix. The tensile test results show that the addition of Fe3O4 nanoparticles to a PLLA matrix greatly improved the elastic modulus, tensile strength, elongation at break, and the shape memory properties as well. Moreover, the shape recovery process of the nanocomposites driven by an alternating magnetic field was also observed. However, the shape recovery ratio and the recovery speed in an alternating magnetic field are lower than that occurred in 70 °C water. The lower shape recovery ratio and the recovery speed in an alternating magnetic field is attributed to the low frequency and strength of the magnetic field, which lead to small heat generated by Fe3O4 nanoparticles.
Observations on the Pulmonary Arterial Blood Pressure in the Cat

Summary. The pulmonary arterial blood pressure was recorded in anaesthetized cats by means of a special cannula, according to MELLIN's technique. In most experiments the thorax was closed and the animal was breathing spontaneously. The pulmonary arterial pressure in 9 experiments averaged 23 cm water, or approximately 17 mm Hg, at an average systemic pressure of 132 mm Hg. The average ratio thus was about 1: 8, with the limits 1: 5 and 1: 14. Pressure variations of 1–2 cm blood synchronous with the breathing were regularly recorded. In one case, slow large waves of 1–2 minutes duration and about 5 cm amplitude were observed. Even great variations in the systemic blood pressure, elicited from the pressoregulating reflex mechanisms, were hardly accompanied by variations in the pulmonary arterial pressure. During muscular work a moderate rise in pulmonary blood pressure generally occurred, greater when air was breathed than when oxygen alone was administered. Clamping the pulmonary artery to one lung did not cause any change in systemic pressure (confirming LICHTHEIM and TIGERSTEDT) but caused a moderate rise in pulmonary arterial pressure. Breathing of pure oxygen lowered the pulmonary arterial pressure and oxygen-lack raised it. Carbon dioxide 6.5–20.5 per cent in oxygen raised the pressure sligthly, but constantly. These effects were not influenced by vagotomy. The effect of injections of adrenaline, nor-adrenaline, acetylcholine and histamine and of stimulation of pulmonary nerves were studied in some cases. The experiments seem to warrant the conclusion, that the regulation of the pulmonary blood flow is mainly mediated by a local action of the blood and alveolar gases leading to an adequate distribution of the blood through the various parts of the lungs according to the effeciency of aeration.
PKG activity causes photoreceptor cell death in two retinitis pigmentosa models

Photoreceptor degeneration in retinitis pigmentosa is one of the leading causes of hereditary blindness in the developed world. Although causative genetic mutations have been elucidated in many cases, the underlying neuronal degeneration mechanisms are still unknown. Here, we show that activation of cGMP‐dependent protein kinase (PKG) hallmarks photoreceptor degeneration in rd1 and rd2 human homologous mouse models. When induced in wild‐type retinae, PKG activity was both necessary and sufficient to trigger cGMP‐mediated photoreceptor cell death. Target‐specific, pharmacological inhibition of PKG activity in both rd1 and rd2 retinae strongly reduced photoreceptor cell death in organotypic retinal explants. Likewise, inhibition of PKG in vivo, using three different application paradigms, resulted in robust photoreceptor protection in the rd1 retina. These findings suggest a pivotal role for PKG activity in cGMP‐mediated photoreceptor degeneration mechanisms and highlight the importance of PKG as a novel target for the pharmacological intervention in RP.
Training Needs for the Treatment of Combat-Related Posttraumatic Stress Disorder: A Survey of Department of Defense Clinicians

In 2004, the United States Departments of Veterans Affairs (VA) and Defense jointly published clinical-practice guidelines for posttraumatic stress disorder (CPG-PTSD). These identified 4 psychotherapies for PTSD: cognitive therapy, eye-movement desensitization and reprocessing, exposure therapy, and stress inoculation therapy. One hundred thirty-seven mental-health professionals employed by the military or the VA were surveyed as to whether they used any of these psychotherapies and the extent of their training in them. Ninety percent of respondents reported not using any of the 4 psychotherapies. Of those who did, most had received their training before their affiliation with the military, and only a handful had training in the specific use of psychotherapy with PTSD. The lack of available, CPG-identified, effective psychotherapies is discussed as a barrier to treatment, as are possible reasons the psychotherapies are not used. A brief description of a training program is provided along with suggestions for the future. Language: en
Sept8 controls the binding of vesicle‐associated membrane protein 2 to synaptophysin

Septins, a conserved family of GTP/GDP‐binding proteins, are present in organisms as diverse as yeast and mammals. We analyzed the distribution of five septins, Sept6, Sept7, Sept8, Sept9 and Sept11, in various rat tissues by western blot analyses and found all septins to be expressed in brain. We also examined the developmental changes of expression of these septins in the rat brain and found that the level of Sept8 increased during post‐natal development. Morphological analyses revealed that Sept8 is enriched at pre‐synapses. Using yeast two‐hybrid screening, we identified vesicle‐associated membrane protein 2 (VAMP2), a soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE), as an interacting protein for Sept8. Synaptophysin is reported to associate with and recruit VAMP2 to synaptic vesicles and dissociate prior to forming the SNARE complex consisting of VAMP2, syntaxin and synaptosome‐associated protein of 25 kDa. We showed that Sept8 suppresses the interaction between VAMP2 and synaptophysin through binding to VAMP2. In addition, we found that Sept8 forms a complex with syntaxin1A, and the Sept8‐VAMP2 interaction is disrupted by synaptosome‐associated protein of 25 kDa. These results suggest that Sept8 may participate in the process of the SNARE complex formation and subsequent neurotransmitter release.
Now I know my ABC. A systems neurochemistry and functional metabolomic approach to understanding the GABAergic system

Here, we describe use of a reductionist brain model, the brain tissue slice, to generate snapshots of functional metabolism in response to a pharmacological (GABAergic) perturbation. Tissue slices prepared from Guinea pig cerebral cortex were incubated for 1 h in the presence of [3‐13C]‐pyruvate and ligands with affinity for GABA receptors. The resultant patterns of 13C flux and metabolite levels were measured by 13C/1H NMR spectroscopy, generating ‘metabolic fingerprints’ for each ligand. Effects of agonists and effectors at GABA receptors (A, B, and C types) were examined, compared to those of exogenous GABA and evaluated using multivariate statistical models. Data clusterings did not directly correlate with GABA receptor types but produced at least five distinct groups ranked according to their affinity for GABA. As our experimental model retains, to a large extent, the structure and function of normal brain tissue, the generated database can be used to assess GABAergic ligands and make unique inferences relevant to their modes of action in brain.
Contributions of Ca2+ and Zn2+ to spreading depression‐like events and neuronal injury

The phenomenon of spreading depression (SD) involves waves of profound neuronal and glial depolarization that spread throughout brain tissue. Under many conditions, tissue recovers full function after SD has occurred, but SD‐like events are also associated with spread of injury following ischemia or trauma. Initial large cytosolic Ca2+ increases accompany all forms of SD, but persistently elevated Ca2+ loading is likely responsible for neuronal injury following SD in tissues where metabolic capacity is insufficient to restore ionic gradients. Ca2+ channels are also involved in the propagation of SD, but the channel subtypes and cation fluxes differ significantly when SD is triggered by different types of stimuli. Ca2+ influx via P/Q type channels is important for SD generated by localized application of high K+ solutions. In contrast, SD‐like events recorded in in vitro ischemia models are not usually prevented by Ca2+ removal, but under some conditions, Zn2+ influx via L‐type channels contributes to SD initiation. This review addresses different roles of Ca2+ in the initiation and consequences of SD, and discusses recent evidence that selective chelation of Zn2+ can be sufficient to prevent SD under circumstances that may have relevance for ischemic injury.
Pleiotropic effects of spastin on neurite growth depending on expression levels

Hereditary spastic paraplegia (HSP) is characterized by weakness and spasticity of the lower limbs, owing to degeneration of corticospinal axons. The most common form is due to heterozygous mutations in the SPG4 gene, encoding spastin, a microtubule (MT)‐severing protein. Here, we show that neurite growth in immortalized and primary neurons responds in pleiotropic ways to changes in spastin levels. Spastin depletion alters the development of primary hippocampal neurons leading to abnormal neuron morphology, dystrophic neurites, and axonal growth defects. By live imaging with End‐Binding Protein 3‐Fluorescent Green Protein (EB3‐GFP), a MT plus‐end tracking protein, we ascertained that the assembly rate of MTs is reduced when spastin is down‐regulated. Spastin over‐expression at high levels strongly suppresses neurite maintenance, while slight spastin up‐regulation using an endogenous promoter enhances neurite branching and elongation. Spastin severing activity is exerted preferentially on stable acetylated and detyrosinated MTs. We further show that SPG4 nonsense or splice site mutations found in hereditary spastic paraplegia patients result in reduced spastin levels, supporting haploinsufficiency as the molecular cause of the disease. Our study reveals that SPG4 is a dosage‐sensitive gene, and broadens the understanding of the role of spastin in neurite growth and MT dynamics.
Role of the ERK/MSK1 signalling pathway in chromatin remodelling and brain responses to drugs of abuse

Drugs of abuse induce neuroadaptations through regulation of gene expression. Although much attention has focused on transcription factor activities, new concepts have recently emerged on the role of chromatin remodelling as a prerequisite for regulation of gene expression in neurons. Thus, for transcription to occur, chromatin must be decondensed, a dynamic process that depends on post‐translational modifications of histones. We review here these modifications with a particular emphasis on the role of histone H3 phosphorylation at the promoter of specific genes, including c‐fos and c‐jun. We trace the signalling pathways involved in H3 phosphorylation and provide evidence for a role of mitogen and stress‐activated protein kinase‐1 (MSK1) downstream from the MAPK/extracellular‐signal regulated kinase (ERK) cascade. In response to cocaine, MSK1 controls an early phase of histone H3 phosphorylation at the c‐fos promoter in striatal neurons. MSK1 action may be potentiated by the concomitant inhibition of protein phosphatase 1 by nuclear translocation of dopamine‐ and cAMP‐regulated phosphoprotein Mr = 32 000. H3 phosphorylation by MSK1 is critically involved in c‐fos transcription, and cocaine‐induced locomotor sensitization. Thus, ERK plays a dual role in gene regulation and drug addiction by direct activation of transcription factors and by chromatin remodelling.
Contrast-induced nephropathy: do statins offer protection?

Purpose of review Contrast-induced nephropathy (CIN) is a commonly occurring complication associated with the use of contrast media in radiological studies. Various clinical studies have been reported investigating the nephroprotective role of statins. In this article, we review relevant clinical studies reported in 2010. Recent findings An overview of these indicates that the evidence for the use of statins specifically for offering renal protection against CIN is conflicting and inconclusive. Summary Pending large, well designed, adequately powered randomized controlled trials, it can be concluded that at present there is no definite evidence for their use in preventing CIN apart from their antiatherosclerotic use. However, using the analogy of beneficial effect of statin preloading with percutaneous coronary intervention, it can be speculated that high-dose statin may be beneficial in affording nephroprotection against CIN.
SUMOylation participates in induction of ischemic tolerance

Ground squirrels in hibernation torpor have been shown to have striking increases in global SUMOylation on tissue immunoblots. Here, we find evidence that global SUMOylation is also involved in ischemic tolerance in primary cortical neuronal cultures (from rats and mice) and SHSY5Y human neuroblastoma cells. Cultured cortical neurons preconditioned by sublethal oxygen/glucose deprivation (OGD) were less vulnerable to severe OGD than non‐preconditioned neurons. Preconditioned neurons maintained elevated SUMO‐1 conjugation levels (and, to a lesser extent those of SUMO‐2/3) on western blots in contrast to non‐preconditioned cells. Further, cortical neurons and SHSY5Y cells in which transfected SUMO‐1 or SUMO‐2 were over‐expressed showed increased survival after severe OGD. In contrast, cell cultures subjected to depletion of endogenous SUMO‐1 protein by RNAi had reduced survival after exposure to this form of in vitro ischemia and an attenuated protective response to preconditioning. These findings suggest that maintenance of a globally elevated SUMO‐1 (and maybe SUMO‐2/3) conjugation level as revealed by immunoblot assays is a component of ischemic tolerance.
Opposite effects of anandamide and n‐arachidonoyl dopamine in the regulation of prostaglandin E2 and 8‐iso‐PGF2α formation in primary glial cells

It is widely accepted that neuroinflammation is a key player in various pathological events associated with brain injury. More specifically, glial activation and the subsequent release of pro‐inflammatory cytokines, reactive oxygen species (ROS), and prostaglandins play a role of paramount importance in cerebral damage. In this study, we examined the role of two endocannabinoids, anandamide (AEA) and N‐arachidonoyldopamine (NADA) in the regulation of prostaglandin E2 (PGE2) synthesis in primary glial cells. We show that NADA is a potent inhibitor of PGE2 synthesis in lipopolysaccharide (LPS) stimulated cells, without modifying the expression or enzymatic activity of COX‐2 and the production of prostaglandin D2. We also show that NADA has the ability to prevent the free radical formation in primary microglial cells. The key findings of this investigation are our observation that AEA and NADA have opposite effects on glial cells and, most importantly, the first description of NADA as a potential antioxidative and anti‐inflammatory agent acting through a mechanism that involves reduction in the synthesis of microsomal prostaglandin E synthase in LPS‐activated microglia. These findings provide new mechanistic insights into the anti‐inflammatory activities of NADA in the CNS and its potential to design novel therapeutic strategies to manage neuroinflammatory diseases.
The inflammatory response in the MPTP model of Parkinson’s disease is mediated by brain angiotensin: relevance to progression of the disease

The neurotoxin MPTP reproduces most of the biochemical and pathological hallmarks of Parkinson’s disease. In addition to reactive oxygen species (ROS) generated as a consequence of mitochondrial complex I inhibition, microglial NADPH‐derived ROS play major roles in the toxicity of MPTP. However, the exact mechanism regulating this microglial response remains to be clarified. The peptide angiotensin II (AII), via type 1 receptors (AT1), is one of the most important inflammation and oxidative stress inducers, and produces ROS by activation of the NADPH‐oxidase complex. Brain possesses a local angiotensin system, which modulates striatal dopamine (DA) release. However, it is not known if AII plays a major role in microglia‐derived oxidative stress and DA degeneration. The present study indicates that in primary mesencephalic cultures, DA degeneration induced by the neurotoxin MPTP/MPP+ is amplified by AII and inhibited by AT1 receptor antagonists, and that protein kinase C, NADPH‐complex activation and microglial activation are involved in this effect. In mice, AT1 receptor antagonists inhibited both DA degeneration and early microglial and NADPH activation. The brain angiotensin system may play a key role in the self‐propelling mechanism of Parkinson’s disease and constitutes an unexplored target for neuroprotection, as previously reported for vascular diseases.