Miracle-dz/UniFAR-FTUs huggingface dataset:
Short‐term modern life‐like stress exacerbates Aβ‐pathology and synapse loss in 3xTg‐AD mice

Alzheimer's disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD‐related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short‐term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short‐term, multi‐modal ‘modern life‐like’ stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg‐AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild‐type mice and tended to impact it in already low‐performing 3xTg‐AD mice. This stress reduced the number of synapse‐bearing dendritic spines in 3xTg‐AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short‐term stress simulating modern‐life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers.
Size dimorphism and avian‐perceived sexual dichromatism in a New Zealand endemic bird, the whitehead Mohoua albicilla

Sex differences in behavior, morphology, and physiology are common in animals. In many bird species, differences in the feather colors of the sexes are apparent when judged by human observers and using physical measures of plumage reflectance, cryptic (to human) plumage dichromatism has also been detected in several additional avian lineages. However, it remains to be confirmed in almost all species whether sexual dichromatism is perceivable by individuals of the studied species. This latter step is essential because it allows the evaluation of alternative hypotheses regarding the signaling and communication functions of plumage variation. We applied perceptual modeling of the avian visual system for the first time to an endemic New Zealand bird to provide evidence of subtle but consistent sexual dichromatism in the whitehead, Mohoua albicilla. Molecular sexing techniques were also used in this species to confirm the extent of the sexual size dimorphism in plumage and body mass. Despite the small sample sizes, we now validate previous reports based on human perception that in male whiteheads head and chest feathers are physically brighter than in females. We further suggest that the extent of sexual plumage dichromatism is pronounced and can be perceived by these birds. In contrast, although sexual dimorphism was also detectable in the mass among the DNA‐sexed individuals, it was found to be less extensive than previously thought. Sexual size dimorphism and intraspecifically perceivable plumage dichromatism represent reliable traits that differ between female and male whiteheads. These traits, in turn, may contribute to honest communication displays within the complex social recognition systems of communally breeding whitehead and other group‐breeding taxa. J. Morphol. , 2010. © 2010 Wiley‐Liss, Inc.
miR‐144‐3p exerts anti‐tumor effects in glioblastoma by targeting c‐Met

The study aimed to explore the specific function and mechanism of miR‐144‐3p in glioblastoma (GBM) cells with different phosphatase and tensin homolog (PTEN) phenotypes. We demonstrated that the miR‐144‐3p level was significantly down‐regulated in glioma compared with the non‐neoplastic brain tissues, and decreased with ascending grades. The loss of miR‐144‐3p effectively predicted the decreased overall survival in glioma patients. Interestingly, the expression of MET was up‐regulated and inversely associated with miR‐144‐3p level in glioma tissues. Next, we certified that miR‐144‐3p specifically bound to MET 3′‐untranslated region (3′ UTR) and inhibited its expression. miR‐144‐3p potently repressed GBM cell proliferation and invasion via suppressing MET in vitro and in vivo. In addition, our results showed no difference in malignancy inhibition induced by miR‐144‐3p in GBM cells with different PTEN phenotypes. miR‐144‐3p inhibited several survival signaling pathways by targeting MET independent of PTEN status in GBM cells. Over‐expression of miR‐144‐3p inhibited survival capability and increased apoptosis, resulting in enhancement of radiation and temozolomide sensitivity. Our data provide new insights into the potential application of miR‐144‐3p in GBM therapy by targeting MET and then inhibiting the downstream signaling.
Novel synthetic sulfoglycolipid IG20 facilitates exocytosis in chromaffin cells through the regulation of sodium channels

In search of druggable synthetic lipids that function as potential modulators of synaptic transmission and plasticity, we synthesized sulfoglycolipid IG20, which stimulates neuritic outgrowth. Here, we have explored its effects on ion channels and exocytosis in bovine chromaffin cells. IG20 augmented the rate of basal catecholamine release. Such effect did not depend on Ca2+ mobilization from intracellular stores; rather, IG20‐elicited secretion entirely dependent on Ca2+ entry through L‐subtype voltage‐activated Ca2+ channels. Those channels were recruited by cell depolarization mediated by IG20 likely through its ability to enhance the recruitment of Na+ channels at more hyperpolarizing potentials. Confocal imaging with fluorescent derivative IG20‐NBD revealed its rapid incorporation and confinement into the plasmalemma, supporting the idea that IG20 effects are exerted through a plasmalemmal‐delimited mechanism. Thus, synthetic IG20 seems to mimic several physiological effects of endogenous lipids such as regulation of ion channels, Ca2+ signaling, and exocytosis. Therefore, sulfoglycolipid IG20 may become a pharmacological tool for investigating the role of the lipid environment on neuronal excitability, ion channels, neurotransmitter release, synaptic efficacy, and neuronal plasticity. It may also inspire the synthesis of druggable sulfoglycolipids aimed at increasing synaptic plasticity and efficacy in neurodegenerative diseases and traumatic brain–spinal cord injury.
1,8‐ and 1,4‐cineole enhance spontaneous excitatory transmission by activating different types of transient receptor potential channels in the rat spinal substantia gelatinosa

Although transient receptor potential (TRP) channels expressed in the spinal substantia gelatinosa play a role in modulating nociceptive transmission, their properties have not been fully examined yet. In order to address this issue, the effects of 1,8‐cineole and its stereoisomer 1,4‐cineole on excitatory transmission were examined by applying the whole‐cell patch‐clamp technique to substantia gelatinosa neurons in adult rat spinal cord slices. Miniature excitatory postsynaptic current frequency was increased by 1,8‐ and 1,4‐cineole. The cineole activities were repeated and resistant to voltage‐gated Na+‐channel blocker tetrodotoxin. The 1,8‐cineole activity was inhibited by TRP ankyrin‐1 (TRPA1) antagonists (HC‐030031 and mecamylamine) but not TRP vanilloid‐1 (TRPV1) antagonists (capsazepine and SB‐366791), whereas the 1,4‐cineole activity was depressed by the TRPV1 but not TRPA1 antagonists. Although 1,8‐ and 1,4‐cineole reportedly activate TRP melastatin‐8 (TRPM8) channels, their activities were unaffected by TRPM8 antagonist 4‐(3‐chloro‐2‐pyridinyl)‐N‐[4‐(1,1‐dimethylethyl)phenyl]‐1‐piperazinecarboxamide. Monosynaptically evoked C‐fiber, but not Aδ‐fiber excitatory postsynaptic current amplitude, was reduced by 1,8‐ and 1,4‐cineole. These results indicate that 1,8‐ and 1,4‐cineole increase spontaneous l‐glutamate release from nerve terminals by activating TRPA1 and TRPV1 channels, respectively, while inhibiting C‐fiber but not Aδ‐fiber evoked l‐glutamate release. This difference between 1,8‐ and 1,4‐cineole may serve to know the properties of TRP channels located in the central terminals of primary‐afferent neurons.
RNA polymerase I transcription is modulated by spatial learning in different brain regions

Long‐term memory is accompanied by changes in neuronal morphology and connectivity. These alterations are thought to depend upon new gene expression and protein synthesis over a distributed network of brain structures. Although much evidence supports the idea that the creation of stable, persistent memory traces requires synthesis of new proteins, the role of rRNA transcription and nucleolar activity in learning and memory has hardly been explored. rRNAs needed for protein synthesis result from the activity of two different RNA polymerases, RNA polymerase I and RNA polymerase III, transcribing for 47S RNA and 5S RNA, respectively. In this study, we first investigated the effects of spatial training in the Morris water maze on 47S RNA transcription in the central nervous system, demonstrating bidirectional modulation of its expression over a distributed neural network. We found learning‐induced increases in the nucleolar organizer regions in the hippocampus. Finally, we demonstrated that intrahippocampal administrations of CX‐5461 (0.6 μg/side), the specific RNA Polymerase I inhibitor, impair the ability of mice to locate the platform in the same task. These results suggest that de novo rRNA transcription is a necessary step for spatial memory consolidation, and that after learning, it occurs in several brain regions with a complex spatiotemporal dynamic.
Sex‐dependent mitochondrial respiratory impairment and oxidative stress in a rat model of neonatal hypoxic‐ischemic encephalopathy

Increased male susceptibility to long‐term cognitive deficits is well described in clinical and experimental studies of neonatal hypoxic‐ischemic encephalopathy. While cell death signaling pathways are known to be sexually dimorphic, a sex‐dependent pathophysiological mechanism preceding the majority of secondary cell death has yet to be described. Mitochondrial dysfunction contributes to cell death following cerebral hypoxic‐ischemia (HI). Several lines of evidence suggest that there are sex differences in the mitochondrial metabolism of adult mammals. Therefore, this study tested the hypothesis that brain mitochondrial respiratory impairment and associated oxidative stress is more severe in males than females following HI. Maximal brain mitochondrial respiration during oxidative phosphorylation was two‐fold more impaired in males following HI. The endogenous antioxidant glutathione was 30% higher in the brain of sham females compared to males. Females also exhibited increased glutathione peroxidase (GPx) activity following HI injury. Conversely, males displayed a reduction in mitochondrial GPx4 protein levels and mitochondrial GPx activity. Moreover, a 3–4‐fold increase in oxidative protein carbonylation was observed in the cortex, perirhinal cortex, and hippocampus of injured males, but not females. These data provide the first evidence for sex‐dependent mitochondrial respiratory dysfunction and oxidative damage, which may contribute to the relative male susceptibility to adverse long‐term outcomes following HI.
Revisiting the neuronal localization and trafficking of CLN3 in juvenile neuronal ceroid lipofuscinosis

Juvenile neuronal ceroid lipofuscinosis, the most common neurodegenerative disease affecting children, is caused by mutations of the CLN3 gene encoding CLN3, a transmembrane protein with so far undefined function. The embryonic expression of the gene has not been studied in detail before. Moreover, the protein CLN3 was mostly localized on the subcellular level to lysosomes but the exclusiveness is still under debate. Here, we analyze the expression pattern of murine CLN3 at different developmental stages by in situ hybridizations. We observe expression maxima in the developing thalamus and cerebral cortex and outside of the central nervous system in the gastrointestinal tract and other peripheral organs. In differentiated primary neurons, the protein CLN3 shows mainly a somatodendritic localization. In primary neurons, we thoroughly revisit the subcellular localization of CLN3 and find a predominant localization in late endosomal–lysosomal compartments. Moreover, we expressed the major mutant form of CLN3 – CLN3deltaExon7/8 – in neurons and demonstrate that it is retained in the endoplasmatic reticulum. Time‐lapse microscopy analysis of neurons revealed co‐trafficking of CLN3 with the late endosomal marker Rab7, but not with the early endosomal marker Rab5. Furthermore, a constitutive active mutant of Rab7 traps CLN3 in enlarged endosomes. Our subcellular localization study in neurons refines the localization and subcellular targeting of CLN3 to late endosomal–lysosomal compartments and provides information on the velocity of CLN3 in living neurons which has not been investigated before.
The skeleton flight apparatus of North American bluebirds (Sialia): Phylogenetic thrushes or functional flycatchers?

To better understand ecological traits of organisms, one can study them from two, not necessarily mutually exclusive perspectives: how the traits evolved, and their current adaptive utility. In birds, foraging behavior and associated morphological traits generally are explained by a combination of adaptive and phylogenetic predictors. The avian skeleton and more specifically, the skeletal flight apparatus is under well‐known functional and phylogenetic constraints. This is an interesting area to partition the relative contributions of adaptive correlated evolution and phylogenetic constraint to species clustering in morphological space. A prediction of convergent evolution is that nonphylogenetic morphological clustering is a characteristic of ecological similarity. We tested this using representatives of North American birds from two clades, one with a mixture of foraging modes (Turdid thrushes, solitaires, and bluebirds) and one with more canalized foraging behaviors (Tyrannid flycatchers). Nine characters on the skeletal flight apparatus from 19 species were used to characterize the morphological space and test for ecomorphological clustering. When body size and phylogeny are considered, the three bluebird species and Townsend's solitaire cluster with the ecologically similar flycatchers rather than with their phylogenetic close relatives. Furthermore, sit‐and‐wait foragers tend to exhibit relatively long distal elements and a long keel while active ground foragers have deeper keels and a longer humerus. Distal elements, expected to be relatively shorter and more bowed in the flycatchers and bluebirds, were actually longer and narrower. A reduction of distal element mass may be more important for facilitating maneuverability than surface area for insertion of wing‐rotational musculature. J. Morphol. 274:909–917, 2013. © 2013 Wiley Periodicals, Inc.
Using the whole body as a sucker: Combining respiration and feeding with an attached lifestyle in hill stream loaches (Balitoridae, Cypriniformes)

Small fishes living in fast‐flowing rivers face a harsh environment as they can easily be swept away by the rapid currents. To survive such circumstances, teleosts evolved a wide variety of attachment mechanisms, based on friction, negative pressure or both. Balitorinae (Balitoridae, Cypriniformes) are exceptional in using their whole body as an adhesive apparatus. We investigated the morphological adaptations of Balitorinae by studying the osteology and myology of four species (Beaufortia leveretti, Sewellia lineolata, Pseudogastromyzon myersi, and Gastromyzon punctulatus) using clearing and staining, serial cross‐sections and CT‐scanning. A kinematic analysis was performed to study the respiration and feeding mechanisms and to identify key structures in these mechanisms. Our research showed that the whole body of Balitorinae acts as a suction disc, with friction‐enhancing structures (unculi) on the thickened anterior rays of the paired fins. The abruptly rising head profile, supported by the extremely enlarged lacrimal bone and the flat ventral body surface facilitate effective substrate attachment. During attachment, the pelvic girdle is pulled anterodorsally, suggesting the formation of a negative pressure underneath the body. Detachment by water inflow underneath the body is prevented by three mechanisms. 1) Barbels control the water inflow by detachment and reattachment to the substrate. 2) Most water present underneath the body is removed during inspiration. 3) Excess water is regularly removed by movements of the posterior pectoral fin rays. The balitorine body is thus modified as such that it allows effective attachment, while not impairing respiration. Comparison with other teleosts living in similar environments shows that most species use more locally concentrated modifications of the paired fins and/or the mouth for attachment. The high diversity in teleostean adhesive apparatuses and associated myological modifications suggest a substantial functional convergent evolution, without necessarily highly convergent anatomical adaptations. J. Morphol. 275:1066–1079, 2014. © 2014 Wiley Periodicals, Inc.
Globuli ossei in the long limb bones of Pleurodeles waltl (Amphibia, Urodela, Salamandridae)

To date, little is known about the structure of the cells and the fibrillar matrix of the globuli ossei, globular structures showing histochemical properties of an osseous tissue, sometimes found in the resorption front of the hypertrophied cartilage in many tetrapods, and easily observed in the long bones of the Urodele Pleurodeles waltl. Here, we present the results obtained from the appendicular long bones of metamorphosed juveniles and subadults using histological and histochemical methods and transmission electron microscopy. The distal part of the cone‐shaped cartilage contains a heterogeneous cell population composed of the typical “light” hypertrophic chondrocytes and scarce “dark” hypertrophic chondrocytes. The “dark” chondrocytes display ultrastructural characteristics suggesting that they probably undergo degeneration through chondroptosis. However, in the hypertrophic, calcified cartilage close to the erosion front by the marrow, several noninvaded chondrocytic lacunae retained cells that do not show any morphological characteristics of degeneration and that cannot be identified as regular chondrocytes or osteocytes. These modified chondrocytes that have lost their regular morphology, appear to be active in the terminal cartilage and synthesize collagen fibrils of a peculiar diameter intermediate between the Type I collagen found in bone and the Type II collagen characteristic of cartilage. It is suggested that the local occurrence of globuli ossei is linked to a low rate of longitudinal growth as is the case in the long bones of postmetamorphic urodeles. J. Morphol. 275:1226–1237, 2014. © 2014 Wiley Periodicals, Inc.
Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR‐based metabolomics analysis

Tissue non‐specific alkaline phosphatase (TNAP) is a key player of bone mineralization and TNAP gene (ALPL) mutations in human are responsible for hypophosphatasia (HPP), a rare heritable disease affecting the mineralization of bones and teeth. Moreover, TNAP is also expressed by brain cells and the severe forms of HPP are associated with neurological disorders, including epilepsy and brain morphological anomalies. However, TNAP's role in the nervous system remains poorly understood. To investigate its neuronal functions, we aimed to identify without any a priori the metabolites regulated by TNAP in the nervous tissue. For this purpose we used 1H‐ and 31P NMR to analyze the brain metabolome of Alpl (Akp2) mice null for TNAP function, a well‐described model of infantile HPP. Among 39 metabolites identified in brain extracts of 1‐week‐old animals, eight displayed significantly different concentration in Akp2−/− compared to Akp2+/+ and Akp2+/− mice: cystathionine, adenosine, GABA, methionine, histidine, 3‐methylhistidine, N‐acetylaspartate (NAA), and N‐acetyl‐aspartyl‐glutamate, with cystathionine and adenosine levels displaying the strongest alteration. These metabolites identify several biochemical processes that directly or indirectly involve TNAP function, in particular through the regulation of ecto‐nucleotide levels and of pyridoxal phosphate‐dependent enzymes. Some of these metabolites are involved in neurotransmission (GABA, adenosine), in myelin synthesis (NAA, NAAG), and in the methionine cycle and transsulfuration pathway (cystathionine, methionine). Their disturbances may contribute to the neurodevelopmental and neurological phenotype of HPP.
The P2X7 receptor links mechanical strain to cytokine IL‐6 up‐regulation and release in neurons and astrocytes

Mechanical strain in neural tissues can lead to the up‐regulation and release of multiple cytokines including interleukin 6 (IL‐6). In the retina, the mechanosensitive release of ATP can autostimulate P2X7 receptors on both retinal ganglion cell neurons and optic nerve head astrocytes. Here, we asked whether the purinergic signaling contributed to the IL‐6 response to increased intraocular pressure (IOP) in vivo, and stretch or swelling in vitro. Rat and mouse eyes were exposed to non‐ischemic elevations in IOP to 50–60 mmHg for 4 h. A PCR array was used to screen cytokine changes, with quantitative (q)PCR used to confirm mRNA elevations and immunoblots used for protein levels. P2X7 antagonist Brilliant Blue G (BBG) and agonist (4‐benzoyl‐benzoyl)‐ATP (BzATP) were injected intravitreally. ELISA was used to quantify IL‐6 release from optic nerve head astrocytes or retinal ganglion cells. Receptor identity was confirmed pharmacologically and in P2X7−/− mice, acute elevation of IOP altered retinal expression of multiple cytokine genes. Elevation of IL‐6 was greatest, with expression of IL1rn, IL24, Tnf, Csf1, and Lif also increased more than twofold, while expression of Tnfsf11, Gdf9, and Tnfsf4 were reduced. qPCR confirmed the rise in IL‐6 and extracellular ATP marker ENTPD1, but not pro‐apoptotic genes. Intravitreal injection of P2X7 receptor antagonist BBG prevented the pressure‐dependent rise in IL‐6 mRNA and protein in the rat retina, while injection of P2X7 receptor agonist BzATP was sufficient to elevate IL‐6 expression. IOP elevation increased IL‐6 in wild‐type but not P2X7R knockout mice. Application of mechanical strain to isolated optic nerve head astrocytes increased IL‐6 levels. This response was mimicked by agonist BzATP, but blocked by antagonists BBG and A839977. Stretch or BzATP led to IL‐6 release from both astrocytes and isolated retinal ganglion cells. The mechanosensitive up‐regulation and release of cytokine IL‐6 from the retina involves the P2X7 receptor, with both astrocytes and neurons contributing to the response.