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Gastrin, a hormone produced in the stomach, stimulates acid release from the stomach and the secretion of hormones from the gallbladder, pancreas and small intestine. Gastrins are released by the stomach after a meal, or the ingestion of 10 percent ethyl alcohol, and when the antrum portion of the stomach distends. The secretion of gastrin after a meal is referred to as the postprandial gastrin response. This response is inhibited by a single dose of enprostil, a synthetic drug that is similar to prostaglandin E2 (a fatty acid with biological activity). However, the effect of long-term treatment with enprostil on gastrin secretion is not known. The blood levels of gastrin were assessed over a 24-hour period prior to and on the last day of a two-week period of treatment with enprostil in 9 healthy subjects, who averaged 29 years in age. Blood levels of gastrin were measured at 30-minute intervals during the day and 2-hour intervals during the night. A dose of 35 micrograms (ug) of enprostil was taken at 8:00 AM and 8:00 PM; meals were scheduled at 8:30 AM, 12:30 PM, and 8:30 PM. The postprandial gastrin response was measured after the three meals and was shown to be inhibited after breakfast and after dinner. Enprostil treatment was associated with decreased gastrin levels at night. Two weeks of enprostil therapy was associated with a persistent inhibition of gastric acid secretion. (Consumer Summary produced by Reliance Medical Information, Inc.)

Breaking is a performative art that has recently undergone a process of sportification, developing into an aesthetic sport included in the 2024 Paris Olympic Games. Despite its growing worldwide popularity, there is a lack of research on Breaking. Accordingly, this pilot study's aim was twofold: (a) to provide an initial understanding of the anthropometric measures, body composition data, somatotype profiles, and strength performance of male (B-boys) and female (B-girls) Italian Breakers divided into elite (international) and sub-elite (national) levels and (b) to guide further research on the area, providing the methodological approach for future investigations. A total of 24 B-boys (elite n = 5; sub-elite n = 19) and 9 B-girls (elite n = 3; sub-elite n = 6) were included in this study. Descriptive analyses revealed that B-boys and B-girls displayed low height and weight (1.70 m (63.8 kg) and 1.58 m (54.2 kg), respectively), low levels of body fat percentages (10.3% and 17.6%, respectively), and a balanced mesomorph somatotype (2.28-4.64-2.69 and 2.34-5.16-2.38, respectively), revealing a marked development of muscular mass. Due to the small sample size, Welch's test and correlation analyses did not report any elite vs. sub-elite difference. It was hypothesized that Breakers' morphological profiles result from the selection procedures and training regimens related to Breaking aesthetic, athletic, and physiological demands.

The default mode network (DMN) is a complex network that plays a significant and active role during naturalistic stimulation. Previous studies that have used naturalistic stimuli, such as real-life stories or silent or sonorous films, have found that the information processing involved a complex hierarchical set of brain regions, including the DMN nodes. The DMN is not involved in low-level features and is only associated with high-level content-related incoming information. The human sexual experience involves a complex set of processes related to both external context and inner processes. Since the DMN plays an active role in the integration of naturalistic stimuli and aesthetic perception with beliefs, thoughts, and episodic autobiographical memories, we aimed at quantifying the involvement of the nodes of the DMN during visual sexual stimulation. After a systematic search in the principal electronic databases, we selected 83 fMRI studies, and an ALE meta-analysis was calculated. We performed conjunction analyses to assess differences in the DMN related to stimulus modalities, sex differences, and sexual orientation. The results show that sexual stimulation alters the topography of the DMN and highlights the DMN's active role in the integration of sexual stimuli with sexual schemas and beliefs.

Leading hypotheses of oxytocin's (OT) role in human cognition posit that it enhances salience attribution. However, whether OT exerts its effects predominantly in social (vs non-social) contexts remains debatable, and the time-course of intranasal OT's effects' on salience attribution processing is still unknown. We used the social Salience Attribution Task modified (sSAT) in a double-blind, placebo-controlled intranasal OT (inOT) administration, between-subjects design, with 54 male participants, to test existing theories of OT's role in cognition. Namely, we aimed to test whether inOT would differently affect salience attribution processing of social stimuli (expressing fearfulness) and non-social stimuli (fruits) made relevant via monetary reinforcement, and its neural processing time-course. During electroencephalography (EEG) recording, participants made speeded responses to emotional social (fearful faces) and non-emotional non-social (fruits) stimuli - which were matched for task-relevant motivational salience through their (color-dependent) probability of monetary reinforcement. InOT affected early (rather than late, P3b and LPP) EEG components, increasing N170 amplitude (p = .041) and P2b latency (p .001; albeit not of P1), regardless of stimuli's (emotional) socialness or reinforcement probability. Fear-related socialness affected salience attribution processing EEG (p .05) across time (N170, P2b and P3b), being later modulated by reinforcement probability (LPP). Our data suggest that OT's effects on neural activity during early perception, may exist irrespective of fear-related social- or reward-contexts. This partially supports the tri-phasic model of OT (which posits OT enhances salience attribution in an early perception stage regardless of socialness), and not the social salience nor the general approach-withdrawal hypotheses of OT, for early salience processing event-related potentials., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the study of human behaviour, non-social targets are often used as a control for human-to-human interactions. However, the concept of anthropomorphisation suggests that human-like qualities can be attributed to non-human objects. This can prove problematic in psychological experiments, as computers are often used as non-social targets. Here, we assessed the degree of computer anthropomorphisation in a sequential and iterated prisoner's dilemma. Participants (N = 41) faced three opponents in the prisoner's dilemma paradigm-a human, a computer, and a roulette-all represented by images presented at the commencement of each round. Cooperation choice frequencies and transition probabilities were estimated within subjects, in rounds against each opponent. We found that participants anthropomorphised the computer opponent to a high degree, while the same was not found for the roulette (i.e. no cooperation choice difference vs human opponents; p = .99). The difference in participants' behaviour towards the computer vs the roulette was further potentiated by the precedent roulette round, in terms of both cooperation choice (61%, p = .007) and cooperation probability after reciprocated defection (79%, p = .007). This suggests that there could be a considerable anthropomorphisation bias towards computer opponents in social games, even for those without a human-like appearance. Conversely, a roulette may be a preferable non-social control when the opponent's abilities are not explicit or familiar., (© 2023. The Author(s).)

Sexually objectified women are perceived as dehumanized. This may affect the behavioral and neural responses underlying the observer's empathic reactions for their physical pain, although this hypothesis still lacks empirical support. In the present study, we measured the electrophysiological activity of 30 participants (14 females and 16 males), in an empathy for physical pain paradigm in which pictures of sexualized and non-sexualized women were presented in painful and non-painful situations. The behavioral results revealed that sexualized women were evaluated as experiencing less pain than non-sexualized women. Neural evidence corroborated this finding showing that the perception of vicarious physical pain is lacking for sexualized women in both event-related potentials (ERPs) and brain oscillation domains. Specifically, the P2 component and the event-related synchronization/desynchronization (ERS/ERD) on the mu frequency band differed between painful and non-painful stimulation exclusively when women were not sexualized. Our results provide the first evidence that the neurophysiological responses to the vicarious experience of physical pain are dampened or even absent for sexualized women. These findings expand our understanding of the neurophysiological signatures of empathic processes and highlight the detrimental effect of a sexual-objectification bias in everyday contexts., (© 2023 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

The ribosome is a macromolecular complex composed of RNA and proteins that interact through an integrated and interconnected network to preserve its ancient core activities. In this review, we emphasize the pivotal role played by RNA-binding proteins as a driving force in the evolution of the current form of the ribosome, underscoring their importance in ensuring accurate protein synthesis. This category of proteins includes both ribosomal proteins and ribosome biogenesis factors. Impairment of their RNA-binding activity can also lead to ribosomopathies, which is a group of disorders characterized by defects in ribosome biogenesis that are detrimental to protein synthesis and cellular homeostasis. A comprehensive understanding of these intricate processes is essential for elucidating the mechanisms underlying the resulting diseases and advancing potential therapeutic interventions.

The primary cilium is a non-motile sensory organelle that extends from the surface of most vertebrate cells and transduces signals regulating proliferation, differentiation, and migration. Primary cilia dysfunctions have been observed in cancer and in a group of heterogeneous disorders called ciliopathies, characterized by renal and liver cysts, skeleton and limb abnormalities, retinal degeneration, intellectual disability, ataxia, and heart disease and, recently, in autism spectrum disorder, schizophrenia, and epilepsy. The potassium voltage-gated channel subfamily H member 1 (KCNH1) gene encodes a member of the EAG (ether-à-go-go) family, which controls potassium flux regulating resting membrane potential in both excitable and non-excitable cells and is involved in intracellular signaling, cell proliferation, and tumorigenesis. KCNH1 missense variants have been associated with syndromic neurodevelopmental disorders, including Zimmermann-Laband syndrome 1 (ZLS1, MIM #135500), Temple-Baraitser syndrome (TMBTS, MIM #611816), and, recently, with milder phenotypes as epilepsy. In this work, we provide evidence that KCNH1 localizes at the base of the cilium in pre-ciliary vesicles and ciliary pocket of human dermal fibroblasts and retinal pigment epithelial (hTERT RPE1) cells and that the pathogenic missense variants (L352V and R330Q; NP_002229.1) perturb cilia morphology, assembly/disassembly, and Sonic Hedgehog signaling, disclosing a multifaceted role of the protein. The study of KCNH1 localization, its functions related to primary cilia, and the alterations introduced by mutations in ciliogenesis, cell cycle coordination, cilium morphology, and cilia signaling pathways could help elucidate the molecular mechanisms underlying neurological phenotypes and neurodevelopmental disorders not considered as classical ciliopathies but for which a significant role of primary cilia is emerging., (© 2022. The Author(s).)

RNA-binding proteins (RBPs) play important roles in modulating miRNA-mediated mRNA target repression. Argonaute2 (Ago2) is an essential component of the RNA-induced silencing complex (RISC) that plays a central role in silencing mechanisms via small non-coding RNA molecules known as siRNAs and miRNAs. Small RNAs loaded into Argonaute proteins catalyze endoribonucleolytic cleavage of target RNAs or recruit factors responsible for translational silencing and mRNA target destabilization. In previous studies we have shown that KCC2, a neuronal Cl (-) extruding K (+) Cl (-) co-transporter 2, is regulated by miR-92 in neuronal cells. Searching for Ago2 partners by immunoprecipitation and LC-MS/MS analysis, we isolated among other proteins the Serpine mRNA binding protein 1 (SERBP1) from SH-SY5Y neuroblastoma cells. Exploring the role of SERBP1 in miRNA-mediated gene silencing in SH-SY5Y cells and primary hippocampal neurons, we demonstrated that SERBP1 silencing regulates KCC2 expression through the 3' untranslated region (UTR). In addition, we found that SERBP1 as well as Ago2/miR-92 complex bind to KCC2 3'UTR. Finally, we demonstrated the attenuation of miR-92-mediated repression of KCC2 3'UTR by SERBP1 silencing. These findings advance our knowledge regarding the miR-92-mediated modulation of KCC2 translation in neuronal cells and highlight SERBP1 as a key component of this gene regulation.

Extensive experimental research has been conducted to investigate how individuals empathise with others depending on contextual and motivational factors. However, the effect of sexual objectification (i.e. focus on the individual's physical appearance over his/her mental state) on empathy is scarce at best thus far. The aim of this work is to shed light on whether objectification modulates empathic responses toward humans and human-like objects. In Experiment 1, participants either underwent visuo-tactile stimulation or witnessed another person (a mannequin, a sexualized or a non-sexualized female confederate) being stimulated with pleasant or unpleasant objects. Participants were then asked to report either their own or the other's emotional experience. Results showed that shared representations (i.e. similarity between self-other emotional ratings) are significantly lower for the mannequin, intermediate for the sexualized woman, and reach the highest values for the non-sexualized woman. In Experiment 2, shared representations were assessed during a ball-tossing game in which the participants or one of the two confederates (sexualized or non-sexualized woman) were excluded from the game. Again, results showed reduced similarity between self-other emotional ratings toward sexualized as compared to non-sexualized women. The findings suggest that interacting with sexually objectified women reduces empathic responses typically observed within human relations.

The 'instructive model' of aberrant DNA methylation in human tumors is based on the observation that CpG islands prone to hypermethylation in cancers are embedded in chromatin enriched in H3K27me3 in human embryonic stem cells (hESC). Recent studies also link methylation of CpG islands to the methylation status of H3K4, where H3K4me3 is inversely correlated with DNA methylation. To provide insight into these conflicting findings, we generated DNA methylation profiles for acute myeloid leukemia samples from patients and leukemic cell lines and integrated them with publicly available ChIp-seq data, containing H3K4me3 and H3K27me3 CpG island occupation in hESC, or hematopoietic stem or progenitor cells (hHSC/MPP). Hypermethylated CpG islands in AML samples displayed H3K27me3 enrichments in hESC and hHSC/MPP; however, ChIp analysis of specific hypermethylated CpG islands revealed a significant reduction in H3K4me3 signal with a concomitant increase in H3K4me0 levels as opposed to a nonsignificant increase in H3K27me3 marks. The integration of AML DNA methylation profiles with the ChIp-seq data in hESC and hHSC/MPP also led to the identification of Iroquois homeobox 2 (IRX2) as a previously unknown factor promoting differentiation of leukemic cells. Our results indicate that in contrast to the 'instructive model', H3K4me3 levels are strongly associated with DNA methylation patterns in AML and have a role in the regulation of critical genes, such as the putative tumor suppressor IRX2., (© 2019 Federation of European Biochemical Societies.)

Objectification - reducing a someone to a something - represents a powerful and potentially damaging way in which we can see and treat others. Women are often victims of processes of objectification that occur whenever a woman is reduced to her body or certain body parts. What remains unclear is the extent to which a woman becomes an object when objectified. Using the oddball paradigm in three experiments, participants' neural activity was measured while they analyzed frequently presented male and female human stimuli and infrequently presented gender-matched doll-like objects. The infrequent doll-like objects were expected to trigger a late event-related neurophysiological response (P300) the more they were perceived different from the repeated, human stimuli (i.e., the oddball effect). In Experiment 1, the oddball effect was significantly smaller for objectified women compared to objectified men. Results of Experiment 2 confirmed that this effect was confined to objectified depictions of women. In Experiment 3, no semantic references to the human-object divide were provided, but objectified women were still perceived more similar to real objects. Taken together, these results are the first to demonstrate that the perception of women, when objectified, changes in essence beyond the metaphor.

Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity-dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis -Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3' UTR. These include two conserved introns which distinctively modulate Arc mRNA stability by targeting it for destruction via the nonsense mediated decay pathway. Here, we further investigated how splicing of the Arc mRNA 3' UTR region contributes to modulate Arc expression in cultured neurons. Unexpectedly, upon induction with brain derived neurotrophic factor, translational efficiency of a luciferase reporter construct harboring Arc 3' UTR is significantly upregulated and this effect is dependent on splicing of Arc introns. We find that, eIF2α dephosphorylation, mTOR, ERK, PKC, and PKA activity are key to this process. Additionally, CREB-dependent transcription is required to couple Arc 3' UTR-splicing to its translational upregulation, suggesting the involvement of de novo transcribed trans- acting factors. Overall, splicing of Arc 3' UTR exerts a dual and unique effect in fine-tuning Arc expression upon synaptic signaling: while inducing mRNA decay to limit the time window of Arc expression, it also elicits translation of the decaying mRNA. This antagonistic effect likely contributes to the achievement of a confined yet efficient burst of Arc protein expression, facilitating its role as an effector of synapse-specific plasticity.

A controversial hypothesis, named the Sexualized Body Inversion Hypothesis (SBIH), claims similar visual processing of sexually objectified women (i.e., with a focus on the sexual body parts) and inanimate objects as indicated by an absence of the inversion effect for both type of stimuli. The current study aims at shedding light into the mechanisms behind the SBIH in a series of 4 experiments. Using a modified version of Bernard et al.´s (2012) visual-matching task, first we tested the core assumption of the SBIH, namely that a similar processing style occurs for sexualized human bodies and objects. In Experiments 1 and 2 a non-sexualized (personalized) condition plus two object-control conditions (mannequins, and houses) were included in the experimental design. Results showed an inversion effect for images of personalized women and mannequins, but not for sexualized women and houses. Second, we explored whether this effect was driven by differences in stimulus asymmetry, by testing the mediating and moderating role of this visual feature. In Experiment 3, we provided the first evidence that not only the sexual attributes of the images but also additional perceptual features of the stimuli, such as their asymmetry, played a moderating role in shaping the inversion effect. Lastly, we investigated the strategy adopted in the visual-matching task by tracking eye movements of the participants. Results of Experiment 4 suggest an association between a specific pattern of visual exploration of the images and the presence of the inversion effect. Findings are discussed with respect to the literature on sexual objectification.

Sexual objectification is a widespread phenomenon characterized by a focus on the individual's physical appearance over his/her mental state. This has been associated with negative social consequences, as objectified individuals are judged to be less human, competent, and moral. Moreover, behavioral responses toward the person change as a function of the degree of the perceived sexual objectification. In the present study, we investigated how behavioral and neural representations of other social pain are modulated by the degree of sexual objectification of the target. Using a within-subject fMRI design, we found reduced empathic feelings for positive (but not negative) emotions toward sexually objectified women as compared to non-objectified (personalized) women when witnessing their participation to a ball-tossing game. At the brain level, empathy for social exclusion of personalized women recruited areas coding the affective component of pain (i.e., anterior insula and cingulate cortex), the somatosensory components of pain (i.e., posterior insula and secondary somatosensory cortex) together with the mentalizing network (i.e., middle frontal cortex) to a greater extent than for the sexually objectified women. This diminished empathy is discussed in light of the gender-based violence that is afflicting the modern society., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The finding that small non-coding RNAs (ncRNAs) are able to control gene expression in a sequence specific manner has had a massive impact on biology. Recent improvements in high throughput sequencing and computational prediction methods have allowed the discovery and classification of several types of ncRNAs. Based on their precursor structures, biogenesis pathways and modes of action, ncRNAs are classified as small interfering RNAs (siRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), endogenous small interfering RNAs (endo-siRNAs or esiRNAs), promoter associate RNAs (pRNAs), small nucleolar RNAs (snoRNAs) and sno-derived RNAs. Among these, miRNAs appear as important cytoplasmic regulators of gene expression. miRNAs act as post-transcriptional regulators of their messenger RNA (mRNA) targets via mRNA degradation and/or translational repression. However, it is becoming evident that miRNAs also have specific nuclear functions. Among these, the most studied and debated activity is the miRNA-guided transcriptional control of gene expression. Although available data detail quite precisely the effectors of this activity, the mechanisms by which miRNAs identify their gene targets to control transcription are still a matter of debate. Here, we focus on nuclear functions of miRNAs and on alternative mechanisms of target recognition, at the promoter lavel, by miRNAs in carrying out transcriptional gene silencing., Competing Interests: The authors declare no conflict of interest.

Objectives: Carcinomas of the left colon represent a neoplasm of older patients (late onset), but epidemiologic evidence has been showing an increasing incidence in patients 50 years or younger (early onset). In this study, we investigate pathologic and molecular features of early- and late-onset carcinoma of the left colon., Methods: We selected 22 patients 50 years or younger and 21 patients 70 years or older with left-sided colorectal carcinoma (CRC). All samples were evaluated for pathologic features, microsatellite instability, and KRAS and BRAF mutations. Moreover, both groups were analyzed to identify CpG island methylator phenotype features and assessed with restriction landmark genome scanning (RLGS) to unveil differential DNA methylation patterns., Results: Early-onset patients had advanced pathologic stages compared with late-onset patients (P = .0482). All cases showed a microsatellite stable profile and BRAF wild-type sequence. Early-onset patients (43%) more frequently had mutations at KRAS codon 12 compared with late-onset patients (14%) (P =.0413). RLGS showed that patients younger than 50 years who had CRC had a significantly lower percentage of methylated loci than did patients 70 years or older (P = .04124), and differential methylation of several genomic loci was observed in the two groups., Conclusions: Our results suggest that left-sided CRCs may present differential patterns of aberrant DNA methylation when they are separated by age., (Copyright© by the American Society for Clinical Pathology.)

Post-transcriptional gene regulation mediated by microRNAs (miRNAs) is implicated in memory formation; however, the function of miR-92 in this regulation is uncharacterized. The present study shows that training mice in contextual fear conditioning produces a transient increase in miR-92 levels in the hippocampus and decreases several miR-92 gene targets, including: (i) the neuronal Cl(-) extruding K(+) Cl(-) co-transporter 2 (KCC2) protein; (ii) the cytoplasmic polyadenylation protein (CPEB3), an RNA-binding protein regulator of protein synthesis in neurons; and (iii) the transcription factor myocyte enhancer factor 2D (MEF2D), one of the MEF2 genes which negatively regulates memory-induced structural plasticity. Selective inhibition of endogenous miR-92 in CA1 hippocampal neurons, by a sponge lentiviral vector expressing multiple sequences imperfectly complementary to mature miR-92 under the control of the neuronal specific synapsin promoter, leads to up-regulation of KCC2, CPEB3 and MEF2D, impairs contextual fear conditioning, and prevents a memory-induced increase in the spine density. Taken together, the results indicate that neuronal-expressed miR-92 is an endogenous fine regulator of contextual fear memory in mice., (© 2014 Wiley Periodicals, Inc.)

Although research in moral psychology in the last decade has relied heavily on hypothetical moral dilemmas and has been effective in understanding moral judgment, how these judgments translate into behaviors remains a largely unexplored issue due to the harmful nature of the acts involved. To study this link, we follow a new approach based on a desktop virtual reality environment. In our within-subjects experiment, participants exhibited an order-dependent judgment-behavior discrepancy across temporally separated sessions, with many of them behaving in utilitarian manner in virtual reality dilemmas despite their nonutilitarian judgments for the same dilemmas in textual descriptions. This change in decisions reflected in the autonomic arousal of participants, with dilemmas in virtual reality being perceived more emotionally arousing than the ones in text, after controlling for general differences between the two presentation modalities (virtual reality vs. text). This suggests that moral decision-making in hypothetical moral dilemmas is susceptible to contextual saliency of the presentation of these dilemmas.

Abstract Argonaute proteins play a central role in gene silencing pathways mediated by small RNA molecules. The ancestral function of small RNA-dependent silencing is related to genome protection against parasitic nucleic acids, such as transposons and viruses. However, new classes of small RNAs are continuously being uncovered in all higher eukaryotes in which they play important functions in processes ranging from embryonic development to differentiation to cell proliferation and metabolism. Small RNAs have variegated biogenesis pathways and accomplish distinct functions. Nevertheless, it appears that all small RNAs work merely as guides in recognizing the target RNAs invariably relying on the interaction with Argonaute proteins and associated factors for their biological function. Here, we discuss recent findings on the structure and regulation of mammalian Argonaute proteins and overview the various roles that these versatile proteins play in regulating gene expression.

In the past few years, the understanding of microRNA (miRNA) biogenesis, the molecular mechanisms by which miRNAs regulate gene expression, and the functional roles of miRNAs has been expanded. Interestingly, numerous miRNAs are expressed in a spatially and temporally controlled manner in the nervous system, suggesting that their post-transcriptional regulation may be particularly relevant in neural development and function. miRNA studies in neurobiology have shown their involvement in synaptic plasticity and brain diseases. Approaches for manipulating miRNA levels in neuronal cells in vitro and in vivo are described here. Recent applications of miRNA antisense oligonucleotides, miRNA gene knockout and miRNA sponges in neuronal cells are reviewed. Finally, miRNA-based therapies for neurological pathologies related to alterations in miRNA functions are discussed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Argonaute are a conserved class of proteins central to the microRNA pathway. We have highlighted a novel and non-redundant function of Ago1 versus Ago2; the two core factors of the miRNA-associated RISC complex. Stable overexpression of Ago1 in neuroblastoma cells causes the cell cycle to slow down, a decrease in cellular motility and a stronger apoptotic response upon UV irradiation. These effects, together with a significant increase in p53 levels, suggest that Ago1 may act as a tumor-suppressor factor, a function also supported by GEO Profiles microarrays that inversely correlate Ago1 expression levels with cell proliferation rates., (Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3'UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3'UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3'UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptide's localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3'UTR functional variants altering miRNAs-BDNF binding.

Amyloid Precursor Protein (APP) and its proteolytic product amyloid beta (Aβ) are critical in the pathogenesis of Alzheimer's Disease (AD). APP gene duplication and transcriptional upregulation are linked to AD. In addition, normal levels of APP appear to be required for some physiological functions in the developing brain. Several studies in mammalian cell lines and primary neuron cultures indicate that RNA binding proteins and microRNAs interacting with regulatory regions of the APP mRNA modulate expression of APP post-transcriptionally. However, when the various mechanisms of APP post-transcriptional regulation are recruited and which of them are acting in a synergistic fashion to balance APP protein levels, is unclear. Recent studies suggest that further investigation of the molecules and pathways involved in APP post-transcriptional regulation are warranted.

Background: In mdx mice, the absence of dystrophin leads to the deficiency of other components of the dystrophin-glycoprotein complex (DAPC), making skeletal muscle fibers more susceptible to necrosis. The mechanisms involved in the disappearance of the DAPC are not completely understood. The muscles of mdx mice express normal amounts of mRNA for the DAPC components, thus suggesting post-transcriptional regulation., Methodology/principal Findings: We investigated the hypothesis that DAPC reduction could be associated with the microRNA system. Among the possible microRNAs (miRs) found to be upregulated in the skeletal muscle tissue of mdx compared to wt mice, we demonstrated that miR-222 specifically binds to the 3'-UTR of β1-syntrophin and participates in the downregulation of β1-syntrophin. In addition, we documented an altered regulation of the 3'-UTR of β1-syntrophin in muscle tissue from dystrophic mice., Conclusion/significance: These results show the importance of the microRNA system in the regulation of DAPC components in dystrophic muscle, and suggest a potential role of miRs in the pathophysiology of dystrophy.

The amyloid precursor protein (APP) and its proteolytic product amyloid beta (Abeta) are associated with both familial and sporadic forms of Alzheimer disease (AD). Aberrant expression and function of microRNAs has been observed in AD. Here, we show that in rat hippocampal neurons cultured in vitro, the down-regulation of Argonaute-2, a key component of the RNA-induced silencing complex, produced an increase in APP levels. Using site-directed mutagenesis, a microRNA responsive element (RE) for miR-101 was identified in the 3'-untranslated region (UTR) of APP. The inhibition of endogenous miR-101 increased APP levels, whereas lentiviral-mediated miR-101 overexpression significantly reduced APP and Abeta load in hippocampal neurons. In addition, miR-101 contributed to the regulation of APP in response to the proinflammatory cytokine interleukin-1beta (IL-lbeta). Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of Abeta, suggesting a possible role for miR-101 in neuropathological conditions.

MicroRNAs have been associated to fine-tuning spatial and temporal control of gene expression during neuronal development. The neuronal Cl(-) extruding, K(+)Cl(-) co-transporter 2 (KCC2) is known to play an important role in neuronal Cl(-) homeostasis and in determining the physiological response to activation of anion selective GABA receptors. Here we show that microRNA-92 is developmentally down-regulated during maturation of rat cerebellar granule neurons (CGNs) in vitro. Computational predictions suggest several high-ranking targets for microRNA-92 including the KCC2 gene. Consistently, the KCC2 protein levels were up-regulated in mature CGN in vitro and a functional association between microRNA-92 and KCC2 3' untranslated region was established using luciferase assays. The generation of an inward directed Cl(-) electrochemical gradient, necessary for the hyperpolarizing effect of GABA, requires robust KCC2 expression in several neuronal types. Here we show that lentiviral-mediated microRNA-92 over-expression reduced KCC2 protein levels and positively shifted reversal potential of GABA induced Cl(-) currents in CGNs. In addition KCC2 re-expression reversed microRNA-92 electrophysiological phenotype. Consistently microRNA-92 inhibition induced both an increase of the level of KCC2 and a negative shift in GABA reversal potential. These findings introduce a new player in the developmental change of GABA from depolarization to hyperpolarization.

RNA-Induced Silencing Complex (RISC) mediates post-transcriptional control of gene expression and contains Argonaute 2 (AGO2) protein as a central effector of cleavage or inhibition of mRNA translation. In the brain, the RISC pathway is involved in neuronal functions, such as synaptic development and local protein synthesis, which are potentially critical for memory. In this study, we examined the role of RISC in memory formation in rodents, by silencing AGO2 expression in dorsal hippocampus of C57BL/6 mice and submitting animals to hippocampus-related tasks. One week after surgery, AGO2 downregulation impaired both short-term and long-term contextual fear memories. Conversely, no long-lasting effects were observed three weeks after surgery, when AGO2 levels were re-established. These results show that altered RISC activity severely affects learning and memory processes in rodents.

The basis of allogeneic hemopoietic stem cell (HSC) transplantation in thalassemia consists in substituting the ineffective thalassemic erythropoiesis with and allogeneic effective one. This cellular replacement therapy is an efficient way to obtain a long lasting, probably permanent, clinical effective correction of the anaemia avoiding transfusion requirement and subsequent complications like iron overload. The first HSC transplant for thalassemia was performed in Seattle on Dec 2, 1981. In the early eighties transplantation procedure was limited to very few centres worldwide. Between 17 December 1981 and 31 January 2003, over 1000 consecutive patients, aged from 1 to 35 years, underwent transplantation in Pesaro. After the pioneering work by the Seattle and Pesaro groups, this therapeutic approach is now widely applied worldwide. Medical therapy of thalassemia is one of the most spectacular successes of the medical practice in the last decades. In recent years advances in knowledge of iron overload patho-physiopathology, improvement and diffusion of diagnostic capability together with the development of new effective and safe oral chelators promise to further increase success of medical therapy. Nevertheless situation is dramatically different in non-industrialized countries were the very large majority of patients live today. Transplantation technologies have improved substantially during the last years and transplantation outcome is likely to be much better today than in the '80s. Recent data indicated a probability of overall survival and thalassemia free survival of 97% and 89% for patients with no advanced disease and of 87% and 80% for patients with advanced disease. Thus the central role of HSC in thalassemia has now been fully established. HSC remains the only definitive curative therapy for thalassemia and other hemoblobinopathies. The development of oral chelators has not changed this position. However this has not settled the controversy on how this curative but potentially lethal treatment stands in front of medical therapy for adults and advanced disease patients. In sickle cell disease HSC transplantation currently is reserved almost exclusively for patients with clinical features that indicate a poor outcome or significant sickle-related morbidity.

Background: RNA silencing occurs in a broad range of organisms. Although its ancestral function is probably related to the genome defense mechanism against repetitive selfish elements, it has been found that RNA silencing regulates different cellular processes such as gene expression and chromosomal segregation. In Neurospora crassa, a RNA silencing mechanism, called quelling, acts to repress the expression of transgenes and transposons, but until now no other cellular functions have been shown to be regulated by this mechanism., Results: Here, we detected by northern blotting endogenous short interfering RNA (siRNAs) from the repetitive ribosomal DNA locus (rDNA) that are loaded onto the argonaute protein QDE-2. Moreover, we found a bidirectional transcription that can generate double strand RNA (dsRNA) molecules. Interestingly, quelling mutants have a reduced rDNA gene copy number., Conclusion: Our finding could suggest a new biological function for RNA silencing in the maintenance of the integrity and stability of the Neurospora rDNA locus.

In few years our understanding of microRNA (miRNA) biogenesis, molecular mechanisms by which miRNAs regulate gene expression, and the functional roles of miRNAs has been expanded. Interestingly, numerous miRNAs are expressed in a spatially and temporally controlled manner in the nervous system, suggesting that their posttrascriptional regulation may be particularly relevant in neural development and function. MiRNA studies in neurobiology showed their involvement in synaptic plasticity and brain diseases. In this review ,correlations between miRNA-mediated gene silencing and Alzheimer's, Parkinson's, and other neurodegenerative diseases will be discussed. Molecular and cellular neurobiological studies of the miRNAs in neurodegeneration represent the exploration of a new Frontier of miRNAs biology and the potential development of new diagnostic tests and genetic therapies for neurodegenerative diseases.

MicroRNAs (miRNAs) are a recently discovered class of small RNA molecules implicated in a wide range of diverse gene regulatory mechanisms. Interestingly, numerous miRNAs are expressed in a spatially and temporally controlled manner in the nervous system. This suggests that gene regulation networks based on miRNA activities may be particularly relevant in neurons. Recent studies show the involvement of RNA-mediated gene silencing in neurogenesis, neural differentiation, synaptic plasticity, and neurologic and psychiatric diseases. This review focuses on the roles of miRNAs in the gene regulation of the nervous system.