Why should we keep the cerebellum in mind when thinking about addiction?

Increasing evidence has involved the cerebellum in functions beyond the sphere of motor control. In the present article, we review evidence that involves the cerebellum in addictive behaviour. We aimed on molecular and cellular targets in the cerebellum where addictive drugs can act and induce mechanisms of neuroplasticity that may contribute to the development of an addictive pattern of behaviour. Also, we analyzed the behavioural consequences of repetitive drug administration that result from activitydependent changes in the efficacy of cerebellar synapses. Revised research involves the cerebellum in drug-induced long-term memory, druginduced sensitization and the perseverative behavioural phenotype. Results agree to relevant participation of the cerebellum in the functional systems underlying drug addiction. The molecular and cellular actions of addictive drugs in the cerebellum involve long-term adaptative changes in receptors, neurotransmitters and intracellular signalling transduction pathways that may lead to the re-organization of cerebellar microzones and in turn to functional networks where the cerebellum is an important nodal structure. We propose that drug induced activity-dependent synaptic changes in the cerebellum are crucial to the transition from a pattern of recreational drug taking to the compulsive behavioural phenotype. Functional and structural modifications produced by drugs in the cerebellum may enhance the susceptibility of fronto-cerebellar circuitry to be changed by repeated drug exposure. As a part of this functional reorganization, drug-induced cerebellar hyper-responsiveness appears to be central to reducing the influence of executive control of the prefrontal cortex on behaviour and aiding the transition to an automatic mode of contro

Acute hydroxyurea-induced replication blockade results in replisome components disengagement from nascent DNA without causing fork collapse

During S phase, replication forks can encounter several obstacles that lead to fork stalling, which if persistent might result in fork collapse. To avoid this collapse and to preserve the competence to restart, cells have developed mechanisms that maintain fork stability upon replication stress. In this study, we aimed to understand the mechanisms involved in fork stability maintenance in non-transformed human cells by performing an isolation of proteins on nascent DNA-mass spectrometry analysis in hTERT-RPE cells under different replication stress conditions. Our results show that acute hydroxyurea-induced replication blockade causes the accumulation of large amounts of single-stranded DNA at the fork. Remarkably, this results in the disengagement of replisome components from nascent DNA without compromising fork restart. Notably, Cdc45-MCM-GINS helicase maintains its integrity and replisome components remain associated with chromatin upon acute hydroxyurea treatment, whereas replisome stability is lost upon a sustained replication stress that compromises the competence to restart

ATM regulates ATR chromatin loading in response to DNA double-strand breaks

DNA double-strand breaks (DSBs) are among the most deleterious lesions that can challenge genomic integrity. Concomitant to the repair of the breaks, a rapid signaling cascade must be coordinated at the lesion site that leads to the activation of cell cycle checkpoints and/or apoptosis. In this context, ataxia telangiectasia mutated (ATM) and ATM and Rad-3–related (ATR) protein kinases are the earliest signaling molecules that are known to initiate the transduction cascade at damage sites. The current model places ATM and ATR in separate molecular routes that orchestrate distinct pathways of the checkpoint responses. Whereas ATM signals DSBs arising from ionizing radiation (IR) through a Chk2-dependent pathway, ATR is activated in a variety of replication-linked DSBs and leads to activation of the checkpoints in a Chk1 kinase–dependent manner. However, activation of the G2/M checkpoint in response to IR escapes this accepted paradigm because it is dependent on both ATM and ATR but independent of Chk2. Our data provides an explanation for this observation and places ATM activity upstream of ATR recruitment to IR-damaged chromatin. These data provide experimental evidence of an active cross talk between ATM and ATR signaling pathways in response to DNA damage

A study of the prostate, androgens and sexual activity of male rats

BACKGROUND: The prostate is a sexual gland that produces important substances for the potency of sperm to fertilize eggs within the female reproductive tract, and is under complex endocrine control. Taking advantage of the peculiar behavioral pattern of copulating male rats, we developed experimental paradigms to determine the influence of sexual behavior on the level of serum testosterone, prostate androgen receptors, and mRNA for androgen receptors in male rats displaying up to four consecutive ejaculations. METHODS: The effect of four consecutive ejaculations was investigated by determining levels of (i) testosterone in serum by solid phase RIA, (ii) androgen receptors at the ventral prostate with Western Blots, and (iii) androgen receptors-mRNA with RT-PCR. Data were analyzed with a one-way ANOVA followed by a post hoc application of Dunnett's test if required. RESULTS: The constant execution of sexual behavior did not produce any change in the weight of the ventral prostate. Serum testosterone increased after the second ejaculation, and remained elevated even after four ejaculations. The androgen receptor at the ventral prostate was higher after the first to third ejaculations, but returned suddenly to baseline levels after the fourth ejaculation. The level of mRNA increased after the first ejaculation, continued to increase after the second, and reached the highest peak after the third ejaculation; however, it returned suddenly to baseline levels after the fourth ejaculation. CONCLUSION: Four consecutive ejaculations by sexually experienced male rats had important effects on the physiological responses of the ventral prostate. Fast responses were induced as a result of sexual behavior that involved an increase and decrease in androgen receptors after one and four ejaculations, respectively. However, a progressive response was observed in the elevation of mRNA for androgen receptors, which also showed a fast decrease after four ejaculations. All of these changes with the prostate gland occurred in the presence of a sustained elevation of testosterone in the serum that started after two ejaculations. A consideration of these fast-induced changes suggests that the nerve supply plays a key role in prostate physiology during the sexual behavior of male rats

Molecular implications of adenosine in obesity

Adenosine has broad activities in organisms due to the existence of multiple receptors, the differential adenosine concentrations necessary to activate these receptors and the presence of proteins able to synthetize, degrade or transport this nucleoside. All adenosine receptors have been reported to be involved in glucose homeostasis, inflammation, adipogenesis, insulin resistance, and thermogenesis, indicating that adenosine could participate in the process of obesity. Since adenosine seems to be associated with several effects, it is plausible that adenosine participates in the initiation and development of obesity or may function to prevent it. Thus, the purpose of this review was to explore the involvement of adenosine in adipogenesis, insulin resistance and thermogenesis, with the aim of understanding how adenosine could be used to avoid, treat or improve the metabolic state of obesity. Treatment with specific agonists and/or antagonists of adenosine receptors could reverse the obesity state, since adenosine receptors normalizes several mechanisms involved in obesity, such as lipolysis, insulin sensitivity and thermogenesis. Furthermore, obesity is a preventable state, and the specific activation of adenosine receptors could aid in the prevention of obesity. Nevertheless, for the treatment of obesity and its consequences, more studies and therapeutic strategies in addition to adenosine are necessary

Altered patterns of expression of members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family in lung cancer

hnRNP A2/B1 has been suggested as a useful early detection marker for lung carcinoma. hnRNP A2/B1 is a member of a large family of heterogeneous nuclear ribonucleoproteins (hnRNP proteins) involved in a variety of functions, including regulation of transcription, mRNA metabolism, and translation. In lung cancer, we have evaluated the expression and cellular localization of several members of the hnRNP family, hnRNP A1, A2, B1, C1, C2 and K. 16 cell lines (SCLC and NSCLC) and biopsies from 32 lung cancer patients were analyzed. Our results suggest that, besides hnRNP A2/B1, the expression of other members of the hnRNP family is altered both in SCLC and NSCLC. In the biopsies, negative or low expression of the hnRNP proteins analyzed was observed in normal epithelial cells whereas lung cancer cells showed highly intense nuclear or cytoplasmic immunolocalization. In all the lung cancer cell lines, the mRNA for all the hnRNP proteins was detected. In general, higher levels of hnRNP mRNAs were found in SCLC as compared with NSCLC. Our results also suggest that the expression and processing of each hnRNP protein in lung cancer is independently regulated and is not exclusively related to proliferation status. In SCLC cell lines, hnRNP A1 protein expression correlated with that of Bcl-x(L). In the lung cancer cell lines, hnRNP K protein localization varied with the cellular confluence

The Brain-Like Enteric Nervous System

Understanding the autonomic supply at the gastrointestinal tract is one of the significant challenges for science. Its complex network of neurons exists on a broad evolutionary scale, from Hydra to mammals, and in a higher number than those found in the vertebrate spinal cord. Inside the gastrointestinal tract, enteric neurons regulate several functions with intrinsic processes and communicate with the other complex known as the microbiome. Outside the gastrointestinal tract, the enteric neurons project to the brain stem and spinal cord via the gut–brain axis. Furthermore, this enteric system has close functional relationships with the immune system for a rapid response to unhealthy food. The present chapter focuses on the structure, function, and pathologies of the enteric nervous system

Prostate response to prolactin in sexually active male rats

BACKGROUND: The prostate is a key gland in the sexual physiology of male mammals. Its sensitivity to steroid hormones is widely known, but its response to prolactin is still poorly known. Previous studies have shown a correlation between sexual behaviour, prolactin release and prostate physiology. Thus, here we used the sexual behaviour of male rats as a model for studying this correlation. Hence, we developed experimental paradigms to determine the influence of prolactin on sexual behaviour and prostate organization of male rats. METHODS: In addition to sexual behaviour recordings, we developed the ELISA procedure to quantify the serum level of prolactin, and the hematoxilin-eosin technique for analysis of the histological organization of the prostate. Also, different experimental manipulations were carried out; they included pituitary grafts, and haloperidol and ovine prolactin treatments. Data were analyzed with a One way ANOVA followed by post hoc Dunnet test if required. RESULTS: Data showed that male prolactin has a basal level with two peaks at the light-dark-light transitions. Consecutive ejaculations increased serum prolactin after the first ejaculation, which reached the highest level after the second, and started to decrease after the third ejaculation. These normal levels of prolactin did not induce any change at the prostate tissue. However, treatments for constant elevations of serum prolactin decreased sexual potency and increased the weight of the gland, the alveoli area and the epithelial cell height. Treatments for transient elevation of serum prolactin did not affect the sexual behaviour of males, but triggered these significant effects mainly at the ventral prostate. CONCLUSION: The prostate is a sexual gland that responds to prolactin. Mating-induced prolactin release is required during sexual encounters to activate the epithelial cells in the gland. Here we saw a precise mechanism controlling the release of prolactin during ejaculations that avoid the detrimental effects produced by constant levels. However, we showed that minor elevations of prolactin which do not affect the sexual behaviour of males, produced significant changes at the prostate epithelium that could account for triggering the development of hyperplasia or cancer. Thus, it is suggested that minute elevations of serum prolactin in healthy subjects are at the etiology of prostate abnormal growth

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected