Extra centrosomes induce PIDD1-mediated inflammation and immunosurveillance.

Unscheduled increases in ploidy underlie defects in tissue function, premature aging, and malignancy. A concomitant event to polyploidization is the amplification of centrosomes, the main microtubule organization centers in animal cells. Supernumerary centrosomes are frequent in tumors, correlating with higher aggressiveness and poor prognosis. However, extra centrosomes initially also exert an onco-protective effect by activating p53-induced cell cycle arrest. If additional signaling events initiated by centrosomes help prevent pathology is unknown. Here, we report that extra centrosomes, arising during unscheduled polyploidization or aberrant centriole biogenesis, induce activation of NF-κB signaling and sterile inflammation. This signaling requires the NEMO-PIDDosome, a multi-protein complex composed of PIDD1, RIPK1, and NEMO/IKKγ. Remarkably, the presence of supernumerary centrosomes suffices to induce a paracrine chemokine and cytokine profile, able to polarize macrophages into a pro-inflammatory phenotype. Furthermore, extra centrosomes increase the immunogenicity of cancer cells and render them more susceptible to NK-cell attack. Hence, the PIDDosome acts as a dual effector, able to engage not only the p53 network for cell cycle control but also NF-κB signaling to instruct innate immunity.

CBP Is Required for Establishing Adaptive Gene Programs in the Adult Mouse Brain.

Environmental factors and life experiences impinge on brain circuits triggering adaptive changes. Epigenetic regulators contribute to this neuroadaptation by enhancing or suppressing specific gene programs. The paralogous transcriptional coactivators and lysine acetyltransferases CREB binding protein (CBP) and p300 are involved in brain plasticity and stimulus-dependent transcription, but their specific roles in neuroadaptation are not fully understood. Here we investigated the impact of eliminating either CBP or p300 in excitatory neurons of the adult forebrain of mice from both sexes using inducible and cell type-restricted knock-out strains. The elimination of CBP, but not p300, reduced the expression and chromatin acetylation of plasticity genes, dampened activity-driven transcription, and caused memory deficits. The defects became more prominent in elderly mice and in paradigms that involved enduring changes in transcription, such as kindling and environmental enrichment, in which CBP loss interfered with the establishment of activity-induced transcriptional and epigenetic changes in response to stimulus or experience. These findings further strengthen the link between CBP deficiency in excitatory neurons and etiopathology in the nervous system.SIGNIFICANCE STATEMENT How environmental conditions and life experiences impinge on mature brain circuits to elicit adaptive responses that favor the survival of the organism remains an outstanding question in neurosciences. Epigenetic regulators are thought to contribute to neuroadaptation by initiating or enhancing adaptive gene programs. In this article, we examined the role of CREB binding protein (CBP) and p300, two paralogous transcriptional coactivators and histone acetyltransferases involved in cognitive processes and intellectual disability, in neuroadaptation in adult hippocampal circuits. Our experiments demonstrate that CBP, but not its paralog p300, plays a highly specific role in the epigenetic regulation of neuronal plasticity gene programs in response to stimulus and provide unprecedented insight into the molecular mechanisms underlying neuroadaptation.

Areas of Interest and Attitudes Toward Antiobesity Drugs: Thematic and Quantitative Analysis Using Twitter.

BACKGROUND: Antiobesity drugs are prescribed for the treatment of obesity in conjunction with healthy eating, physical activity, and behavior modification. However, poor adherence rates have been reported. Attitudes or beliefs toward medications are important to ascertain because they may be associated with patient behavior. The analysis of tweets has become a tool for health research. OBJECTIVE: The aim of this study is to investigate the content and key metrics of tweets referring to antiobesity drugs. METHODS: In this observational quantitative and qualitative study, we focused on tweets containing hashtags related to antiobesity drugs between September 20, 2019, and October 31, 2019. Tweets were first classified according to whether they described medical issues or not. Tweets with medical content were classified according to the topic they referred to: side effects, efficacy, or adherence. We additionally rated it as positive or negative. Furthermore, we classified any links included within a tweet as either scientific or nonscientific. Finally, the number of retweets generated as well as the dissemination and sentiment score obtained by the antiobesity drugs analyzed were also measured. RESULTS: We analyzed a total of 2045 tweets, 945 of which were excluded according to the criteria of the study. Finally, 320 out of the 1,100 remaining tweets were also excluded because their content, although related to drugs for obesity treatment, did not address the efficacy, side effects, or adherence to medication. Liraglutide and semaglutide accumulated the majority of tweets (682/780, 87.4%). Notably, the content that generated the highest frequency of tweets was related to treatment efficacy, with liraglutide-, semaglutide-, and lorcaserin-related tweets accumulating the highest proportion of positive consideration. We found the highest percentages of tweets with scientific links in those posts related to liraglutide and semaglutide. Semaglutide-related tweets obtained the highest probability of likes and were the most disseminated within the Twitter community. CONCLUSIONS: This analysis of posted tweets related to antiobesity drugs shows that the interest, beliefs, and experiences regarding these pharmacological treatments are heterogeneous. The efficacy of the treatment accounts for the majority of interest among Twitter users.

Contribution of spurious transcription to intellectual disability disorders.

During the development of multicellular organisms, chromatin-modifying enzymes orchestrate the establishment of gene expression programmes that characterise each differentiated cell type. These enzymes also contribute to the maintenance of cell type-specific transcription profiles throughout life. But what happens when epigenomic regulation goes awry? Genomic screens in experimental models of intellectual disability disorders (IDDs) caused by mutations in epigenetic machinery-encoding genes have shown that transcriptional dysregulation constitutes a hallmark of these conditions. Here, we underscore the connections between a subset of chromatin-linked IDDs and spurious transcription in brain cells. We also propose that aberrant gene expression in neurons, including both the ectopic transcription of non-neuronal genes and the activation of cryptic promoters, may importantly contribute to the pathoaetiology of these disorders.

Eating Disorder Awareness Campaigns: Thematic and Quantitative Analysis Using Twitter.

BACKGROUND: Health awareness initiatives are frequent but their efficacy is a matter of controversy. We have investigated the effect of the Eating Disorder Awareness Week and Wake Up Weight Watchers campaigns on Twitter. OBJECTIVE: We aimed to examine whether the Eating Disorder Awareness Week and Wake Up Weight Watchers initiatives increased the volume and dissemination of Twitter conversations related to eating disorders and investigate what content generates the most interest on Twitter. METHODS: Over a period of 12 consecutive days in 2018, we collected tweets containing the hashtag #wakeupweightwatchers and hashtags related to Eating Disorder Awareness Week (#eatingdisorderawarenessweek, #eatingdisorderawareness, or #EDAW), with the hashtag #eatingdisorder as a control. The content of each tweet was rated as medical, testimony, help offer, awareness, pro-ana, or anti-ana. We analyzed the number of retweets and favorites generated, as well as the potential reach and impact of the hashtags and the characteristics of contributors. RESULTS: The number of #wakeupweightwatchers tweets was higher than that of Eating Disorder Awareness Week and #eatingdisorder tweets (3900, 2056, and 1057, respectively). The content of tweets was significantly different between the hashtags analyzed (P<.001). Medical content was lower in the awareness campaigns. Awareness and help offer content were lower in #wakeupweightwatchers tweets. Retweet and favorite ratios were highest in #wakeupweightwatchers tweets. Eating Disorder Awareness Week achieved the highest impact, and very influential contributors participated. CONCLUSIONS: Both awareness campaigns effectively promoted tweeting about eating disorders. The majority of tweets did not promote any specific preventive or help-seeking behaviors.

Exploring the Extent of the Hikikomori Phenomenon on Twitter: Mixed Methods Study of Western Language Tweets.

BACKGROUND: Hikikomori is a severe form of social withdrawal, originally described in Japan but recently reported in other countries. Debate exists as to what extent hikikomori is viewed as a problem outside of the Japanese context. OBJECTIVE: We aimed to explore perceptions about hikikomori outside Japan by analyzing Western language content from the popular social media platform, Twitter. METHODS: We conducted a mixed methods analysis of all publicly available tweets using the hashtag #hikikomori between February 1 and August 16, 2018, in 5 Western languages (Catalan, English, French, Italian, and Spanish). Tweets were first classified as to whether they described hikikomori as a problem or a nonproblematic phenomenon. Tweets regarding hikikomori as a problem were then subclassified in terms of the type of problem (medical, social, or anecdotal) they referred to, and we marked if they referenced scientific publications or the presence of hikikomori in countries other than Japan. We also examined measures of interest in content related to hikikomori, including retweets, likes, and associated hashtags. RESULTS: A total of 1042 tweets used #hikikomori, and 656 (62.3%) were included in the content analysis. Most of the included tweets were written in English (44.20%) and Italian (34.16%), and a majority (56.70%) discussed hikikomori as a problem. Tweets referencing scientific publications (3.96%) and hikikomori as present in countries other than Japan (13.57%) were less common. Tweets mentioning hikikomori outside Japan were statistically more likely to be retweeted (P=.01) and liked (P=.01) than those not mentioning it, whereas tweets with explicit scientific references were statistically more retweeted (P=.01) but not liked (P=.10) than those without that reference. Retweet and like figures were not statistically significantly different among other categories and subcategories. The most associated hashtags included references to Japan, mental health, and the youth. CONCLUSIONS: Hikikomori is a repeated word in non-Japanese Western languages on Twitter, suggesting the presence of hikikomori in countries outside Japan. Most tweets treat hikikomori as a problem, but the ways they post about it are highly heterogeneous.

Areas of Interest and Stigmatic Attitudes of the General Public in Five Relevant Medical Conditions: Thematic and Quantitative Analysis Using Twitter.

BACKGROUND: Twitter is an indicator of real-world performance, thus, is an appropriate arena to assess the social consideration and attitudes toward psychosis. OBJECTIVE: The aim of this study was to perform a mixed-methods study of the content and key metrics of tweets referring to psychosis in comparison with tweets referring to control diseases (breast cancer, diabetes, Alzheimer, and human immunodeficiency virus). METHODS: Each tweet's content was rated as nonmedical (NM: testimonies, health care products, solidarity or awareness and misuse) or medical (M: included a reference to the illness's diagnosis, treatment, prognosis, or prevention). NM tweets were classified as positive or pejorative. We assessed the appropriateness of the medical content. The number of retweets generated and the potential reach and impact of the hashtags analyzed was also investigated. RESULTS: We analyzed a total of 15,443 tweets: 8055 classified as NM and 7287 as M. Psychosis-related tweets (PRT) had a significantly higher frequency of misuse 33.3% (212/636) vs 1.15% (853/7419; P<.001) and pejorative content 36.2% (231/636) vs 11.33% (840/7419; P<.001). The medical content of the PRT showed the highest scientific appropriateness 100% (391/391) vs 93.66% (6030/6439; P<.001) and had a higher frequency of content about disease prevention. The potential reach and impact of the tweets related to psychosis were low, but they had a high retweet-to-tweet ratio. CONCLUSIONS: We show a reduced number and a different pattern of contents in tweets about psychosis compared with control diseases. PRT showed a predominance of nonmedical content with increased frequencies of misuse and pejorative tone. However, the medical content of PRT showed high scientific appropriateness aimed toward prevention.

Epigenetic Etiology of Intellectual Disability.

Intellectual disability (ID) is a prevailing neurodevelopmental condition associated with impaired cognitive and adaptive behaviors. Many chromatin-modifying enzymes and other epigenetic regulators have been genetically associated with ID disorders (IDDs). Here we review how alterations in the function of histone modifiers, chromatin remodelers, and methyl-DNA binding proteins contribute to neurodevelopmental defects and altered brain plasticity. We also discuss how progress in human genetics has led to the generation of mouse models that unveil the molecular etiology of ID, and outline the direction in which this field is moving to identify therapeutic strategies for IDDs. Importantly, because the chromatin regulators linked to IDDs often target common downstream genes and cellular processes, the impact of research in individual syndromes goes well beyond each syndrome and can also contribute to the understanding and therapy of other IDDs. Furthermore, the investigation of these disorders helps us to understand the role of chromatin regulators in brain development, plasticity, and gene expression, thereby answering fundamental questions in neurobiology.

The evaluation of pelvic floor muscle strength in women with pelvic floor dysfunction: A reliability and correlation study.

AIMS: The purposes of this study were: (i) to evaluate the reliability of vaginal palpation, vaginal manometry, vaginal dynamometry; and surface (transperineal) electromyography (sEMG), when evaluating pelvic floor muscle (PFM) strength and/or activation; and (ii) to determine the associations among PFM strength measured using these assessments. METHODS: One hundred and fifty women with pelvic floor disorders participated on one occasion, and 20 women returned for the same investigations by two different raters on 3 different days. At each session, PFM strength was assessed using palpation (both the modified Oxford Grading Scale and the Levator ani testing), manometry, and dynamometry; and PFM activation was assessed using sEMG. RESULTS: The interrater reliability of manometry, dynamometry, and sEMG (both root-mean-square [RMS] and integral average) was high (Lin's Concordance Correlation Coefficient [CCC] = 0.95, 0.93, 0.91, 0.86, respectively), whereas the interrater reliability of both palpation grading scales was low (Cohen's Kappa [k] = 0.27-0.38). The intrarater reliability of manometry (CCC = 0.96), and dynamometry (CCC = 0.96) were high, whereas intrarater reliability of both palpation scales (k = 0.78 for both), and of sEMG (CCC = 0.79 vs 0.80 for RMS vs integral average) was moderate. The Bland-Altman plot showed good inter and intrarater agreement, with little random variability for all instruments. The correlations among palpation, manometry, and dynamometry were moderate (coefficient of determination [r2 ] ranged from 0.52 to 0.75), however, transperineal sEMG amplitude was only weakly correlated with all measures of strength (r2 = 0.23-0.30). CONCLUSIONS: Manometry and dynamometry are more reliable tools than vaginal palpation for the assessment of PFM strength in women with pelvic floor disorders, especially when different raters are involved. The different PFM strength measures used clinically are moderately correlated; whereas, PFM activation recorded using transperineal sEMG is only weakly correlated with PFM strength. Results from perineal sEMG should not be interpreted in the context of reporting PFM strength.

Increasing Interest of Mass Communication Media and the General Public in the Distribution of Tweets About Mental Disorders: Observational Study.

BACKGROUND: The contents of traditional communication media and new internet social media reflect the interests of society. However, certain barriers and a lack of attention towards mental disorders have been previously observed. OBJECTIVE: The objective of this study is to measure the relevance of influential American mainstream media outlets for the distribution of psychiatric information and the interest generated in these topics among their Twitter followers. METHODS: We investigated tweets generated about mental health conditions and diseases among 15 mainstream general communication media outlets in the United States of America between January 2007 and December 2016. Our study strategy focused on identifying several psychiatric terms of primary interest. The number of retweets generated from the selected tweets was also investigated. As a control, we examined tweets generated about the main causes of death in the United States of America, the main chronic neurological degenerative diseases, and HIV. RESULTS: In total, 13,119 tweets about mental health disorders sent by the American mainstream media outlets were analyzed. The results showed a heterogeneous distribution but preferential accumulation for a select number of conditions. Suicide and gender dysphoria accounted for half of the number of tweets sent. Variability in the number of tweets related to each control disease was also found (5998). The number of tweets sent regarding each different psychiatric or organic disease analyzed was significantly correlated with the number of retweets generated by followers (1,030,974 and 424,813 responses to mental health disorders and organic diseases, respectively). However, the probability of a tweet being retweeted differed significantly among the conditions and diseases analyzed. Furthermore, the retweeted to tweet ratio was significantly higher for psychiatric diseases than for the control diseases (odds ratio 1.11, CI 1.07-1.14; P<.001). CONCLUSIONS: American mainstream media outlets and the general public demonstrate a preferential interest for psychiatric diseases on Twitter. The heterogeneous weights given by the media outlets analyzed to the different mental health disorders and conditions are reflected in the responses of Twitter followers.

Can changes in histone acetylation contribute to memory formation?

Neuronal histone acetylation has been postulated to be a mnemonic substrate and a target for memory enhancers and neuropsychiatric drugs. Here we critically evaluate this view and examine the apparent conflict between the proposed instructive role for histone acetylation in memory-related transcription and the insights derived from genomic and genetic studies in other systems. We next discuss the suitability of activity-dependent neuronal histone acetylation as a mnemonic substrate and debate alternative interpretations of current evidence. We believe that further progress in our understanding of the role of histone acetylation and other epigenetic modifications in neuronal plasticity, memory, and neuropsychiatric disorders requires a clear discrimination between cause and effect so that novel epigenetics-related processes can be distinguished from classical transcriptional mechanisms.

Blocking miRNA Biogenesis in Adult Forebrain Neurons Enhances Seizure Susceptibility, Fear Memory, and Food Intake by Increasing Neuronal Responsiveness.

The RNase Dicer is essential for the maturation of most microRNAs, a molecular system that plays an essential role in fine-tuning gene expression. To gain molecular insight into the role of Dicer and the microRNA system in brain function, we conducted 2 complementary RNA-seq screens in the hippocampus of inducible forebrain-restricted Dicer1 mutants aimed at identifying the microRNAs primarily affected by Dicer loss and their targets, respectively. Functional genomics analyses predicted the main biological processes and phenotypes associated with impaired microRNA maturation, including categories related to microRNA biology, signal transduction, seizures, and synaptic transmission and plasticity. Consistent with these predictions, we found that, soon after recombination, Dicer-deficient mice exhibited an exaggerated seizure response, enhanced induction of immediate early genes in response to different stimuli, stronger and more stable fear memory, hyperphagia, and increased excitability of CA1 pyramidal neurons. In the long term, we also observed slow and progressive excitotoxic neurodegeneration. Overall, our results indicate that interfering with microRNA biogenesis causes an increase in neuronal responsiveness and disrupts homeostatic mechanisms that protect the neuron against overactivation, which may explain both the initial and late phenotypes associated with the loss of Dicer in excitatory neurons.

Relationship of the Lateral Rectus Muscle, the Supraorbital Nerve, and Binocular Coordination with Episodic Tension-Type Headaches Frequently Associated with Visual Effort.

Objective: To study the relationship between tension-type headaches and the oculomotor system in terms of binocular coordination, mechanosensitivity of the supraorbital nerve, and myofascial trigger points in the lateral rectus muscle, assessing the influence of visual effort caused by using a computer at work. Design: Observational study with blind evaluation of the response variable. Methods: Two groups were compared: 19 subjects with tension-type headaches and 16 healthy subjects, both exposed to computer use at work. A blinded assessor conducted three tests: measurement of the supraorbital nerve pressure pain threshold using a pressure algometer, evaluation of myofascial trigger points of the lateral rectus using the verbal numerical scale, and assessment of binocular coordination in smooth pursuit eye movements using an innovative video-oculography system. Tests were performed before work began and four hours later, and subjects in the headache group were examined when they presented a headache score of less than or equal to 3 on the verbal numerical scale. Results: The headache group presented a greater sensitivity of the supraorbital nerve and greater local and referred pain of the lateral rectus ( P < 0.05). Visual effort caused a significant worsening of these variables in both groups. However, binocular coordination after visual effort was only significantly affected in the headache group ( P < 0.05), primarily in horizontal movements. Conclusions: The finding of a higher alteration of the sensitivity of the supraorbital nerve, the myofascial trigger points of the lateral rectus, binocular coordination, and the significant influence of visual effort in patients with tension-type headaches suggest a new clinical perspective for problems related to tension-type headaches.

Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury.

The clinical challenge in acute injury as in traumatic brain injury (TBI) is to halt the delayed neuronal loss that occurs hours and days after the insult. Here we report that the activation of CREB-dependent transcription in reactive astrocytes prevents secondary injury in cerebral cortex after experimental TBI. The study was performed in a novel bitransgenic mouse in which a constitutively active CREB, VP16-CREB, was targeted to astrocytes with the Tet-Off system. Using histochemistry, qPCR, and gene profiling we found less neuronal death and damage, reduced macrophage infiltration, preserved mitochondria, and rescued expression of genes related to mitochondrial metabolism in bitransgenic mice as compared to wild type littermates. Finally, with meta-analyses using publicly available databases we identified a core set of VP16-CREB candidate target genes that may account for the neuroprotective effect. Enhancing CREB activity in astrocytes thus emerges as a novel avenue in acute brain post-injury therapeutics.

Specific promoter deacetylation of histone H3 is conserved across mouse models of Huntington's disease in the absence of bulk changes.

Defective epigenetic regulation has been postulated as a possible cause for the extensive and premature transcriptional dysregulation observed in experimental models of Huntington's disease (HD). In this study, we extended our observations in the N171-82Q mouse strain relating to the limited impact of polyQ pathology on the global histone acetylation to other animal and cellular models of HD, namely the R6/1 and YAC128 strains, striatal-electroporated mice, primary neuronal cultures and stably transfected PC12 cells. In the absence of bulk chromatin changes, we nonetheless documented histone deacetylation events at the transcription start sites (TSS) of genes relevant to neuronal functions (e.g., Rin1, Plk5, Igfbp5, Eomes, and Fos). In some instances, these local deficits were associated with an increased susceptibility to transcriptional dysregulation (e.g., Camk1g and Rasl11b) and the defective trimethylation of histone H3 at lysine 4 (H3K4me3), another covalent modification of histone tails that is related to active transcription and is also altered in HD. Overall, this study provides further insight into the nature and extent of epigenetic dysregulation in HD pathology.

Role of Dicer and the miRNA system in neuronal plasticity and brain function.

MicroRNAs (miRNAs) are small regulatory non-coding RNAs that contribute to fine-tuning regulation of gene expression by mRNA destabilization and/or translational repression. Their abundance in the nervous system, their temporally and spatially regulated expression and their ability to respond in an activity-dependent manner make miRNAs ideal candidates for the regulation of complex processes in the brain, including neuronal plasticity, memory formation and neural development. The conditional ablation of the RNase III Dicer, which is essential for the maturation of most miRNAs, is a useful model to investigate the effect of the loss of the miRNA system, as a whole, in different tissues and cellular types. In this review, we first provide an overview of Dicer function and structure, and discuss outstanding questions concerning the role of miRNAs in the regulation of gene expression and neuronal function, to later focus on the insight derived from studies in which the genetic ablation of Dicer was used to determine the role of the miRNA system in the nervous system. In particular, we highlight the collective role of miRNAs fine-tuning plasticity-related gene expression and providing robustness to neuronal gene expression networks.

cAMP-responsive element-binding protein (CREB) and cAMP co-regulate activator protein 1 (AP1)-dependent regeneration-associated gene expression and neurite growth.

To regenerate damaged axons, neurons must express a cassette of regeneration-associated genes (RAGs) that increases intrinsic growth capacity and confers resistance to extrinsic inhibitory cues. Here we show that dibutyrl-cAMP or forskolin combined with constitutive-active CREB are superior to either agent alone in driving neurite growth on permissive and inhibitory substrates. Of the RAGs examined, only arginase 1 (Arg1) expression correlated with the increased neurite growth induced by the cAMP/CREB combination, both of which were AP1-dependent. This suggests that cAMP-induced AP1 activity is necessary and interacts with CREB to drive expression of RAGs relevant for regeneration and demonstrates that combining a small molecule (cAMP) with an activated transcription factor (CREB) stimulates the gene expression necessary to enhance axonal regeneration.

CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement.

The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CREB-binding protein (CBP), a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioural adaptations to environmental enrichment (EE). Morphological and behavioural analyses demonstrated that EE ameliorates deficits associated to CBP deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-mediated enhancement of spatial navigation and pattern separation ability. These defects correlated with an attenuation of the transcriptional programme induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics.

The number of circulating monocytes as biomarkers of the clinical response to methotrexate in untreated patients with rheumatoid arthritis.

BACKGROUND: The aim of this work was to analyze the number and distribution of circulating monocytes, and of their CD14(+high)CD16(-), CD14(+high)CD16(+) and CD14(+low)CD16(+) subset cells, in treatment-naive patients with rheumatoid arthritis (RA), and to determine their value in predicting the clinical response to methotrexate (MTX) treatment. METHODS: This prospective work investigated the number of circulating monocytes, and the numbers of CD14(+high)CD16(-), CD14(+high)CD16(+) and CD14(+low)CD16(+) subset cells, in 52 untreated patients with RA before MTX treatment, and at 3 and 6 months into treatment, using flow cytometry. RESULTS: The absolute number of circulating monocytes, and the numbers of CD14(+high)CD16(-), CD14(+high)CD16(+) and CD14(+low)CD16(+) subset cells, were significantly higher in MTX non-responders than in responders and healthy controls before starting and throughout treatment. Responders showed normal numbers of monocytes, and of their subset cells, over the study period. The pre-treatment absolute number of circulating monocytes, and the numbers of CD14(+high)CD16(-) and CD14(+high)CD16(+) subset cells, were found to be predictive of the clinical response to MTX, with a sensitivity and specificity of >70% and >88%, respectively. CONCLUSIONS: Treatment-naive patients with RA showed an anomalous distribution of circulating monocyte subsets, and an anomalous number of cells in each subset. A higher pre-treatment number of circulating monocytes, and higher numbers of CD14(+high)CD16(-) and CD14(+high)CD16(+) subset cells, predict a reduced clinical response to MTX in untreated patients with RA.

Genomic targets, and histone acetylation and gene expression profiling of neural HDAC inhibition.

Histone deacetylase inhibitors (HDACis) have been shown to potentiate hippocampal-dependent memory and synaptic plasticity and to ameliorate cognitive deficits and degeneration in animal models for different neuropsychiatric conditions. However, the impact of these drugs on hippocampal histone acetylation and gene expression profiles at the genomic level, and the molecular mechanisms that underlie their specificity and beneficial effects in neural tissue, remains obscure. Here, we mapped four relevant histone marks (H3K4me3, AcH3K9,14, AcH4K12 and pan-AcH2B) in hippocampal chromatin and investigated at the whole-genome level the impact of HDAC inhibition on acetylation profiles and basal and activity-driven gene expression. HDAC inhibition caused a dramatic histone hyperacetylation that was largely restricted to active loci pre-marked with H3K4me3 and AcH3K9,14. In addition, the comparison of Chromatin immunoprecipitation sequencing and gene expression profiles indicated that Trichostatin A-induced histone hyperacetylation, like histone hypoacetylation induced by histone acetyltransferase deficiency, had a modest impact on hippocampal gene expression and did not affect the transient transcriptional response to novelty exposure. However, HDAC inhibition caused the rapid induction of a homeostatic gene program related to chromatin deacetylation. These results illuminate both the relationship between hippocampal gene expression and histone acetylation and the mechanism of action of these important neuropsychiatric drugs.