An orchestrated intron retention program in meiosis controls timely usage of transcripts during germ cell differentiation

Global transcriptome reprogramming during sper-matogenesis ensures timely expression of factors in each phase of male germ cell differentiation. Sper-matocytes and spermatids require particularly exten-sive reprogramming of gene expression to switch from mitosis to meiosis and to support gamete morphogenesis. Here, we uncovered an extensive alternative splicing program during this transmeiotic differentiation. Notably, intron retention was largely the most enriched pattern, with spermatocytes showing generally higher levels of retention compared with spermatids. Retained introns are characterized by weak splice sites and are enriched in genes with strong relevance for gamete func-tion. Meiotic intron-retaining transcripts (IRTs) were exclusively localized in the nucleus. However, differ-ently from other developmentally regulated IRTs, they are stable RNAs, showing longer half-life than properly spliced transcripts. Strikingly, fate-mapping experiments revealed that IRTs are recruited onto polyribosomes days after synthesis. These studies reveal an unexpected function for regulated intron retention in modulation of the timely expression of select transcripts during spermatogenesis

The role of short-term weather conditions in temporal dynamics of fire regime features in mainland Spain

In this paper we investigate spatial-temporal associations of fire weather danger and fire regime features from 1979 to 2013. We analyze monthly time series of fire activity (number of fires and burned area) and fire weather danger rating indices (Fire Weather Index, Burning Index and Forest Fire Danger Index) at two spatial scales: (i) regionally, splitting the Spanish mainland into Northwest, Hinterland and Mediterranean regions; and (ii) locally, using the EMCWF grid. All analyses are based on decomposing time series to retrieve differential indicators of seasonal cycles, temporal evolution and anomalies. At regional scale we apply lagged cross-correlation analysis (4 lags or months before fire) to explore seasonal associations; and trend detection tests on the temporal evolution component. At the local scale, we calculate Pearson correlation coefficients between each individual index and the 18 possible fire-activity subsets according to fire size (all sizes, > 1 ha and > 100 ha) and source of ignition (natural, unintended and arson); this analysis is applied to both cycles, temporal and anomalies series. Results suggest that weather controls seasonal fire activity although it has limited influence on temporal evolution, i.e. trends. Stronger associations are detected in the number of fires in the Northwest and Hinterland regions compared to the Mediterranean, which has desynchronized from weather since 1994. Cross-correlation analysis revealed significant fire-weather associations in the Hinterland and Mediterranean, extending up to two months prior fire ignition. On the other hand, the association between temporal trends and weather is weaker, being negative along the Mediterranean and even significant in the case of burned area. The spatial disaggregation into grid cells reveals different spatial patterns across fire-activity subsets. Again, the connection at seasonal level is noticeable, especially in natural-caused fires. In turn, human-related wildfires are occasionally found independent from weather in some areas along the northern coast or the Ebro basin. In any case, this effect diminishes as the size of the fire increases. Our work suggests that for some regions of mainland Spain, these fire danger indices could provide useful information about upcoming fire activity up to two months ahead of time and this information could be used to better inform wildland fire prevention and suppression activities

A Upf3b-mutant mouse model with behavioral and neurogenesis defects.

Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B-regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation and disease. We suggest Upf3b-null mice serve as a novel model system to decipher cellular and molecular defects underlying ID and neurodevelopmental disorders

Recruitment of ethnic minority patients to a cardiac rehabilitation trial: The Birmingham Rehabilitation Uptake Maximisation (BRUM) study [ISRCTN72884263]

Background: Concerns have been raised about low participation rates of people from minority ethnic groups in clinical trials. However, the evidence is unclear as many studies do not report the ethnicity of participants and there is insufficient information about the reasons for ineligibility by ethnic group. Where there are data, there remains the key question as to whether ethnic minorities more likely to be ineligible (e.g. due to language) or decline to participate. We have addressed these questions in relation to the Birmingham Rehabilitation Uptake Maximisation (BRUM) study, a randomized controlled trial (RCT) comparing a home-based with a hospital-based cardiac rehabilitation programme in a multi-ethnic population in the UK. Methods: Analysis of the ethnicity, age and sex of presenting and recruited subjects for a trial of cardiac rehabilitation in the West-Midlands, UK. Participants: 1997 patients presenting post-myocardial infarction, percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery. Data collected: exclusion rates, reasons for exclusion and reasons for declining to participate in the trial by ethnic group. Results: Significantly more patients of South Asian ethnicity were excluded (52% of 'South Asian' v 36% 'White European' and 36% 'Other', p < 0.001). This difference in eligibility was primarily due to exclusion on the basis of language (i.e. the inability to speak English or Punjabi). Of those eligible, similar proportions were recruited from the different ethnic groups (white, South Asian and other). There was a marked difference in eligibility between people of Indian, Pakistani or Bangladeshi origin

Identifying inhibitors of epithelial&#8211;mesenchymal plasticity using a network topology-based approach

Metastasis is the cause of over 90% of cancer-related deaths. Cancer cells undergoing metastasis can switch dynamically between different phenotypes, enabling them to adapt to harsh challenges, such as overcoming anoikis and evading immune response. This ability, known as phenotypic plasticity, is crucial for the survival of cancer cells during metastasis, as well as acquiring therapy resistance. Various biochemical networks have been identified to contribute to phenotypic plasticity, but how plasticity emerges from the dynamics of these networks remains elusive. Here, we investigated the dynamics of various regulatory networks implicated in Epithelial-mesenchymal plasticity (EMP)-an important arm of phenotypic plasticity-through two different mathematical modelling frameworks: a discrete, parameter-independent framework (Boolean) and a continuous, parameter-agnostic modelling framework (RACIPE). Results from either framework in terms of phenotypic distributions obtained from a given EMP network are qualitatively similar and suggest that these networks are multi-stable and can give rise to phenotypic plasticity. Neither method requires specific kinetic parameters, thus our results emphasize that EMP can emerge through these networks over a wide range of parameter sets, elucidating the importance of network topology in enabling phenotypic plasticity. Furthermore, we show that the ability to exhibit phenotypic plasticity correlates positively with the number of positive feedback loops in a given network. These results pave a way toward an unorthodox network topology-based approach to identify crucial links in a given EMP network that can reduce phenotypic plasticity and possibly inhibit metastasis-by reducing the number of positive feedback loops

Measurement and application of electron stripping of ultrarelativistic 208Pb81+^{208}\textrm{Pb}^{81+}

New measurements of the stripping cross-section for ultrarelativistic hydrogen-like lead ions passing through aluminium and silicon have been performed at the Advanced Wakefield experiment at CERN. Agreement with existing measurements and theory has been obtained. Improvements in terms of electron beam quality and ion beam diagnostic capability, as well as further applications of such an electron beam, are discussed

Evaluation of a standard provision versus an autonomy promotive exercise referral programme: rationale and study design

Background The National Institute of Clinical Excellence in the UK has recommended that the effectiveness of ongoing exercise referral schemes to promote physical activity should be examined in research trials. Recent empirical evidence in health care and physical activity promotion contexts provides a foundation for testing the utility of a Self Determination Theory (SDT) -based exercise referral consultation. Methods/Design Design: An exploratory cluster randomised controlled trial comparing standard provision exercise on prescription with a Self Determination Theory-based (SDT) exercise on prescription intervention. Participants: 347 people referred to the Birmingham Exercise on Prescription scheme between November 2007 and July 2008. The 13 exercise on prescription sites in Birmingham were randomised to current practice (n=7) or to the SDT-based intervention (n=6). Outcomes measured at 3 and 6-months: Minutes of moderate or vigorous physical activity per week assessed using the 7-day Physical Activity Recall; physical health: blood pressure and weight; health status measured using the Dartmouth CO-OP charts; anxiety and depression measured by the Hospital Anxiety and Depression Scale and vitality measured by the subjective vitality score; motivation and processes of change: perceptions of autonomy support from the advisor, satisfaction of the needs for competence, autonomy, and relatedness via physical activity, and motivational regulations for exercise. Discussion This trial will determine whether an exercise referral programme based on Self Determination Theory increases physical activity and other health outcomes compared to a standard programme and will test the underlying SDT-based process model (perceived autonomy support, need satisfaction, motivation regulations, outcomes) via structural equation modelling. Trial registration The trial is registered as Current Controlled trials ISRCTN07682833

PHYTOCHEMICAL COMPOSITION AND ANTIMICROBIAL EFFICACY OF ACHYRANTHES ASPERA STEM AND ROOT EXTRACTS: AN IN VITRO STUDY

The aim of this study was to investigate the antimicrobial efficacy of Achyranthes aspera (Prickly Chaff) and to study their effectiveness&nbsp; against the test microorganisms. Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa were selected as test microorganisms.&nbsp; The Achyranthes aspera (Prickly Chaff) plants were gathered by the researchers at the Adventist University of the Philippines campus. The roots and stem of Achyranthes aspera were dried using a multi-commodity heat pump dryer.&nbsp; The dried powdered roots and stem were sent to the Chemical and Testing Division of the Department of Science and Technology (DOST) for extraction. The generated root and stem extracts were tested for phytochemical analysis and antimicrobial&nbsp; activity. The antimicrobial testing conducted to test the inhibitory activity of the Achyranthes Aspera roots and stem extract on the three microorganisms using the Disc agar diffusion method or Kirby – Bauer Test. Levofloxacin and Clindamycin 2 ug/ml were used as positive control of standard drugs. The results of the phytochemical&nbsp; test showed the following plant constituents: flavonoids and triterpenes which are the most abundant, followed by saponins and glycosides which showed the moderate amount and lastly, sterols, tannins, and alkaloids which revealed traces in Achyranthes Aspera (Prickly Chaff) roots and stem extract. For the antimicrobial activity test, the results revealed that the Achyranthes Aspera (Prickly Chaff) roots and stem extract produced a zone inhibition of 10 mm and complete inhibitory activity with mild reactivity against Escherichia coli and Pseudomonas aeruginosa. However, it produced no inhibitory activity with no reactivity against Staphylococcus aureus. &nbsp

Characterization of Blood Immune Cells in Patients With Decompensated Cirrhosis Including ACLF

Background and Aims: Patients with cirrhosis and acute-on-chronic liver failure (ACLF) have immunosuppression, indicated by an increase in circulating immune-deficient monocytes. The aim of this study was to investigate simultaneously the major blood-immune cell subsets in these patients. Material and Methods: Blood taken from 67 patients with decompensated cirrhosis (including 35 critically ill with ACLF in the intensive care unit), and 12 healthy subjects, was assigned to either measurements of clinical blood counts and microarray (genomewide) analysis of RNA expression in whole-blood; microarray (genomewide) analysis of RNA expression in blood neutrophils; or assessment of neutrophil antimicrobial functions. Results: Several features were found in patients with ACLF and not in those without ACLF. Indeed, clinical blood count measurements showed that patients with ACLF were characterized by leukocytosis, neutrophilia, and lymphopenia. Using the CIBERSORT method to deconvolute the whole-blood RNA-expression data, revealed that the hallmark of ACLF was the association of neutrophilia with increased proportions of macrophages M0-like monocytes and decreased proportions of memory lymphocytes (of B-cell, CD4 T-cell lineages), CD8 T cells and natural killer cells. Microarray analysis of neutrophil RNA expression revealed that neutrophils from patients with ACLF had a unique phenotype including induction of glycolysis and granule genes, and downregulation of cell-migration and cell-cycle genes. Moreover, neutrophils from these patients had defective production of the antimicrobial superoxide anion. Conclusions: Genomic analysis revealed that, among patients with decompensated cirrhosis, those with ACLF were characterized by dysregulation of blood immune cells, including increases in neutrophils (that had a unique phenotype) and macrophages M0-like monocytes, and depletion of several lymphocyte subsets (including memory lymphocytes). All these lymphocyte alterations, along with defective neutrophil superoxide anion production, may contribute to immunosuppression in ACLF, suggesting targets for future therapies