A physiologically-motivated compartment-based model of the effect of inhaled hypertonic saline on mucociliary clearance and liquid transport in cystic fibrosis

Background: Cystic Fibrosis (CF) lung disease is characterized by liquid hyperabsorption, airway surface dehydration, and impaired mucociliary clearance (MCC). Herein, we present a compartment-based mathematical model of the airway that extends the resolution of functional imaging data. Methods: Using functional imaging data to inform our model, we developed a system of mechanism-motivated ordinary differential equations to describe the mucociliary clearance and absorption of aerosolized radiolabeled particle and small molecules probes from human subjects with and without CF. We also utilized a novel imaging metric in vitro to gauge the fraction of airway epithelial cells that have functional ciliary activity. Results: This model, and its incorporated kinetic rate parameters, captures the MCC and liquid dynamics of the hyperabsorptive state in CF airways and the mitigation of that state by hypertonic saline treatment. Conclusions: We postulate, based on the model structure and its ability to capture clinical patient data, that patients with CF have regions of airway with diminished MCC function that can be recruited with hypertonic saline treatment. In so doing, this model structure not only makes a case for durable osmotic agents used in lung-region specific treatments, but also may provide a possible clinical endpoint, the fraction of functional ciliated airway

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Measurement of the top quark mass using the matrix element technique in dilepton final states

We present a measurement of the top quark mass in pp¯ collisions at a center-of-mass energy of 1.96 TeV at the Fermilab Tevatron collider. The data were collected by the D0 experiment corresponding to an integrated luminosity of 9.7  fb−1. The matrix element technique is applied to tt¯ events in the final state containing leptons (electrons or muons) with high transverse momenta and at least two jets. The calibration of the jet energy scale determined in the lepton+jets final state of tt¯ decays is applied to jet energies. This correction provides a substantial reduction in systematic uncertainties. We obtain a top quark mass of mt=173.93±1.84  GeV

Double Dissociation of Amygdala and Hippocampal Contributions to Trace and Delay Fear Conditioning

A key finding in studies of the neurobiology of learning memory is that the amygdala is critically involved in Pavlovian fear conditioning. This is well established in delay-cued and contextual fear conditioning; however, surprisingly little is known of the role of the amygdala in trace conditioning. Trace fear conditioning, in which the CS and US are separated in time by a trace interval, requires the hippocampus and prefrontal cortex. It is possible that recruitment of cortical structures by trace conditioning alters the role of the amygdala compared to delay fear conditioning, where the CS and US overlap. To investigate this, we inactivated the amygdala of male C57BL/6 mice with GABA A agonist muscimol prior to 2-pairing trace or delay fear conditioning. Amygdala inactivation produced deficits in contextual and delay conditioning, but had no effect on trace conditioning. As controls, we demonstrate that dorsal hippocampal inactivation produced deficits in trace and contextual, but not delay fear conditioning. Further, pre- and post-training amygdala inactivation disrupted the contextual but the not cued component of trace conditioning, as did muscimol infusion prior to 1- or 4-pairing trace conditioning. These findings demonstrate that insertion of a temporal gap between the CS and US can generate amygdala-independent fear conditioning. We discuss the implications of this surprising finding for current models of the neural circuitry involved in fear conditioning

Ciprofloxacin, diclofenac, ibuprofen and 17α-ethinylestradiol differentially affect the activity of acetogens and methanogens in anaerobic communities

Pharmaceutical compounds end up in wastewater treatment plants but little is known on their effect towards the different microbial groups in anaerobic communities. In this work, the effect of the antibiotic Ciprooxacin (CIP), the non-steroidal anti-inammatory drugs Diclofenac (DCF) and Ibuprofen (IBP), and the hormone 17-ethinylestradiol (EE2), on the activity of acetogens and methanogens in anaerobic communities, was investigated. Microbial communities were more affected by CIP, followed by EE2, DCF and IBP, but the response of the different microbial groups was dissimilar. For concentrations of 0.01 to 0.1 mg/L, the specic methanogenic activity was not affected. Acetogenic bacteria were sensitive to CIP concentrations above 1 mg/L, while DCF and EE2 toxicity was only detected for concentrations higher than 10 mg/L, and IBP had no effect in all concentrations tested. Acetoclastic methanogens showed higher sensitivity to the presence of these micropollutants, being affect by all the tested pharmaceutical compounds although at different degrees. Hydrogenotrophic methanogens were not affected by any concentration, indicating their lower sensitivity to these compounds when compared to acetoclasts and acetogens.e Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2019 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. Ana Rita Silva holds a Grant from FCT, reference SFRH/BD/131905/2017info:eu-repo/semantics/publishedVersio

Oral and anal sex practices among high school youth in Addis Ababa, Ethiopia

<p>Abstract</p> <p>Background</p> <p>Understanding the full range of sexual behaviors of young people is crucial in developing appropriate interventions to prevent and control sexually transmitted infections including HIV. However, such information is meager in developing countries. The objective of this study was to describe oral and anal sex practices and identify associated factors among high school youth.</p> <p>Methods</p> <p>A cross-sectional study was conducted among high school youth in Addis Ababa, Ethiopia. A multi-stage sampling procedure was followed to select a representative sample of school youth. The total sample size for this study was 3840. Data were collected using a self-administered questionnaire. Data analysis was guided by the ecological framework.</p> <p>Results</p> <p>The overall proportion of people who reported ever having oral sex was 5.4% (190) and that of anal sex was 4.3% (154). Of these 51.6% (98) had oral sex and 57.1% (87) had anal sex in the past 12 months. Multiple partnerships were reported by 61.2% of the respondents who had oral sex and 51.1% of students practicing anal sex. Consistent condom use was reported by 12.2% of those practicing oral sex and 26.1% of anal sex. Reasons for oral and anal sex included prevention of pregnancy, preserving virginity, and reduction of HIV and STIs transmission. Oral sex practice was strongly and significantly associated with perception of best friends engagement in oral sex (AOR = 5.7; 95% CI 3.6-11.2) and having illiterate mothers (AOR = 11.5; 95%CI 6.4-18.5). Similarly, anal sex practice was strongly and significantly associated with favorable attitude towards anal sex (AOR = 6.2; 95%CI 3.8-12.4), and perceived best friends engagement in anal sex (AOR = 9.7; 95%CI 5.4-17.7).</p> <p>Conclusion</p> <p>Considerable proportion of adolescents had engaged in oral and anal sex practices. Multiple sexual partnerships were common while consistent condom use was low. Sexual health education and behavior change communication strategies need to cover a full range of sexual practices.</p

Psychoactive Pharmaceuticals Induce Fish Gene Expression Profiles Associated with Human Idiopathic Autism

Idiopathic autism, caused by genetic susceptibility interacting with unknown environmental triggers, has increased dramatically in the past 25 years. Identifying environmental triggers has been difficult due to poorly understood pathophysiology and subjective definitions of autism. The use of antidepressants by pregnant women has been associated with autism. These and other unmetabolized psychoactive pharmaceuticals (UPPs) have also been found in drinking water from surface sources, providing another possible exposure route and raising questions about human health consequences. Here, we examined gene expression patterns of fathead minnows treated with a mixture of three psychoactive pharmaceuticals (fluoxetine, venlafaxine & carbamazepine) in dosages intended to be similar to the highest observed conservative estimates of environmental concentrations. We conducted microarray experiments examining brain tissue of fish exposed to individual pharmaceuticals and a mixture of all three. We used gene-class analysis to test for enrichment of gene sets involved with ten human neurological disorders. Only sets associated with idiopathic autism were unambiguously enriched. We found that UPPs induce autism-like gene expression patterns in fish. Our findings suggest a new potential trigger for idiopathic autism in genetically susceptible individuals involving an overlooked source of environmental contamination

Turbot reovirus (SMReV) genome encoding a FAST protein with a non-AUG start site

<p>Abstract</p> <p>Background</p> <p>A virus was isolated from diseased turbot <it>Scophthalmus maximus </it>in China. Biophysical and biochemical assays, electron microscopy, and genome electrophoresis revealed that the virus belonged to the genus <it>Aquareovirus</it>, and was named <it>Scophthalmus maximus </it>reovirus (SMReV). To the best of our knowledge, no complete sequence of an aquareovirus from marine fish has been determined. Therefore, the complete characterization and analysis of the genome of this novel aquareovirus will facilitate further understanding of the taxonomic distribution of aquareovirus species and the molecular mechanism of its pathogenesis.</p> <p>Results</p> <p>The full-length genome sequences of SMReV were determined. It comprises eleven dsRNA segments covering 24,042 base pairs and has the largest S4 genome segment in the sequenced aquareoviruses. Sequence analysis showed that all of the segments contained six conserved nucleotides at the 5' end and five conserved nucleotides at the 3' end (5'-GUUUUA ---- UCAUC-3'). The encoded amino acid sequences share the highest sequence identities with the respective proteins of aquareoviruses in species group <it>Aquareovirus </it>A. Phylogenetic analysis based on the major outer capsid protein VP7 and RNA-dependent RNA polymerase were performed. Members in <it>Aquareovirus </it>were clustered in two groups, one from fresh water fish and the other from marine fish. Furthermore, a fusion associated small transmembrane (FAST) protein NS22, which is translated from a non-AUG start site, was identified in the S7 segment.</p> <p>Conclusions</p> <p>This study has provided the complete genome sequence of a novel isolated aquareovirus from marine fish. Amino acids comparison and phylogenetic analysis suggested that SMReV was a new aquareovirus in the species group <it>Aquareovirus </it>A. Phylogenetic analysis among aquareoviruses revealed that VP7 could be used as a reference to divide the aquareovirus from hosts in fresh water or marine. In addition, a FAST protein with a non-AUG start site was identified, which partially contributed to the cytopathic effect caused by the virus infection. These results provide new insights into the virus-host and virus-environment interactions.</p

Differential roles of the Drosophila EMT-inducing transcription factors Snail and Serpent in driving primary tumour growth.

Several transcription factors have been identified that activate an epithelial-to-mesenchymal transition (EMT), which endows cells with the capacity to break through basement membranes and migrate away from their site of origin. A key program in development, in recent years it has been shown to be a crucial driver of tumour invasion and metastasis. However, several of these EMT-inducing transcription factors are often expressed long before the initiation of the invasion-metastasis cascade as well as in non-invasive tumours. Increasing evidence suggests that they may promote primary tumour growth, but their precise role in this process remains to be elucidated. To investigate this issue we have focused our studies on two Drosophila transcription factors, the classic EMT inducer Snail and the Drosophila orthologue of hGATAs4/6, Serpent, which drives an alternative mechanism of EMT; both Snail and GATA are specifically expressed in a number of human cancers, particularly at the invasive front and in metastasis. Thus, we recreated conditions of Snail and of Serpent high expression in the fly imaginal wing disc and analysed their effect. While either Snail or Serpent induced a profound loss of epithelial polarity and tissue organisation, Serpent but not Snail also induced an increase in the size of wing discs. Furthermore, the Serpent-induced tumour-like tissues were able to grow extensively when transplanted into the abdomen of adult hosts. We found the differences between Snail and Serpent to correlate with the genetic program they elicit; while activation of either results in an increase in the expression of Yorki target genes, Serpent additionally activates the Ras signalling pathway. These results provide insight into how transcription factors that induce EMT can also promote primary tumour growth, and how in some cases such as GATA factors a ‘multi hit’ effect may be achieved through the aberrant activation of just a single gene

High recombination rates and hotspots in a Plasmodium falciparum genetic cross

Using the universal P2/P8 primers, we were able to obtain the gene segments of chromo-helicase-DNA binding protein (CHD)-Z and CHD-W from ten species of ardeid birds including Chinese egret (Egretta eulophotes), little egret (E. garzetta), eastern reef egret (E. sacra), great egret (Ardea alba), grey heron (A. cinerea), Chinese pond-heron (Ardeola bacchus), cattle egret (Bubulcus ibis), black-crowned night-heron (Nycticorax nycticorax), cinnamon bittern (Ixobrychus cinnamomeus) and yellow bittern (I. sinensis). Based on conserved regions inside the P2/P8-derived sequences, we designed new PCR primers for sex identification in these ardeid species. Using agarose gel electrophoresis, the PCR products showed two bands for females (140 bp derived from CHD-W and the other 250 bp from CHD-ZW), whereas the males showed only the 250 bp band. The results indicated that our new primers could be used for accurate and convenient sex identification in ardeid species.National Natural Science Foundation of China[30970380, 40876077]; Fujian Natural Science Foundation of China[2008S0007, 2009J01195