Comparing adenoma and polyp miss rates for total underwater colonoscopy versus standard CO2: a randomized controlled trial using a tandem colonoscopy approach

Background and Aims Although water exchange may improve adenoma detection when compared to CO2, it is unclear whether water is a better medium to fill the lumen during withdrawal and visualize the mucosa. Total underwater (TUC) involves the use of water exchange with the air valve off during insertion followed by the inspection of the mucosa under water. Our goal was to use a tandem colonoscopy design to compare miss rates for TUC to standard CO2 for polyps and adenomas. Methods We randomized participants (NCT03231917; clinicaltrials.gov) to undergo tandem colonoscopies using TUC or CO2 first. In TUC, water exchange was performed during insertion and withdrawal was performed under water. For the CO2 colonoscopy both insertion and withdrawal were performed with CO2. The main outcomes were miss rates for polyps and adenomas for the first examination calculated as the number of additional polyps/adenomas detected during the second examination divided by the total number of polyps/adenomas detected for both examinations. Inspection times were calculated by subtracting time for polypectomy and care was given to keep the times equal for both examinations. Results A total of 121 participants were randomized with 61 having CO2 first. The overall miss rate for polyps was higher for the TUC first group (81/237; 34%) as compared to the CO2 first cohort (57/264; 22%)(p=0.002). In addition, the overall miss rate for all adenomas was higher for the TUC first group (52/146; 36%) as compared with the CO2 group (37/159; 23%) (p=0.025). However, 1 of the 3 endoscopists had higher polyp/adenoma miss rates for CO2 but these were not statistically significant differences. The insertion time was longer for TUC than CO2. After adjusting for times, participant characteristics and bowel preparation, the miss rate for polyps was higher for TUC than CO2. Conclusions We found that TUC had an overall higher polyp and adenoma miss rate than colonoscopy performed with CO2, and TUC took longer to perform. However, TUC may benefit some endoscopists, an issue that requires further study

Toxoplasma gondii AP2IX-4 Regulates Gene Expression during Bradyzoite Development

Toxoplasma gondii is a protozoan parasite of great importance to human and animal health. In the host, this obligate intracellular parasite persists as a tissue cyst that is imperceptible to the immune response and unaffected by current therapies. The tissue cysts facilitate transmission through predation and give rise to chronic cycles of toxoplasmosis in immunocompromised patients. Transcriptional changes accompany conversion of the rapidly replicating tachyzoites into the encysted bradyzoites, and yet the mechanisms underlying these alterations in gene expression are not well defined. Here we show that AP2IX-4 is a nuclear protein exclusively expressed in tachyzoites and bradyzoites undergoing division. Knockout of AP2IX-4 had no discernible effect on tachyzoite replication but resulted in a reduced frequency of tissue cyst formation following alkaline stress induction-a defect that is reversible by complementation. AP2IX-4 has a complex role in regulating bradyzoite gene expression, as the levels of many bradyzoite mRNAs dramatically increased beyond those seen under conditions of normal stress induction in AP2IX-4 knockout parasites exposed to alkaline media. The loss of AP2IX-4 also resulted in a modest virulence defect and reduced cyst burden in chronically infected mice, which was reversed by complementation. These findings illustrate that the transcriptional mechanisms responsible for tissue cyst development operate across the intermediate life cycle from the dividing tachyzoite to the dormant bradyzoite. IMPORTANCEToxoplasma gondii is a single-celled parasite that persists in its host as a transmissible tissue cyst. How the parasite converts from its replicative form to the bradyzoites housed in tissue cysts is not well understood, but the process clearly involves changes in gene expression. Here we report that parasites lacking a cell cycle-regulated transcription factor called AP2IX-4 display reduced frequencies of tissue cyst formation in culture and in a mouse model of infection. Parasites missing AP2IX-4 lose the ability to regulate bradyzoite genes during tissue cyst development. Expressed in developing bradyzoites still undergoing division, AP2IX-4 may serve as a useful marker in the study of transitional forms of the parasite

SWI/SNF-like chromatin remodeling factor Fun30 supports point centromere function in S. cerevisiae

Budding yeast centromeres are sequence-defined point centromeres and are, unlike in many other organisms, not embedded in heterochromatin. Here we show that Fun30, a poorly understood SWI/SNF-like chromatin remodeling factor conserved in humans, promotes point centromere function through the formation of correct chromatin architecture at centromeres. Our determination of the genome-wide binding and nucleosome positioning properties of Fun30 shows that this enzyme is consistently enriched over centromeres and that a majority of CENs show Fun30-dependent changes in flanking nucleosome position and/or CEN core micrococcal nuclease accessibility. Fun30 deletion leads to defects in histone variant Htz1 occupancy genome-wide, including at and around most centromeres. FUN30 genetically interacts with CSE4, coding for the centromere-specific variant of histone H3, and counteracts the detrimental effect of transcription through centromeres on chromosome segregation and suppresses transcriptional noise over centromere CEN3. Previous work has shown a requirement for fission yeast and mammalian homologs of Fun30 in heterochromatin assembly. As centromeres in budding yeast are not embedded in heterochromatin, our findings indicate a direct role of Fun30 in centromere chromatin by promoting correct chromatin architecture

Characterizing the efficacy of methods to subtract terrestrial transient noise near gravitational wave events and the effects on parameter estimation

We investigate the impact of transient noise artifacts, or {\it glitches}, on gravitational wave inference, and the efficacy of data cleaning procedures in recovering unbiased source properties. Due to their time-frequency morphology, broadband glitches demonstrate moderate to significant biasing of posterior distributions away from true values. In contrast, narrowband glitches have negligible biasing effects owing to distinct signal and glitch morphologies. We inject simulated binary black hole signals into data containing three common glitch types from past LIGO-Virgo observing runs, and reconstruct both signal and glitch waveforms using {\tt BayesWave}, a wavelet-based Bayesian analysis. We apply the standard LIGO-Virgo-KAGRA deglitching procedure to the detector data - we subtract the glitch waveform estimated by the joint {\tt BayesWave} inference before performing parameter estimation with detailed compact binary waveform models. We find that this deglitching effectively mitigates bias from broadband glitches, with posterior peaks aligning with true values post deglitching. This provides a baseline validation of existing techniques, while demonstrating waveform reconstruction improvements to the Bayesian algorithm for robust astrophysical characterization in glitch-prone detector data.Comment: 22 pages, 17 figure

phot1 inhibition of ABCB19 primes lateral auxin fluxes in the shoot apex required for phototropism

It is well accepted that lateral redistribution of the phytohormone auxin underlies the bending of plant organs towards light. In monocots, photoreception occurs at the shoot tip above the region of differential growth. Despite more than a century of research, it is still unresolved how light regulates auxin distribution and where this occurs in dicots. Here, we establish a system in Arabidopsis thaliana to study hypocotyl phototropism in the absence of developmental events associated with seedling photomorphogenesis. We show that auxin redistribution to the epidermal sites of action occurs at and above the hypocotyl apex, not at the elongation zone. Within this region, we identify the auxin efflux transporter ATP-BINDING CASSETTE B19 (ABCB19) as a substrate target for the photoreceptor kinase PHOTOTROPIN 1 (phot1). Heterologous expression and physiological analyses indicate that phosphorylation of ABCB19 by phot1 inhibits its efflux activity, thereby increasing auxin levels in and above the hypocotyl apex to halt vertical growth and prime lateral fluxes that are subsequently channeled to the elongation zone by PIN-FORMED 3 (PIN3). Together, these results provide new insights into the roles of ABCB19 and PIN3 in establishing phototropic curvatures and demonstrate that the proximity of light perception and differential phototropic growth is conserved in angiosperm

Preparing aquatic research for an extreme future: call for improved definitions and responsive, multidisciplinary approaches

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Aoki, L. R., Brisbin, M. M., Hounshell, A. G., Kincaid, D. W., Larson, E., Sansom, B. J., Shogren, A. J., Smith, R. S., & Sullivan-Stack, J. Preparing aquatic research for an extreme future: call for improved definitions and responsive, multidisciplinary approaches. Bioscience, 72(6), (2022): 508-520, https://doi.org/10.1093/biosci/biac020.Extreme events have increased in frequency globally, with a simultaneous surge in scientific interest about their ecological responses, particularly in sensitive freshwater, coastal, and marine ecosystems. We synthesized observational studies of extreme events in these aquatic ecosystems, finding that many studies do not use consistent definitions of extreme events. Furthermore, many studies do not capture ecological responses across the full spatial scale of the events. In contrast, sampling often extends across longer temporal scales than the event itself, highlighting the usefulness of long-term monitoring. Many ecological studies of extreme events measure biological responses but exclude chemical and physical responses, underscoring the need for integrative and multidisciplinary approaches. To advance extreme event research, we suggest prioritizing pre- and postevent data collection, including leveraging long-term monitoring; making intersite and cross-scale comparisons; adopting novel empirical and statistical approaches; and developing funding streams to support flexible and responsive data collection

Preterm birth is associated with immune dysregulation which persists in infants exposed to histologic chorioamnionitis

IntroductionPreterm infants are at increased risk of exposure to histologic chorioamnionitis (HCA) when compared to term-born controls, and this is associated with several neonatal morbidities involving brain, lungs and gut. Preterm infants could benefit from immunomodulatory therapies in the perinatal period, but development of rational treatment strategies requires improved characterization of the perinatal response to HCA. We had two objectives: The first, to characterize the umbilical cord blood immune profile in preterm infants compared to term-born controls; the second, to investigate the postnatal immune response in preterm infants exposed to HCA versus those who were not.PopulationFor objective one 59 term infants [mean gestational age (GA) 39+4 (37+3 to 42+0)] and 55 preterm infants [mean GA29+0(23+3 to 32+0)] with umbilical cord samples available were included; for objective two we studied 96 preterm infants [mean GA29+1(23+2 to 32+0)] for whom placental histology and postnatal blood samples were available.MethodsPlacental histopathology was used to identify reaction patterns indicative of HCA, and a customized immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group.ResultsThe umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10-14. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 8 immune proteins on postnatal day 5 (BDNF, C3, C5a, C9, IL-8, MCP-1, MIP-1β and MMP-9) when compared to preterm infants who were not exposed.ConclusionPreterm birth is associated with a distinct immune profile in umbilical cord blood and preterm infants exposed to HCA with evidence of a fetal inflammatory response have specific alterations in immune function that are apparent on day 5 of postnatal life

TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite Toxoplasma gondii

New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite's replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the "reader" module of acetylated lysines. In independent studies, we sought to determine the targets of these two compounds using forward genetics, generating resistant mutants and identifying the determinants of resistance with comparative genome sequencing. Despite the dissimilarity of the two compounds, we recovered resistant mutants with nonsynonymous mutations in the same domain of the same gene, TGGT1_254250, which we found encodes a protein that localizes to the parasite mitochondrion (designated TgPRELID after the name of said domain). We found that mutants selected with one compound were cross resistant to the other compound, suggesting a common mechanism of resistance. To further support our hypothesis that TgPRELID mutations facilitate resistance to both I-BET151 and F3215-0002, CRISPR (clustered regularly interspaced short palindromic repeat)/CAS9-mediated mutation of TgPRELID directly led to increased F3215-0002 resistance. Finally, all resistance mutations clustered in the same subdomain of TgPRELID. These findings suggest that TgPRELID may encode a multidrug resistance factor or that I-BET151 and F3215-0002 have the same target(s) despite their distinct chemical structures. IMPORTANCE We report the discovery of TgPRELID, a previously uncharacterized mitochondrial protein linked to multidrug resistance in the parasite Toxoplasma gondii. Drug resistance remains a major problem in the battle against parasitic infection, and understanding how TgPRELID mutations augment resistance to multiple, distinct compounds will reveal needed insights into the development of new therapies for toxoplasmosis and other related parasitic diseases

FCRL5 Delineates Functionally Impaired Memory B Cells Associated with Plasmodium falciparum Exposure.

Exposure to Plasmodium falciparum is associated with circulating "atypical" memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals. Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda. Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs. Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs. Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation. Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs. Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum