bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment strategies for protein-losing enteropathy in Fontan-palliated patients
Authors: Schleiger Anastasia , Ovroutski Stanislav , Peters Björn , Schubert Stephan , Photiadis Joachim , Berger Felix , Kramer Peter
Published: May 2020

Objective:

Protein-losing enteropathy is an infrequent but severe condition occurring after Fontan procedure. The multifactorial pathogenesis remains unclear and no single proposed treatment strategy has proven universally successful. Therefore, we sought to describe different treatment strategies and their effect on clinical outcome and mortality.

Material and Methods:

We performed a retrospective observational study. From the total cohort of 439 Fontan patients treated in our institution during the study period 1986–2019, 30 patients (6.8%) with protein-losing enteropathy were identified. Perioperative, clinical, echocardiographic, laboratory, and invasive haemodynamic findings and treatment details were analysed.

Results:

Median follow-up after disease onset was 13.1 years [interquartile range 10.6]. Twenty-five patients received surgical or interventional treatment for haemodynamic restrictions. Medical treatment, predominantly pulmonary vasodilator and/or systemic anti-inflammatory therapy with budesonide, was initiated in 28 patients. In 15 patients, a stable remission could be achieved by medical or surgical procedures (n = 3 each), by combined multimodal therapy (n = 8), or ultimately by cardiac transplantation (n = 1). Phrenic palsy, bradyarrhythmia, Fontan pathway stenosis, and absence of a fenestration were significantly associated with development of protein-losing enteropathy (p = 0.001–0.48). Ten patients (33.3%) died during follow-up; 5-year survival estimate was 96.1%. In unadjusted analysis, medical therapy with budesonide and pulmonary vasodilator therapy in combination was associated with improved survival.

Conclusions:

Protein-losing enteropathy is a serious condition limiting survival after the Fontan procedure. Comprehensive assessment and individual treatment strategies are mandatory to achieve best possible outcome. Nevertheless, relapse is frequent and long-term mortality substantial. Cardiac transplantation should be considered early as treatment option.
Exercise echocardiography demonstrates potential myocardial damage in patients with repaired tetralogy of Fallot using layer-specific strain analysis
Authors: Yazaki Kana , Takahashi Ken , Kobayashi Maki , Yamada Mariko , Iso Takeshi , Akimoto Satoshi , Shigemitsu Sachie , Matsui Kotoko , Akimoto Katsumi , Kishiro Masahiko , Nakanishi Keisuke , Kawasaki Shiori , Shimizu Toshiaki
Published: May 2020

Introduction:

Exercise stress echocardiography and layer-specific strains are emerging as important tools for cardiac assessment. This study was aimed to evaluate layer-specific strains and torsion parameters during exercise in order to investigate the characteristics of cardiac dysfunction in patients with repaired tetralogy of Fallot and to detect subclinical left ventricular dysfunction.

Materials and Methods:

Thirteen patients with repaired tetralogy of Fallot (median age, 17.3 [interquartile range, 14.5–22.9] years; 6 males) and 13 controls (median age, 28.5 [interquartile range, 27.6–31.6] years; 13 males) underwent echocardiography at rest and during supine exercise. Layer-specific longitudinal strain and circumferential strain of three myocardial layers (endocardium, midmyocardium, and epicardium), torsion, and untwisting rate were measured using two-dimensional speckle-tracking echocardiography.

Results:

Peak endocardial papillary circumferential strain (−21.1 ± 2.6% vs. −25.8 ± 3.8%, p = 0.007), midmyocardial apical circumferential strain (−11.1 ± 4.0% vs. −15.6 ± 3.2%, p = 0.001), epicardial apical circumferential strain (−11.1 ± 4.0% vs. −15.6 ± 3.2%, p = 0.021), and torsion (8.9 ± 6.0 vs. 14.9 ± 4.8 degree, p = 0.021) were significantly lower in the repaired tetralogy of Fallot group than in the control group during exercise, though no significant difference was found between patients and controls at rest.

Conclusions:

Analysis of layer-specific strains and torsion parameters during exercise could detect subclinical left ventricular dysfunction in patients with repaired tetralogy of Fallot, which might reflect potential myocardial damage, at a stage where these parameters have normal values at rest. This finding provides new insight into the mechanisms of cardiac dysfunction in patients with repaired tetralogy of Fallot.
Inhibition of wheat growth planted after glyphosate application to weeds
Authors: Jang Se Ji , Mallory-Smith Carol , Kuk Yong In
Published: May 2020

Glyphosate is easily translocated from shoots to roots and released into the rhizosphere. The objective of this study was to clarify the influence of glyphosate residues in the root tissue of glyphosate-treated weeds on wheat (Triticum aestivum L.) growth and shikimate accumulation. Foliar application to 5-leaf downy brome (Bromus tectorum L.) planted in sandy loam soil reduced wheat (‘Tubbs 06’) shoot fresh weight by 37% to 46% compared with the control when seeds were planted 0 and 1 d after applications. With Italian ryegrass [Lolium perenne L. ssp. multiflorum (Lam.) Husnot], wheat shoot fresh weight was inhibited by 20% to 34% compared with the control at 0, 1, 3, and 5 d after applications to 1.5- and 5-leaf-stage plants. Using a different wheat cultivar (‘Stephens’), shoot fresh weight was inhibited by 19% to 43% when seeds were planted 0 d after glyphosate applications to 1.5-, 2-, and 5-leaf-stage B. tectorum and L. perenne planted in sandy loam soil compared with control. In contrast, some studies using treated L. perenne and B. tectorum planted in clay loam soil resulted in increases in wheat shoot fresh weight. Lolium perenne planted in water-saturated sandy loam soil showed no differences in either shoot or root fresh weight or shikimate accumulation in shoots or roots. Compared with the control plants, shikimate accumulation in roots increased 51- to 59-fold in wheat planted in sandy loam soil that previously contained B. tectorum and 13- to 49-fold in soil that previously contained L. perenne. In both studies, glyphosate was applied at the 1.5-leaf stage, and wheat seeds were sown 0, 1, and 3 d after glyphosate applications. Thus, plant damage caused by glyphosate was associated with increased shikimate accumulation in the root tissue. Overall, crop damage caused by glyphosate residue to target plants was strongly influenced by soil type, soil water conditions, glyphosate sensitivity, target weed species identity, and weed densities.
An Improved Estimation of SuperDARN Heppner‐Maynard Boundaries Using AMPERE Data
Authors: Fogg A. R. , Lester M. , Yeoman T. K. , Burrell A. G. , Imber S. M. , Milan S. E. , Thomas E. G. , Sangha H. , Anderson B. J.
Published: May 2020

Super Dual Auroral Radar Network (SuperDARN) ionospheric convection maps are a powerful tool for the study of solar wind‐magnetosphere‐ionosphere interactions. SuperDARN data have high temporal (approximately minutes) and spatial (∼45 km) resolution, meaning that the convection can be mapped on fine time scales that show more detail than the large‐scale changes in the pattern. The Heppner‐Maynard boundary (HMB) defines the low‐latitude limit of the convection region, and its identification is an essential component of the standard SuperDARN convection mapping technique. However, the estimation of the latitude of this boundary is dependent on ionospheric scatter availability. Consequentially it is susceptible to nonphysical variations as areas of scatter in different latitude and local time regions appear and disappear, often due to changing propagation conditions. In this paper, the HMB is compared to an independent field‐aligned current data set from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE). A linear trend is found between the HMB and the boundary between the AMPERE Region 1 and Region 2 field‐aligned currents in the Northern Hemisphere, at both solar minimum and solar maximum. The use of this trend and the AMPERE current data set to predict the latitude position of the HMB is found to improve the interpretation of the SuperDARN measurements in convection mapping.
Impacts of Emissions of C2‐C5 Alkanes From the U.S. Oil and Gas Sector on Ozone and Other Secondary Species
Authors: Tzompa‐Sosa Z. A. , Fischer E. V.
Published: May 2020

Inside many U.S. oil and gas‐producing regions, the oil and gas sector dominates local anthropogenic emission fluxes of C2‐C5 alkanes. Here, we present a detailed analysis of the impact of these emissions on secondary species production over the continental United States using the GEOS‐Chem model. Oil‐ and gas‐producing areas in the central United States show the highest summertime surface ozone (O3) enhancements due to oil and gas C2‐C5 alkane emissions. The Colorado Front Range is the most impacted 8‐hr O3 non‐attainment area in the United States with 3‐hr daytime instantaneous O3 enhancements >4 ppb. From three selected non‐attainment areas, the Colorado Front Range has (1) the lowest monthly mean VOC reactivity (1.5 s−1); (2) the highest percent contribution of oil and gas sources (52%) to calculated VOC reactivity; and (3) the largest relative increases in PAN (peroxyacetyl nitrate), PPN (peroxypropionyl nitrate), and >C4 alkyl nitrates. Enhanced abundances of PAN, PPN, and >C4 alkyl nitrates have the potential to perturb remote O3 production through increased NOx export to remote regions via PAN chemistry. Globally, simulated C2‐C5 alkane emissions from the U.S. oil and gas sector contribute 0.5 Tg (~0.17%) to the tropospheric O3 burden with a ~0.27% contribution in the Northern Hemisphere.
A Late Miocene to Late Pleistocene Reconstruction of Precipitation Isotopes and Climate From Hydrated Volcanic Glass Shards and Biomarkers in Central Alaska and Yukon
Authors: Otiniano Gerard A. , Porter Trevor J. , Benowitz Jeff A. , Bindeman Ilya N. , Froese Duane G. , Jensen Britta J. L. , Davies Lauren J. , Phillips Michael A.
Published: May 2020

The Pliocene (5.3–2.6 Ma), an epoch with periods of climatic warmth and possible analogue for the future, has been well‐characterized globally by marine geochemical proxies. However, far less is known about Pliocene warmth at continental high latitudes, where the greatest impacts of warming are expected. This study seeks to better characterize the Pliocene climate of central Alaska and Yukon based on a reconstruction of the stable hydrogen isotope composition of precipitation relative to modern (ΔδDprecip) preserved in volcanic glass shards, a proxy for mean air temperature. The studied tephras are from a regional suite of outcrops that, when assembled into a composite record of ΔδDprecip, can be used to resolve broad trends during the late Miocene (6.7–5.86 Ma, n = 5), Pliocene (5.08–2.81 Ma, n = 7), and late Pleistocene (0.74–0.03 Ma, n = 3). These trends indicate that Pliocene ΔδDprecip estimates were generally more enriched in heavy isotopes than the latest Miocene, Pleistocene, and modern intervals. ΔδDprecip is likely influenced by changes in regional boundary conditions including orographic barriers, depositional environments, and ocean‐atmospheric circulation, but ΔδDprecip trends are most consistent with reconstructed temperatures from Yukon‐Alaska and North Pacific marine records. As such, this record appears predominantly sensitive to regional climate. Furthermore, qualitative temperature inferences from branched‐chain glycerol dialkyl glycerol tetraethers (brGDGTs) from four of our sites dating between 2.91 and 6.17 Ma corroborate elevated temperatures during the early Pliocene. Overall, this study demonstrates the viability of volcanic glass δD as a proxy for ΔδDprecip and late Cenozoic climate change in this region.
Electromagnetic Radial Diffusion in the Earth's Radiation Belts as Determined by the Solar Wind Immediate Time History and a Toy Model for the Electromagnetic Fields
Authors: Lejosne Solène
Published: May 2020

Diffusion‐driven radiation belt models require multiple physics‐based inputs to specify the radiation environment through which spacecraft travel, including diffusion coefficients. Even though event‐specific coefficients are necessary for model accuracy, their routine integration in operational models has not yet been achieved. In fact, one of the key inputs, the radial diffusion coefficient, is still commonly determined by a Kp‐driven parameterization. This work presents a method to determine continuous time series of time‐varying radial diffusion coefficients. A theoretical model is developed in which electromagnetic radial diffusion is controlled by the magnetopause immediate time history. Specifically, radial diffusion is described as a function of the average, variance, and autocorrelation time of the geocentric standoff distance to the subsolar point on the magnetopause. Because the magnitudes of these three magnetopause parameters vary with time and magnetic activity, so does radial diffusion. To a lesser extent, radial diffusion is also controlled by the drift frequency of the radiation belt population. Moreover, radial diffusion is quantified using a standard model in which the magnetopause is controlled by the solar wind. Although the resulting diffusion coefficients span several orders of magnitude per Kp index, the median magnitudes are remarkably similar to the ones provided by the standard Kp‐driven statistical parameterization.
Therapeutic targeting of p300/CBP HAT domain for the treatment of NUT midline carcinoma
Authors: Zhang Xin , Zegar Tim , Lucas Anais , Morrison-Smith Chevaun , Knox Tatiana , French Christopher A. , Knapp Stefan , Müller Susanne , Siveke Jens T.
Published: May 2020

Nuclear protein of the testis (NUT) midline carcinoma (NMC), is a rare and highly aggressive form of undifferentiated squamous cell carcinoma. NMC is molecularly characterized by chromosomal rearrangement of theNUTgene to another gene, most commonly the bromodomain and extraterminal domain (BET) geneBRD4, forming theBRD4-NUTfusion oncogene. Therefore, inhibiting BRD4-NUT oncogenic function directly by BET inhibitors represents an attractive therapeutic approach but toxicity may limit the use of pan-BET inhibitors treating this cancer. We thus performed a drug screening approach using a library consisting of epigenetic compounds and ‘Donated Chemical Probes’ collated by the Structural Genomics Consortium (SGC) and identified the p300/CBP HAT inhibitor A-485, in addition to the well-known BET inhibitor JQ1, to be the most active candidate for NMC treatment. In contrast to JQ1, A-485 was selectively potent in NMC compared to other cell lines tested. Mechanistically, A-485 inhibited p300-mediated histone acetylation, leading to disruption of BRD4-NUT binding to hyperacetylated megadomains. Consistently, BRD4-NUT megadomain-associated genesMYC,CCAT1andTP63were downregulated by A-485. A-485 strongly induced squamous differentiation, cell cycle arrest and apoptosis. Combined inhibition of p300/CBP and BET showed synergistic effects. In summary, we identified the p300/CBP HAT domain as a putative therapeutic target in highly therapy-resistant NMC.
Telomere-based risk models for the early diagnosis of clinically significant prostate cancer
Authors: Rubio Galisteo Juan Manuel , Fernández Luis , Gómez Gómez Enrique , de Pedro Nuria , Cano Castiñeira Roque , Pedregosa Ana Blanca , Guler Ipek , Carrasco Valiente Julia , Esteban Laura , González Sheila , Castelló Nila , Otero Lissette , García Jorge , Segovia Enrique , Requena Tapia María José , Najarro Pilar
Published: May 2020

Background

The objective of this study was to explore telomere-associated variables (TAV) as complementary biomarkers in the early diagnosis of prostate cancer (PCa), analyzing their application in risk models for significant PCa (Gleason score > 6).

Methods

As part of a larger prospective longitudinal study of patients with suspicion of PCa undergoing prostate biopsy according to clinical practice, a subgroup of patients (n = 401) with PSA 3–10 ng/ml and no prior biopsies was used to evaluate the contribution of TAV to discern non-significant PCa from significant PCa. The cohort was randomly split for training (2/3) and validation (1/3) of the models. High-throughput quantitative fluorescence in-situ hybridization was used to evaluate TAV in peripheral blood mononucleated cells. Models were generated following principal component analysis and random forest and their utility as risk predictors was evaluated by analyzing their predictive capacity and accuracy, summarized by ROC curves, and their clinical benefit with decision curves analysis.

Results

The median age of the patients was 63 years, with a median PSA of 5 ng/ml and a percentage of PCa diagnosis of 40.6% and significant PCa of 19.2%. Two TAV-based risk models were selected (TAV models 1 and 2) with an AUC ≥ 0.83 in the full study cohort, and AUC > 0.76 in the internal validation cohort. Both models showed an improvement in decision capacity when compared to the application of the PCPT-RC in the low-risk probabilities range. In the validation cohort, with TAV models 1 and 2, 33% /48% of biopsies would have been avoided losing 0/10.3% of significant PCa, respectively. The models were also tested and validated on an independent, retrospective, non contemporary cohort.

Conclusions

Telomere analysis through TAV should be considered as a new risk-score biomarker with potential to increase the prediction capacity of significant PCa in patients with PSA between 3–10 ng/ml.
Age influences structural brain restoration during weight gain therapy in anorexia nervosa
Authors: Kaufmann Lisa-Katrin , Hänggi Jürgen , Jäncke Lutz , Baur Volker , Piccirelli Marco , Kollias Spyros , Schnyder Ulrich , Martin-Soelch Chantal , Milos Gabriella
Published: May 2020

Neuroimaging studies on anorexia nervosa (AN) have consistently reported globally reduced gray matter in patients with acute AN. While first studies on adolescent AN patients provide evidence for the reversibility of these impairments after weight gain, longitudinal studies with detailed regional analysis for adult AN patients are lacking and factors associated with brain restitution are poorly understood. We investigated structural changes in anorexia nervosa using T1-weighted magnetic resonance images with surface-based morphometry. The sample consisted of 26 adult women with severe AN and 30 healthy controls. The longitudinal design comprised three time points, capturing the course of weight-restoration therapy in AN patients at distinct stages of weight gain (BMI ≤ 15.5 kg/m2; 15.5 < BMI < 17.5 kg/m2; BMI ≥ 17.5 kg/m2). Compared to controls, AN patients showed globally decreased cortical thickness and subcortical volumes at baseline. Linear mixed effect models revealed the reversibility of these alterations, with brain restoration being most pronounced during the first half of treatment. The restoration of cortical thickness of AN patients negatively correlated with age, but not duration of illness. After weight restoration, residual group differences of cortical thickness remained in the superior frontal cortex. These findings indicate that structural brain alterations of adult patients with severe AN recuperate independently of the duration of illness during weight-restoration therapy. The temporal pattern of brain restoration suggests a decrease in restoration rate over the course of treatment, with patients’ age as a strong predictor of brain restitution, possibly reflecting decreases of brain plasticity as patients grow older.
Use of proton pump inhibitors and histamine-2 receptor antagonists and risk of gastric cancer in two population-based studies
Authors: Liu Peipei , McMenamin Úna C. , Johnston Brian T. , Murchie Peter , Iversen Lisa , Lee Amanda J. , Vissers Pauline A. J. , Cardwell Chris R.
Published: May 2020

Background

Studies have shown increased gastric cancer risk in users of proton pump inhibitors (PPI) and histamine-2 receptor antagonists, questioning the safety of gastric acid suppression. Therefore, we conducted a case–control study within the Scottish Primary Care Clinical Informatics Unit (PCCIU) database and a cohort study in the UK Biobank.

Methods

In PCCIU, five controls were matched to cases diagnosed in 1999–2011, and medications were determined from GP records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. In the UK Biobank, medications were self-reported at cohort entry 2006–2010, and gastric cancer ascertained from cancer registries until 2014. Hazard ratios (HR) were calculated using Cox regression.

Results

PCCIU contained 1119 cases and 5394 controls. UK Biobank contained 250 cases in 471,779 participants. PPI users had a higher gastric cancer risk in PCCIU and UK Biobank when applying a 1-year lag (adjusted OR = 1.49, 95% CI 1.24, 1.80; adjusted HR = 1.28, 95% CI 0.86, 1.90, respectively), but these associations were attenuated when using a 2-year lag (adjusted OR = 1.13, 95% CI 0.91, 1.40; adjusted HR = 1.15, 95% CI 0.73, 1.82, respectively).

Conclusions

Overall, we observed little consistent evidence of an increased risk of gastric cancer with PPI use.
Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts
Authors: Jaju Bhattad Gargi , Jeyarajah Mariyan J. , McGill Megan G. , Dumeaux Vanessa , Okae Hiroaki , Arima Takahiro , Lajoie Patrick , Bérubé Nathalie G. , Renaud Stephen J.
Published: May 2020

Cell fusion occurs when several cells combine to form a multinuclear aggregate (syncytium). In human placenta, a syncytialized trophoblast (syncytiotrophoblast) layer forms the primary interface between maternal and fetal tissue, facilitates nutrient and gas exchange, and produces hormones vital for pregnancy. Syncytiotrophoblast development occurs by differentiation of underlying progenitor cells called cytotrophoblasts, which then fuse into the syncytiotrophoblast layer. Differentiation is associated with chromatin remodeling and specific changes in gene expression mediated, at least in part, by histone acetylation. However, the epigenetic regulation of human cytotrophoblast differentiation and fusion is poorly understood. In this study, we found that human syncytiotrophoblast development was associated with deacetylation of multiple core histone residues. Chromatin immunoprecipitation sequencing revealed chromosomal regions that exhibit dynamic alterations in histone H3 acetylation during differentiation. These include regions containing genes classically associated with cytotrophoblast differentiation (TEAD4,TP63,OVOL1,CGB), as well as near genes with novel regulatory roles in trophoblast development and function, such asLHX4andSYDE1. Prevention of histone deacetylation using both pharmacological and genetic approaches inhibited trophoblast fusion, supporting a critical role of this process for trophoblast differentiation. Finally, we identified the histone deacetylases (HDACs) HDAC1 and HDAC2 as the critical mediators driving cytotrophoblast differentiation. Collectively, these findings provide novel insights into the epigenetic mechanisms underlying trophoblast fusion during human placental development.
Apoptosome-dependent myotube formation involves activation of caspase-3 in differentiating myoblasts
Authors: H. Dehkordi Mahshid , Tashakor Amin , O’Connell Enda , Fearnhead Howard O.
Published: May 2020

Caspase-2, -9, and -3 are reported to control myoblast differentiation into myotubes. This had been previously explained by phosphatidylserine exposure on apoptotic myoblasts inducing differentiation in neighboring cells. Here we show for the first time that caspase-3 is activated in the myoblasts undergoing differentiation. Using RNAi, we also demonstrate that differentiation requires both cytochrome c and Apaf-1, and by using a new pharmacological approach, we show that apoptosome formation is required. We also show that Bid, whose cleavage links caspase-2 to the mitochondrial death pathway, was required for differentiation, and that the caspase cleavage product, tBid, was generated during differentiation. Taken together, these data suggest that myoblast differentiation requires caspase-2 activation of the mitochondrial death pathway, and that this occurs in the cells that differentiate. Our data also reveal a hierarchy of caspases in differentiation with caspase-2 upstream of apoptosome activation, and exerting a more profound control of differentiation, while caspases downstream of the apoptosome primarily control cell fusion.
Monitoring for neovascular age-related macular degeneration (AMD) reactivation at home: the MONARCH study
Authors: Ward Elizabeth , Wickens Robin A. , O’Connell Abby , Culliford Lucy A. , Rogers Chris A. , Gidman Eleanor A. , Peto Tunde , Knox Paul C. , Burton Benjamin J. L. , Lotery Andrew J. , Sivaprasad Sobha , Donnelly Michael , Treanor Charlene , Hogg Ruth E. , Reeves Barnaby C.
Published: May 2020

Aims

This study aims to quantify the diagnostic test-accuracy of three visual function self-monitoring tests for detection of active disease in patients with neovascular age-related macular degeneration (nAMD) when compared with usual care. An integrated qualitative study will investigate the acceptability of these home-based testing strategies.

Methods

All consenting participants are provided with an equipment pack containing an iPod touch with two vision test applications installed and a paper journal of reading tests. Participants self-monitor their vision at home each week with all three tests for 12–18 months. Usual care continues over this period. Key eligibility criteria are: age ≥50 years; at least one eye with AMD with ≥6–≤42 months since first AMD treatment; and vision not worse than Snellen 6/60, LogMAR 1.04 or 33 letters. The primary outcome, and reference standard, is diagnosis of active disease during usual care monitoring in the Hospital Eye Service. Secondary outcomes include duration of study participation, ability of participants to do the tests, adherence to weekly testing and acceptability of the tests to participants.

Conclusions

Recruitment is in progress at five NHS centres. Challenges in procuring equipment, setting up the devices and transporting devices containing lithium batteries to participating sites delayed the start of recruitment. The study will describe the performance of the tests self-administered at home in detecting active disease compared to usual care monitoring. It will also describe the feasibility of the NHS implementing patient-administered electronic tests or similar applications at home for monitoring health.
Fast response of cold ice-rich permafrost in northeast Siberia to a warming climate
Authors: Nitzbon Jan , Westermann Sebastian , Langer Moritz , Martin Léo C. P. , Strauss Jens , Laboor Sebastian , Boike Julia
Published: May 2020

The ice- and organic-rich permafrost of the northeast Siberian Arctic lowlands (NESAL) has been projected to remain stable beyond 2100, even under pessimistic climate warming scenarios. However, the numerical models used for these projections lack processes which induce widespread landscape change termed thermokarst, precluding realistic simulation of permafrost thaw in such ice-rich terrain. Here, we consider thermokarst-inducing processes in a numerical model and show that substantial permafrost degradation, involving widespread landscape collapse, is projected for the NESAL under strong warming (RCP8.5), while thawing is moderated by stabilizing feedbacks under moderate warming (RCP4.5). We estimate that by 2100 thaw-affected carbon could be up to three-fold (twelve-fold) under RCP4.5 (RCP8.5), of what is projected if thermokarst-inducing processes are ignored. Our study provides progress towards robust assessments of the global permafrost carbon–climate feedback by Earth system models, and underlines the importance of mitigating climate change to limit its impacts on permafrost ecosystems.
Genomic landscape of platinum resistant and sensitive testicular cancers
Authors: Loveday Chey , Litchfield Kevin , Proszek Paula Z. , Cornish Alex J. , Santo Flavia , Levy Max , Macintyre Geoff , Holryod Amy , Broderick Peter , Dudakia Darshna , Benton Barbara , Bakir Maise Al , Hiley Crispin , Grist Emily , Swanton Charles , Huddart Robert , Powles Tom , Chowdhury Simon , Shipley Janet , O’Connor Simon , Brenton James D. , Reid Alison , de Castro David Gonzalez , Houlston Richard S. , Turnbull Clare
Published: May 2020

While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised.
High-throughput cell and spheroid mechanics in virtual fluidic channels
Authors: Panhwar Muzaffar H. , Czerwinski Fabian , Dabbiru Venkata A. S. , Komaragiri Yesaswini , Fregin Bob , Biedenweg Doreen , Nestler Peter , Pires Ricardo H. , Otto Oliver
Published: May 2020

Microfluidics by soft lithography has proven to be of key importance for biophysics and life science research. While being based on replicating structures of a master mold using benchtop devices, design modifications are time consuming and require sophisticated cleanroom equipment. Here, we introduce virtual fluidic channels as a flexible and robust alternative to microfluidic devices made by soft lithography. Virtual channels are liquid-bound fluidic systems that can be created in glass cuvettes and tailored in three dimensions within seconds for rheological studies on a wide size range of biological samples. We demonstrate that the liquid-liquid interface imposes a hydrodynamic stress on confined samples, and the resulting strain can be used to calculate rheological parameters from simple linear models. In proof-of-principle experiments, we perform high-throughput rheology inside a flow cytometer cuvette and show the Young’s modulus of isolated cells exceeds the one of the corresponding tissue by one order of magnitude.
Olfactory marker protein directly buffers cAMP to avoid depolarization-induced silencing of olfactory receptor neurons
Authors: Nakashima Noriyuki , Nakashima Kie , Taura Akiko , Takaku-Nakashima Akiko , Ohmori Harunori , Takano Makoto
Published: May 2020

Olfactory receptor neurons (ORNs) use odour-induced intracellular cAMP surge to gate cyclic nucleotide-gated nonselective cation (CNG) channels in cilia. Prolonged exposure to cAMP causes calmodulin-dependent feedback-adaptation of CNG channels and attenuates neural responses. On the other hand, the odour-source searching behaviour requires ORNs to be sensitive to odours when approaching targets. How ORNs accommodate these conflicting aspects of cAMP responses remains unknown. Here, we discover that olfactory marker protein (OMP) is a major cAMP buffer that maintains the sensitivity of ORNs. Upon the application of sensory stimuli, OMP directly captured and swiftly reduced freely available cAMP, which transiently uncoupled downstream CNG channel activity and prevented persistent depolarization. Under repetitive stimulation,OMP-/-ORNs were immediately silenced after burst firing due to sustained depolarization and inactivated firing machinery. Consequently,OMP-/-mice showed serious impairment in odour-source searching tasks. Therefore, cAMP buffering by OMP maintains the resilient firing of ORNs.
Intracellular Staphylococcus aureus persisters upon antibiotic exposure
Authors: Peyrusson Frédéric , Varet Hugo , Nguyen Tiep Khac , Legendre Rachel , Sismeiro Odile , Coppée Jean-Yves , Wolz Christiane , Tenson Tanel , Van Bambeke Françoise
Published: May 2020

Bacterial persister cells are phenotypic variants that exhibit a transient non-growing state and antibiotic tolerance. Here, we provide in vitro evidence ofStaphylococcus aureuspersisters within infected host cells. We show that the bacteria surviving antibiotic treatment within host cells are persisters, displaying biphasic killing and reaching a uniformly non-responsive, non-dividing state when followed at the single-cell level. This phenotype is stable but reversible upon antibiotic removal. IntracellularS. aureuspersisters remain metabolically active but display an altered transcriptomic profile consistent with activation of stress responses, including the stringent response as well as cell wall stress, SOS and heat shock responses. These changes are associated with multidrug tolerance after exposure to a single antibiotic. We hypothesize that intracellularS. aureuspersisters may constitute a reservoir for relapsing infection and could contribute to therapeutic failures.
TALPID3 and ANKRD26 selectively orchestrate FBF1 localization and cilia gating
Authors: Yan Hao , Chen Chuan , Chen Huicheng , Hong Hui , Huang Yan , Ling Kun , Hu Jinghua , Wei Qing
Published: May 2020

Transition fibers (TFs) regulate cilia gating and make the primary cilium a distinct functional entity. However, molecular insights into the biogenesis of a functional cilia gate remain elusive. In a forward genetic screen in Caenorhabditis elegans, we uncover that TALP-3, a homolog of the Joubert syndrome protein TALPID3, is a TF-associated component. Genetic analysis reveals that TALP-3 coordinates with ANKR-26, the homolog of ANKRD26, to orchestrate proper cilia gating. Mechanistically, TALP-3 and ANKR-26 form a complex with key gating component DYF-19, the homolog of FBF1. Co-depletion of TALP-3 and ANKR-26 specifically impairs the recruitment of DYF-19 to TFs. Interestingly, in mammalian cells, TALPID3 and ANKRD26 also play a conserved role in coordinating the recruitment of FBF1 to TFs. We thus report a conserved protein module that specifically regulates the functional component of the ciliary gate and suggest a correlation between defective gating and ciliopathy pathogenesis.
A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis
Authors: Quan Chao , Du Qian , Li Min , Wang Ruizhen , Ouyang Qian , Su Shu , Zhu Sangsang , Chen Qiaoli , Sheng Yang , Chen Liang , Wang Hong , Campbell David G. , MacKintosh Carol , Yang Zhongzhou , Ouyang Kunfu , Wang Hong Yu , Chen Shuai
Published: May 2020

Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.
Increased O-GlcNAcylation rapidly decreases GABAAR currents in hippocampus but depresses neuronal output
Authors: Stewart L. T. , Abiraman K. , Chatham J. C. , McMahon L. L.
Published: May 2020

O-GlcNAcylation, a post-translational modification involving O-linkage of β-N-acetylglucosamine to Ser/Thr residues on target proteins, is increasingly recognized as a critical regulator of synaptic function. Enzymes that catalyze O-GlcNAcylation are found at both presynaptic and postsynaptic sites, and O-GlcNAcylated proteins localize to synaptosomes. An acute increase in O-GlcNAcylation can affect neuronal communication by inducing long-term depression (LTD) of excitatory transmission at hippocampal CA3-CA1 synapses, as well as suppressing hyperexcitable circuits in vitro and in vivo. Despite these findings, to date, no studies have directly examined how O-GlcNAcylation modulates the efficacy of inhibitory neurotransmission. Here we show an acute increase in O-GlcNAc dampens GABAergic currents onto principal cells in rodent hippocampus likely through a postsynaptic mechanism, and has a variable effect on the excitation/inhibition balance. The overall effect of increased O-GlcNAc is reduced synaptically-driven spike probability via synaptic depression and decreased intrinsic excitability. Our results position O-GlcNAcylation as a novel regulator of the overall excitation/inhibition balance and neuronal output.
Intra-Day and Inter-Day Reliability of Measurements of the electromyographic signal on masseter and temporal muscles in patients with Down syndrome
Authors: Giannasi Lilian Chrystiane , Politti Fabiano , Dutra Marignês T. S. , Tenguan Vera L. S. , Silva Gabriela R. C. , Mancilha Gabriela P. , Silva Daniel Batista da , Oliveira Luis Vicente Franco , Oliveira Claudia Santos , Amorim Jose B. O. , Salgado Miguel Angel Castillo , Gomes Mônica F.
Published: May 2020

The aim of the present study was to evaluate intra-day (test) and inter-day (re-test) reliability of surface electromyography (sEMG) signals of the masseter and temporal muscles in patients with Down syndrome (DS). We determined the reliability of sEMG variables in 33 patients with DS. EMG signals were recorded at rest as well as during maximum voluntary clenching and maximum habitual intercuspation (MHI). The signals were analyzed considering the amplitude in the root mean square (RMS), mean frequency (MNF), median frequency (MDF) and approximate entropy (ApEn). The intraclass correlation (ICC2,1) for the three trials recorded during MHI in the two sessions (test and retest) revealed excellent intra-session and inter-session reliability (ICC2,1 = 0.76 to 0.97) for all sEMG variables and muscles. In the rest position, excellent reliability was found for RMS and ApEn (ICC2,1 = 0.75 to 1.00) and good to excellent reliability was found for MDF and MNF (ICC2,1 = 0.64 to 0.93). The intra-session (test) and inter-session (re-test) analyses demonstrated the reliability of nonlinear sEMG variables of the masticatory muscles in adults with Down Syndrome.
Enhanced cell density cultivation and rapid expression-screening of recombinant Pichia pastoris clones in microscale
Authors: Kaushik Neha , Lamminmäki Urpo , Khanna Navin , Batra Gaurav
Published: May 2020

Cultivation of yeast Pichia pastoris in the microtiter plate, for optimisation of culture conditions, and expression screening of transformants has gained significance in recent years. However, in the microtiter plate, it has been challenging to attain cell densities similar to well-aerated shake-flask culture, due to the poor mixing resulting in oxygen limitation. To solve this problem, we investigated the influence of multiple cultivation parameters on P. pastoris cell growth, including the architecture of 96-deepwell plate (96-DWP), shaking throw diameter, shaking frequency, culture volume/well, and media composition. In the optimised conditions, a cell density of OD600 ~50 (dry cell weight ~13 g/L) with >99% cell viability was achieved in the casamino acids supplemented buffered-minimal-media in 300 to 1000 μl culture volume/well. We have devised a simplified method for coating of the culture supernatant on the polystyrene surface for immunoassay. Clones for secretory expression of envelope domain III of dengue virus serotype-1 under the control of inducible and constitutive promoter were screened using the developed method. Described microscale cultivation strategy can be used for rapid high-throughput screening of P. pastoris clones, media optimization, and high-throughput recombinant protein production. The knowledge gained through this work may also be applied, to other suspension cultures, with some modifications.
Conductive Highly Filled Suspensions for an Electrochemical Dispensing Approach to Pattern Full-Area Thin Metal Layers by Physical Vapour Deposition
Authors: Gensowski Katharina , Tepner Sebastian , Schweigert Sebastian , Clement Florian , Kamp Mathias , Pospischil Maximilian , Bartsch Jonas
Published: May 2020

This paper presents a systematic approach for the development of highly filled suspensions used for an electrochemical dispensing approach. Electrochemical dispensing is an alternative structuring process to locally pattern PVD full-area thin metal layers with the goal to create contacts on solar cells or circuit boards by anodic metal dissolution. Achieving a narrow patterned line width requires a dispensing paste with a high yield stress, a small particle size distribution and a good electrical conductivity. Therefore this work focuses on the formulation and characterization of dispensing pastes in terms of their rheological and electrical properties and their particle size distribution. Furthermore, the printing performance is evaluated in dispensing experiments. In this study, samples with a yield stress above 5000 Pa and an average particle size below 0.4 µm were produced, resulting in dispensed line widths below 100 µm with a high aspect ratio above 0.6. The lack of electrical conductivity was solved by adding KCl solution to the paste, which will add to the ionic conductivity of the NaNO3 basis paste formulation. With this approach, printed line widths down to 115 µm and etched line widths below 90 µm at high aspect ratio were achieved on 50 nm aluminum layers.
DNA:RNA hybrid G-quadruplex formation upstream of transcription start site
Authors: Zhang Jia-yu , Xia Ye , Hao Yu-hua , Tan Zheng
Published: May 2020

Bioinformatic analysis reveals an enrichment of putative DNA:RNA hybrid G-quadruplex-forming sequences (PHQS) on both sides of the transcription start sites (TSSs) in the genome of warm-blooded animals, suggesting a positive selection of PHQSs in evolution and functional role of DNA:RNA hybrid G-quadruplexes (HQs) in transcription. The formation of HQs downstream of TSS in transcribed DNA has been documented under in vitro conditions; however, it is still not known if such HQs can form at the upstream side of TSSs. In this study, we report that such HQs can form in transcription in DNA with two to three guanine tracts if RNA carrying the required number of G-tracts is supplied. We also show that the formation of such HQs is dependent on the negative supercoiling generated by RNA polymerases. These results suggest that HQs may also form at the upstream side of TSSs in vivo and play a role in transcription since the two requirements are satisfied in cells.
Human pluripotent stem cell-based models suggest preadipocyte senescence as a possible cause of metabolic complications of Werner and Bloom Syndromes
Authors: Goh Kim Jee , Chen Jian-Hua , Rocha Nuno , Semple Robert K.
Published: May 2020

Werner Syndrome (WS) and Bloom Syndrome (BS) are disorders of DNA damage repair caused by biallelic disruption of the WRN or BLM DNA helicases respectively. Both are commonly associated with insulin resistant diabetes, usually accompanied by dyslipidemia and fatty liver, as seen in lipodystrophies. In keeping with this, progressive reduction of subcutaneous adipose tissue is commonly observed. To interrogate the underlying cause of adipose tissue dysfunction in these syndromes, CRISPR/Cas9 genome editing was used to generate human pluripotent stem cell (hPSC) lacking either functional WRN or BLM helicase. No deleterious effects were observed in WRN−/− or BLM−/− embryonic stem cells, however upon their differentiation into adipocyte precursors (AP), premature senescence emerged, impairing later stages of adipogenesis. The resulting adipocytes were also found to be senescent, with increased levels of senescent markers and senescence-associated secretory phenotype (SASP) components. SASP components initiate and reinforce senescence in adjacent cells, which is likely to create a positive feedback loop of cellular senescence within the adipocyte precursor compartment, as demonstrated in normal ageing. Such a scenario could progressively attenuate adipose mass and function, giving rise to “lipodystrophy-like” insulin resistance. Further assessment of pharmacological senolytic strategies are warranted to mitigate this component of Werner and Bloom syndromes.
Singularity of a relativistic vortex beam and proper relativistic observables
Authors: Han Yeong Deok , Choi Taeseung , Cho Sam Young
Published: May 2020

We have studied the phase singularity of relativistic vortex beams for two sets of relativistic operators using circulation. One set includes new spin and orbital angular momentum (OAM) operators, which are derived from the parity-extended Poincaré group, and the other set consists of the (usual) Dirac spin and OAM operators. The first set predicts the same singularity in the circulation as in the case of nonrelativistic vortex beams. On the other hand, the second set anticipates that the singularity of the circulation is spin-orientation-dependent and can disappear, especially for a relativistic paraxial electron beam with spin parallel to the propagating direction. These contradistinctive predictions suggest that a relativistic electron beam experiment with spin-polarized electrons could for the first time answer a long-standing fundamental question, i.e., what are the proper relativistic observables, raised from the beginning of relativistic quantum mechanics following the discovery of the Dirac equation.
Identification, characterization and expression analysis of calmodulin and calmodulin-like proteins in Solanum pennellii
Authors: Shi Jinyan , Du Xiangge
Published: May 2020

In plants, the calmodulin (CaM) proteins is an important calcium-binding protein, which play a crucial role in both regulating plant growth and development, as well as in the resistance mechanisms to various biotic and abiotic stresses. However, there is limited knowledge available on the CaM family functions in Solanum pennellii, a wild tomato species utilized as a genetic resource for cultivated tomatoes. In this study, 6 CaM (SpCaM) and 45 CaM-like (SpCML) genes from Solanum pennellii were selected for bioinformatics analysis to obtain insights into their phylogenetic relationships, gene structures, conserved motifs, chromosomal locations, and promoters. The results showed that the 6 SpCaM proteins contained 4 EF-hand domains each, and the 45 SpCML proteins had 2-4 EF-hand domains. The 51 CaM and CaM-like genes contained different intron/exon patterns and they were unevenly distributed across the 12 chromosomes of S. pennellii. The results of the analysis of the conserved motifs and promoter cis-regulatory elements also indicated that these proteins were involved in the responses to biotic and abiotic stresses. qRT-PCR analysis indicated that the SpCaM and SpCML genes had broad expression patterns in abiotic stress conditions and with hormone treatments, in different tissues. The findings of this study will be important for further investigations of the calcium signal transduction mechanisms under stress conditions and lay a theoretical foundation for further exploration of the molecular mechanisms of plant resistance.