bluuebunny/crossref_metadata_2025 huggingface dataset:
Expanding adolescent access to hormonal contraception: an update on over-the-counter, pharmacist prescribing, and web-based telehealth approaches
Authors: Williams Rebekah L. , Meredith Ashley H. , Ott Mary A.
Published: October 2018

Purpose of review

Hormonal contraceptives are largely responsible for recent declines in unintended adolescent pregnancies, with oral contraceptives being the most commonly used. Young people face multiple barriers to accessing effective contraception in clinical settings. This article reviews innovations in contraceptive access.

Recent findings

The three biggest innovations are over-the-counter oral contraceptives (OTC-OCs), pharmacist-prescribing, and web-based telehealth platforms. In many countries, oral contraceptives are available OTC, and FDA trials for OTC-OCs are underway in the United States. Many states have passed legislation allowing pharmacists to prescribe contraceptives after a brief health screening. Web-based telehealth platforms also provide prescription contraceptive access. There is a small but growing body of literature that demonstrates young people's interest in, and capacity to consent to, hormonal contraceptives in nontraditional settings. State-to-state variability in minor consent, pharmacist prescribing, and telehealth laws act as barriers to young people's access to these newer options.

Access to hormonal contraception is expanding outside of clinical settings, reducing barriers. Adolescents’ unique needs should be considered in the design, implementation, and evaluation of these new approaches. More data is needed to ensure that adolescents are not excluded from expanded contraceptive access options, as they are disproportionately affected by unintended pregnancy.
Pharmacokinetics of Sildenafil in Patients with a Left Ventricular Assist Device: A Word of Caution
Authors: Sabato Leah A. , Johnson Daniel C. , Haglund Nicholas , Keebler Mary , Cox Zachary L.
Published: October 2018

We compared maximal plasma concentrations (C
max) of sildenafil and metabolite n-desmethyl sildenafil in 12 inpatients with left ventricular assist devices (LVADs) on sildenafil (60 mg/day) to the reference range. Sildenafil C
max (156.8 ± 124.5 ng/ml) was elevated in 66% of patients, with a two to fivefold increase over the upper limit of the reference range in 25% of patients. Metabolite C
max (133.3 ± 102.0 ng/ml) was elevated in 75% of patients, with a three to sevenfold increase over the upper limit of the reference range in 40% of patients. Patients with heart failure and LVADs are at increased risk of concentrated-related sildenafil adverse events.
Chronic In Vivo Test of a Right Heart Replacement Blood Pump for Failed Fontan Circulation
Authors: Cysyk Joshua , Clark Joseph Brian , Newswanger Ray , Jhun Choon-Sik , Izer Jenelle , Finicle Heidi , Reibson John , Doxtater Bradley , Weiss William , Rosenberg Gerson
Published: October 2018

An implantable rotary blood pump was developed to provide long-term mechanical right heart support for patients who have failing Fontan circulation. The objective of this study was to evaluate the pump in vivo in a 30 day sheep study. Pump speed was set at 3,900 rpm for the duration of the study, and pump power was between 4.3 and 4.6 W. The pump inlet pressures for the superior vena cava (SVC) and inferior vena cava (IVC) were 14 ± 15 and 11 ± 15 mm Hg, respectively, over the duration of the study. Hematocrit remained stable at 30% ± 4%. Partial thromboplastin time (PTT) steadily increased from 30 s preoperatively to a high of 59 s on postoperative day 20, while prothrombin time (PT) remained at 20 ± 2 s for the duration of the study. The implantation and postoperative recovery were successful, and the animal demonstrated normal physiologic pulmonary and venous pressures and cardiac output. On pump inspection, the IVC and SVC inlets were completely clear of any deposits, but there were small thrombi (approximately 0.5 mm diameter) between each of the three rotor blades and along 20% of the parting line of the two volute halves. A complete right heart bypass was performed, postoperative recovery was successful, and the pump demonstrated adequate circulatory support and normal physiologic pulmonary and venous pressures. This study was the first successful test of a right heart replacement device in a chronic animal study.
Antithrombotic Therapy and Outcomes of Patients With New-Onset Transient Atrial Fibrillation After ST-Segment Elevation Myocardial Infarction
Authors: Kayapinar Osman , Kaya Adnan , Keskin Muhammed , Tatlisu Mustafa Adem
Published: October 2018

Background:

Atrial fibrillation (AF) is a common complication of ST-segment elevation myocardial infarction (STEMI), and AF might require anticoagulant treatment in some conditions.

Study Question:

There are no clear recommendations about vitamin K antagonist (VKA) use in patients with STEMI who complicated with new-onset transient AF. In this study, we examined the association of concomitant use of VKA and dual antiplatelet therapy (DAPT) with clinical outcomes of this patient population.

Study Design:

A total of 4086 patients with STEMI who underwent primary percutaneous coronary intervention retrospectively investigated. Among these patients, a total of 286 patients who developed new-onset transient AF during hospitalization were enrolled. VKA group consisted of 116 patients treated with warfarin, aspirin, and clopidogrel, and DAPT group consisted of 170 patients treated with aspirin and clopidogrel.

Measures and Outcomes:

One-year mortality, ischemic stroke, major, and minor bleeding were determined as clinical outcomes.

Results:

Although VKA group had proportionally lower mortality (17.2% vs. 20.0%) and ischemic stroke (7.8% vs. 11.8%) compared with DAPT group, the differences did not reach to statistical significance, whereas the 1-year major bleeding had higher rates at VKA group and that had 3.5-times higher major bleeding than DAPT group. This relationship was persisted after multivariable analysis (hazard ratio = 3.37, 95% CI, 1.76–10.04, P = 0.012).

Conclusions:

There is not a widely accepted treatment algorithm in patients with STEMI who complicated with new-onset AF in clinical guidelines. The current study indicated that transient form of new-onset AF might not require long-term VKA. Besides, addition of VKA to DAPT therapy may increase the rates of major and minor bleeding.
The Relationship Between Daytime Salivary Melatonin and Gastrointestinal Symptoms in Young Adults Seeking Psychiatric Care
Authors: Söderquist Fanny , Sundberg Isak , Ramklint Mia , Widerström Rebecka , Hellström Per M. , Cunningham Janet L.
Published: October 2018

Objective

The pathophysiology of irritable bowel syndrome (IBS) is not completely understood, although we do know that patients with IBS have a high prevalence of psychiatric comorbidity (mainly depression and anxiety disorders). Melatonin, produced in the gastrointestinal tract, influences gut motility. Psychiatric conditions are associated with circadian disturbances in peripheral melatonin levels. This study aimed to investigate associations between daytime salivary melatonin and gastrointestinal symptoms in young adult psychiatric patients.

Methods

Ninety-six patients (86% women), aged 18–25 years (M (SD) = 21 (2)), seeking psychiatric care with primarily anxiety disorders, affective disorders, or both were included in the study. Total scores from the Gastrointestinal Symptoms Rating Scale - IBS were compared with salivary melatonin measured at three time points (30 minutes after waking up, at 11:00 hours and 30 minutes after lunch) during the waking hours of 1 day.

Results

After adjustment for potential confounders, melatonin levels in saliva 30 minutes after lunch remained significantly correlated to the total Gastrointestinal Symptoms Rating Scale - IBS score after correction for multiple testing (B = 0.016, SE = 0.006, p = .015, q = 0.045). In a post hoc analysis, symptoms of gastrointestinal pain and bloating contributed most to this association.

Conclusions

In young adult psychiatric patients, salivary melatonin levels after lunch are associated with gastrointestinal symptoms, which is consistent with the proposed effect of elevated levels of gastrointestinal melatonin on gut motility. This result suggests a link between IBS symptoms and regulation of melatonin in patients with psychiatric disorders.
Short-term effects of drought on tropical forest do not fully predict impacts of repeated or long-term drought: gas exchange versus growth
Authors: Meir Patrick , Mencuccini Maurizio , Binks Oliver , da Costa Antonio Lola , Ferreira Leandro , Rowland Lucy
Published: October 2018

Are short-term responses by tropical rainforest to drought (e.g. during El Niño) sufficient to predict changes over the long-term, or from repeated drought? Using the world's only long-term (16-year) drought experiment in tropical forest we examine predictability from short-term measurements (1–2 years). Transpiration was maximized in droughted forest: it consumed all available throughfall throughout the 16 years of study. Leaf photosynthetic capacity

was maintained, but only when averaged across tree size groups. Annual transpiration in droughted forest was less than in control, with initial reductions (at high biomass) imposed by foliar stomatal control. Tree mortality increased after year three, leading to an overall biomass loss of 40%; over the long-term, the main constraint on transpiration was thus imposed by the associated reduction in sapwood area. Altered tree mortality risk may prove predictable from soil and plant hydraulics, but additional monitoring is needed to test whether future biomass will stabilize or collapse. Allocation of assimilate differed over time: stem growth and reproductive output declined in the short-term, but following mortality-related changes in resource availability, both showed long-term resilience, with partial or full recovery. Understanding and simulation of these phenomena and related trade-offs in allocation will advance more effectively through greater use of optimization and probabilistic modelling approaches.

This article is part of a discussion meeting issue ‘The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications’.
Quantifying immediate carbon emissions from El Niño-mediated wildfires in humid tropical forests
Authors: Withey Kieran , Berenguer Erika , Palmeira Alessandro Ferraz , Espírito-Santo Fernando D. B. , Lennox Gareth D. , Silva Camila V. J. , Aragão Luiz E. O. C. , Ferreira Joice , França Filipe , Malhi Yadvinder , Rossi Liana Chesini , Barlow Jos
Published: October 2018

Wildfires produce substantial CO
2
emissions in the humid tropics during El Niño-mediated extreme droughts, and these emissions are expected to increase in coming decades. Immediate carbon emissions from uncontrolled wildfires in human-modified tropical forests can be considerable owing to high necromass fuel loads. Yet, data on necromass combustion during wildfires are severely lacking. Here, we evaluated necromass carbon stocks before and after the 2015–2016 El Niño in Amazonian forests distributed along a gradient of prior human disturbance. We then used Landsat-derived burn scars to extrapolate regional immediate wildfire CO
2
emissions during the 2015–2016 El Niño. Before the El Niño, necromass stocks varied significantly with respect to prior disturbance and were largest in undisturbed primary forests (30.2 ± 2.1 Mg ha
−1
, mean ± s.e.) and smallest in secondary forests (15.6 ± 3.0 Mg ha
−1
). However, neither prior disturbance nor our proxy of fire intensity (median char height) explained necromass losses due to wildfires. In our 6.5 million hectare (6.5 Mha) study region, almost 1 Mha of primary (disturbed and undisturbed) and 20 000 ha of secondary forest burned during the 2015–2016 El Niño. Covering less than 0.2% of Brazilian Amazonia, these wildfires resulted in expected immediate CO
2
emissions of approximately 30 Tg, three to four times greater than comparable estimates from global fire emissions databases. Uncontrolled understorey wildfires in humid tropical forests during extreme droughts are a large and poorly quantified source of CO
2
emissions.

This article is part of a discussion meeting issue ‘The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications’.
Drought-induced Amazonian wildfires instigate a decadal-scale disruption of forest carbon dynamics
Authors: Silva Camila V. J. , Aragão Luiz E. O. C. , Barlow Jos , Espirito-Santo Fernando , Young Paul J. , Anderson Liana O. , Berenguer Erika , Brasil Izaias , Foster Brown I. , Castro Bruno , Farias Renato , Ferreira Joice , França Filipe , Graça Paulo M. L. A. , Kirsten Letícia , Lopes Aline P. , Salimon Cleber , Scaranello Marcos Augusto , Seixas Marina , Souza Fernanda C. , Xaud Haron A. M.
Published: October 2018

Drought-induced wildfires have increased in frequency and extent over the tropics. Yet, the long-term (greater than 10 years) responses of Amazonian lowland forests to fire disturbance are poorly known. To understand post-fire forest biomass dynamics, and to assess the time required for fire-affected forests to recover to pre-disturbance levels, we combined 16 single with 182 multiple forest census into a unique large-scale and long-term dataset across the Brazilian Amazonia. We quantified biomass, mortality and wood productivity of burned plots along a chronosequence of up to 31 years post-fire and compared to surrounding unburned plots measured simultaneously. Stem mortality and growth were assessed among functional groups. At the plot level, we found that fire-affected forests have biomass levels 24.8 ± 6.9% below the biomass value of unburned control plots after 31 years. This lower biomass state results from the elevated levels of biomass loss through mortality, which is not sufficiently compensated for by wood productivity (incremental growth + recruitment). At the stem level, we found major changes in mortality and growth rates up to 11 years post-fire. The post-fire stem mortality rates exceeded unburned control plots by 680% (i.e. greater than 40 cm diameter at breast height (DBH); 5–8 years since last fire) and 315% (i.e. greater than 0.7 g cm
−3
wood density; 0.75–4 years since last fire). Our findings indicate that wildfires in humid tropical forests can significantly reduce forest biomass for decades by enhancing mortality rates of all trees, including large and high wood density trees, which store the largest amount of biomass in old-growth forests. This assessment of stem dynamics, therefore, demonstrates that wildfires slow down or stall the post-fire recovery of Amazonian forests.

This article is part of a discussion meeting issue ‘The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications’.
Changes in surface hydrology, soil moisture and gross primary production in the Amazon during the 2015/2016 El Niño
Authors: van Schaik Erik , Killaars Lars , Smith Naomi E. , Koren Gerbrand , van Beek L. P. H. , Peters Wouter , van der Laan-Luijkx Ingrid T.
Published: October 2018

The 2015/2016 El Niño event caused severe changes in precipitation across the tropics. This impacted surface hydrology, such as river run-off and soil moisture availability, thereby triggering reductions in gross primary production (GPP). Many biosphere models lack the detailed hydrological component required to accurately quantify anomalies in surface hydrology and GPP during droughts in tropical regions. Here, we take the novel approach of coupling the biosphere model SiBCASA with the advanced hydrological model PCR-GLOBWB to attempt such a quantification across the Amazon basin during the drought in 2015/2016. We calculate 30–40% reduced river discharge in the Amazon starting in October 2015, lagging behind the precipitation anomaly by approximately one month and in good agreement with river gauge observations. Soil moisture shows distinctly asymmetrical spatial anomalies with large reductions across the north-eastern part of the basin, which persisted into the following dry season. This added to drought stress in vegetation, already present owing to vapour pressure deficits at the leaf, resulting in a loss of GPP of 0.95 (0.69 to 1.20) PgC between October 2015 and March 2016 compared with the 2007–2014 average. Only 11% (10–12%) of the reduction in GPP was found in the (wetter) north-western part of the basin, whereas the north-eastern and southern regions were affected more strongly, with 56% (54–56%) and 33% (31–33%) of the total, respectively. Uncertainty on this anomaly mostly reflects the unknown rooting depths of vegetation.

This article is part of a discussion meeting issue ‘The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications’.
Interactive effects of tree size, crown exposure and logging on drought-induced mortality
Authors: Shenkin Alexander , Bolker Benjamin , Peña-Claros Marielos , Licona Juan Carlos , Ascarrunz Nataly , Putz Francis E.
Published: October 2018

Large trees in the tropics are reportedly more vulnerable to droughts than their smaller neighbours. This pattern is of interest due to what it portends for forest structure, timber production, carbon sequestration and multiple other values given that intensified El Niño Southern Oscillation (ENSO) events are expected to increase the frequency and intensity of droughts in the Amazon region. What remains unclear is what characteristics of large trees render them especially vulnerable to drought-induced mortality and how this vulnerability changes with forest degradation. Using a large-scale, long-term silvicultural experiment in a transitional Amazonian forest in Bolivia, we disentangle the effects of stem diameter, tree height, crown exposure and logging-induced degradation on risks of drought-induced mortality during the 2004/2005 ENSO event. Overall, tree mortality increased in response to drought in both logged and unlogged plots. Tree height was a much stronger predictor of mortality than stem diameter. In unlogged plots, tree height but not crown exposure was positively associated with drought-induced mortality, whereas in logged plots, neither tree height nor crown exposure was associated with drought-induced mortality. Our results suggest that, at the scale of a site, hydraulic factors related to tree height, not air humidity, are a cause of elevated drought-induced mortality of large trees in unlogged plots.

This article is part of a discussion meeting issue ‘The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications'.
Extracellular matrix components are required to protectBacillus subtilisfrom T6SS-dependentPseudomonasinvasion and modulate co-colonization of plants
Authors: Molina-Santiago Carlos , Pearson John R. , Navarro-García Yurena , Berlanga-Clavero María Victoria , Caraballo-Rodriguez Andrés Mauricio , Petras Daniel , Cazorla Francisco M. , de Vicente Antonio , Dorrestein Pieter C. , Romero Diego
Published: October 2018

Bacteria adapt to environmental changes and interact with other microorganisms using a wide array of molecules, metabolic plasticity, secretion systems and the formation of biofilms. Some research has looked at changes in the expression of biofilm related genes during interactions between different bacterial species, however no studies have directly demonstrated the functional significance of biofilms in modulating such interactions. In this study, we have explored this fundamental question by studying the interaction betweenBacillus subtilis3610 andPseudomonas chlororaphisPCL1606. We demonstrate the important role of the extracellular matrix in protectingB. subtiliscolonies from infiltration byPseudomonas. Surprisingly, we find that thePseudomonastype VI secretion system (T6SS) is required in the cell-to-cell contact with matrix-impairedB. subtiliscells, revealing a novel role for T6SS against Gram-positive bacteria. In response toP. chlororaphisinfiltration, we find thatB. subtilisactivates sporulation and expresses motility-related genes. Experiments using plant organs demonstrate the functional importance of these different bacterial strategies in their coexistence as stable bacterial communities. The findings described here further our understanding of the functional role played by biofilms in mediating bacterial social interactions.
Blended Bioinformatics Training in Resource-Limited Settings: A case study of challenges and Opportunities for Implementation
Authors: Ahmed Azza , Awadallah Ayah A. , Elmahdi Mawada T. , Suliman Maram A. , Khalil Atheer E. , Elsafi Hassan , Hamdelnile Basil D. , Abdullateif Mohamed , Fadlelmola Faisal M.
Published: October 2018

Motivation

Delivering high quality distance-based courses in resource limited settings is a challenging task. Besides the needed infrastructure and expertise, effective delivery of a bioinformatics course could benefit from hands-on sessions, interactivity, and problem-based learning approaches.

Results

In this article, we discuss the challenges and best practices in delivering bioinformatics training in limited resource settings taking the example of hosting and running a multiple-delivery online course, Introduction to Bioinformatics (IBT), that was developed by the H3ABioNet Education and Training Working Group and delivered in 27 remote classrooms across Africa in 2017. We take the case of the University of Khartoum classroom. Believing that our local setting is similar to others in less developed countries, so we also reflect upon aspects like classroom environment and recruitment of students to maximize outcomes.

Supplementary information

Supplementary data are available
Evaluation of the Potential of Two Common Pacific Coast Macroalgae for Mitigating Methane Emissions from Ruminants
Authors: Brooke Charles G. , Roque Breanna M. , Najafi Negeen , Gonzalez Maria , Pfefferlen Abigail , DeAnda Vannesa , Ginsburg David W. , Harden Maddelyn C. , Nuzhdin Sergey V. , Salwen Joan King , Kebreab Ermias , Hess Matthias
Published: October 2018

With increasing interest in feed based methane mitigation strategies, fueled by local legal directives aimed at methane production from the agricultural sector in California, identifying local sources of biological feed additives will be critical in keeping the implementation of these strategies affordable. In a recent study, the red alga Asparagopsis taxiformis stood out as the most effective species of seaweed to reduce methane production from enteric fermentation. Due to the potential differences in effectiveness based on the location from where A. taxiformis is collected and the financial burden of collection and transport, we tested the potential of A. taxiformis, as well as the brown seaweed Zonaria farlowii collected in the nearshore waters off Santa Catalina Island, CA, USA, for their ability to mitigate methane production during in-vitro rumen fermentation. At a dose rate of 5% dry matter (DM), A. taxiformis reduced methane production by 74% (p ≤ 0.01) and Z. farlowii reduced methane production by 11% (p ≤ 0.04) after 48 hours and 24 hours of in-vitro rumen fermentation respectively. The methane reducing effect of A. taxiformis and Z. farlowii described here make these local macroalgae promising candidates for biotic methane mitigation strategies in the largest milk producing state in the US. To determine their real potential as methane mitigating feed supplements in the dairy industry, their effect in-vivo requires investigation.
Phylogeny, ancestors and anagenesis in the hominin fossil record
Authors: Parins-Fukuchi Caroline , Greiner Elliot , MacLatchy Laura M. , Fisher Daniel C.
Published: October 2018

Probabilistic approaches to phylogenetic inference have recently gained traction in paleontological studies. Because they directly model processes of evolutionary change, probabilistic methods facilitate a deeper assessment of variability in evolutionary pattern by weighing evidence for competing models. Although phylogenetic methods used in paleontological studies have generally assumed that evolution proceeds by splitting cladogenesis, extensions to previous models help explore the potential for morphological and temporal data to provide differential support for contrasting modes of evolutionary divergence. Recent methodological developments have integrated ancestral relationships into probabilistic phylogenetic methods. These new approaches rely on parameter-rich models and sophisticated inferential methods, potentially obscuring the respective contributions of data and models. In this study, we describe a simple likelihoodist approach that combines probabilistic models of morphological evolution and fossil preservation to reconstruct both cladogenetic and anagenetic relationships. By applying this approach to a dataset of fossil hominins, we demonstrate the capability of existing models to unveil evidence for anagenesis presented by morphological and temporal data. This evidence was previously recognized by qualitative assessments, but largely ignored by quantitative phylogenetic analyses. For example, we find support for directly ancestral relationships in multiple lineages:Sahelanthropusis ancestral to later hominins;Australopithecus anamensisis ancestral toAu. afarensis;Au. garhiis ancestral toHomo;H. antecessoris ancestral toH. heidelbergensis, which in turn is ancestral to bothH. sapiensandH. neanderthalensis. These results show a benefit of accommodating direct ancestry in phylogenetics. By so doing, quantitative results align more closely with previous qualitative expectations.
Region-specific differences and areal interactions underlying transitions in epileptiform activity
Authors: Codadu Neela K , Parrish R Ryley , Trevelyan Andrew J
Published: October 2018

Understanding the nature of epileptic state transitions remains a major goal for epilepsy research. Simple in vitro models offer unique experimental opportunities, which we exploit to show that such transitions can arise from shifts in the ictal source of the activity. These transitions reflect the fact that cortical territories differ both in the type of epileptiform activity they can sustain, and their susceptibility to drug manipulation. In the zero Mg2+ model, the earliest epileptiform activity is restricted to neocortical and entorhinal networks. Hippocampal bursting only starts much later, and triggers a marked transition in neo-/entorhinal cortical activity. Thereafter, the hippocampal activity acts as a pacemaker, entraining the other territories to their discharge pattern. This entrainment persists following transection of the major axonal pathways between hippocampus and cortex, indicating that it can be mediated through a non-synaptic route. Neuronal discharges are associated with large rises in extracellular [K+], but we show that these are very localised, and therefore are not the means of entraining distant cortical areas. We conclude instead that the entrainment occurs through weak field effects distant from the pacemaker, but which are highly effective at recruiting other brain territories that are already hyperexcitable. The hippocampal epileptiform activity appears unusually susceptible to drugs that impact on K+ conductances. These findings demonstrate that the local circuitry gives rise to stereotypical epileptic activity patterns, but these are also influenced by both synaptic and non-synaptic long-range effects. Our results have important implications for our understanding of epileptic propagation, and anti-epileptic drug action.
Alzheimer’s Amyloid-Beta Intermediates Generated by Polymer-Nanodiscs
Authors: Sahoo Bikash R. , Genjo Takuya , Bekier Michael , Cox Sarah J. , Stoddard Andrea K. , Ivanova Magdalena , Yasuhara Kazuma , Fierke Carol A. , Wang Yanzhuang , Ramamoorthy Ayyalusamy
Published: October 2018

Polymethacrylate-copolymer (PMA) encased lipid-nanodiscs (~10 nm) and macro-nanodiscs (>15 nm) are used to study Aβ1-40 aggregation. We demonstrate that PMA-nanodiscs form a ternary association with Aβ and regulate its aggregation kinetics by trapping intermediates. Results demonstrating reduced neurotoxicity of nanodisc-bound Aβ oligomers are also reported.
Sacubitril/valsartan (LCZ696) Significantly Reduces Aldosterone and Increases cGMP Circulating Levels in a Canine Model of RAAS Activation
Authors: Mochel Jonathan P , Teng Chi Hse , Peyrou Mathieu , Giraudel Jerome , Danhof Meindert , Rigel Dean F
Published: October 2018

Simultaneous blockade of angiotensin receptors and enhancement of natriuretic peptides (NP) by the first-in-class angiotensin receptor neprilysin (NEP) inhibitor sacubitril/valsartan constitutes an effective approach to treating heart failure. This study examined the effects of sacubitril/valsartan (225 and 675mg/day) vs. placebo, sacubitril (360mg/day), valsartan (900mg/day), and benazepril (5mg/day) on the dynamics of the renin-angiotensin-aldosterone system (RAAS) and the NP system in dogs. Beagle dogs (n=18) were fed a low-salt diet (0.05% Na) for 15 days to model RAAS activation observed in clinical heart failure. Drugs were administered once daily during the last 10 days, while the effects on the RAAS and NPs were assessed on days 1, 5, and 10. Steady-state pharmacokinetics of the test agents were evaluated on day 5. Compared with placebo, sacubitril/valsartan (675mg) substantially increased cGMP circulating levels, while benazepril and valsartan showed no effect. Additionally, sacubitril/valsartan (675mg) and valsartan significantly increased plasma renin activity, angiotensin I and angiotensin II concentrations. Finally, sacubitril/valsartan (both doses), and valsartan significantly decreased plasma aldosterone vs. placebo. Systemic exposure to valsartan following sacubitril/valsartan 675mg administration was similar to that observed with valsartan 900mg administration alone. Sacubitril/valsartan favorably modulates the dynamics of the renin and NP cascades through complementary NEP and RAAS inhibition.
Multi-lab EcoFAB study shows highly reproducible physiology and depletion of soil metabolites by a model grass
Authors: Sasse Joelle , Kant Josefine , Cole Benjamin J , Klein Andrew P , Arsova Borjana , Schlaepfer Pascal , Gao Jian , Lewald Kyle , Zhalnina Kateryna , Kosina Suzanne , Bowen Benjamin P , Treen Daniel , Vogel John , Visel Axel , Watt Michelle , Dangl Jefferey L , Northen Trent R
Published: October 2018

There is a dynamic reciprocity between plants and their environment: On one hand, the physiochemical properties of soil influence plant morphology and metabolism, while on the other, root morphology and exudates shape the environment surrounding roots. Here, we investigate both of these aspects as well as the reproducibility of these responses across laboratories. The model grass Brachypodium distachyon was grown in phosphate-sufficient and phosphate-deficient mineral media, as well as in sterile soil extract, within fabricated ecosystem (EcoFAB) devices across four laboratories. Tissue weight and phosphate content, total root length, root tissue and exudate metabolic profiles were found to be consistent across laboratories and distinct between experimental treatments. Plants grown in soil extract were morphologically and metabolically distinct in all laboratories, with root hairs four times longer compared to other growth conditions. Further, plants depleted half of the investigated metabolites from the soil extract. To interact with their environment, plants not only adapt morphology and release complex metabolite mixtures; they also selectively deplete a range of soil-derived metabolites. The EcoFABs utilized here generated high inter-laboratory reproducibility, demonstrating that their value in standardized investigations of plant traits.
Rate of photosynthetic acclimation to fluctuating light varies widely among genotypes of wheat
Authors: Salter William T. , Merchant Andrew M. , Richards Richard A. , Trethowan Richard , Buckley Thomas N.
Published: October 2018

Highlight

Significant variation exists in the acclimation time of photosynthesis following dark-to-light transitions across wheat genotypes, under field and controlled conditions. Slow acclimation reduced daily carbon assimilation by up to 16%.

Crop photosynthesis and yield are limited by slow photosynthetic induction in sunflecks. We quantified variation in induction kinetics across diverse genotypes of wheat for the first time. In a preliminary study using penultimate leaves of 58 genotypes grown in the field, we measured induction kinetics for maximum assimilation rate (Amax) after a shift from full darkness to saturating light (1700 μmol m−2 s−1) with 1-4 replicates per genotype. We then grew 10 of these genotypes with contrasting responses in a controlled environment and quantified induction kinetics of carboxylation capacity (Vcmax) from dynamic A vs ci curves after a shift from low to high light (50 to 1500 μmol m−2 s−1), with 5 replicates per genotype. Within-genotype median time for 95% induction (t95) varied from 8.4 to 23.7 min across genotypes for Amax in field-grown penultimate leaves, and from 6.7 to 10.4 min for Vcmaxin chamber-grown flag leaves. Our simulations suggested that non-instantaneous acclimation reduces daily net carbon gain by up to 16%, and that breeding to speed up Vcmax induction in the slowest genotype to match that in the fastest genotype could increase daily net carbon gain by more than 4%, particularly for leaves that experience predominantly short-duration sunflecks.
Targeting RyR2 with a phosphorylation site-specific nanobody Reverses Dysfunction of Failing Cardiomyocytes in Rat
Authors: Li Tian , Shen Yafeng , Lin Fangxing , Fu Wenyan , Liu Shuowu , Fan Xiaoyan , Ye Xuting , Tang Ying , Ding Min , Yang Yongji , Lei Changhai , Hu Shi
Published: October 2018

Chronic PKA phosphorylation of RyR2 has been shown to increased diastolic SR Ca2+ leak and lead to cardiac dysfunction. Since the change of phosphorylation level of RyR2 is a biomarker of failing heart, we attempted to verify the hypothesis that intracellular gene delivery of a RyR2 targeting phosphorylation site-specific nanobody could preserve contractility of failing myocardium. In present study, we acquired the RyR2-specific nanobodies from a phage display library which are variable domains of camellidae heavy chain-only antibodies (VHH). One of the monoclonal nanobodies, AR185, inhibiting RyR2 phosphorylation in an in vitro assay was then chosen for further investigation. We investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of AR185 against post-ischemic heart failure. Adeno-associated virus gene delivery elevated the intracellular expression AR185 protein in the ischemic heart failure model of rats, and this treatment normalized the systolic and diastolic dysfunction of the failing myocardium in vivo and in vitro by reversing myocardial Ca2+ handling. Furthermore, AR185 gene transfer to failing cardiomyocytes reduced the frequency of sarcoplasmic reticulum (SR) calcium leak, thereby restoring the attenuated intracellular calcium transients and SR calcium load. Moreover, AR185 gene transfer inhibited PKA phosphorylation of RyR2 in failing cardiomyocytes. Our results provided strong pre-clinical experimental evidence of the cardiac expression of RyR2 nanobody with AAV9 vectors as a promising therapeutic strategy for ischemic heart failure.
A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity
Authors: Gazestani Vahid H. , Pramparo Tiziano , Nalabolu Srinivasa , Kellman Benjamin P. , Murray Sarah , Lopez Linda , Pierce Karen , Courchesne Eric , Lewis Nathan E.
Published: October 2018

Hundreds of genes are implicated in autism spectrum disorder (ASD) but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here, we analyzed leukocyte transcriptomics from 1-4 year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes genes that are highly expressed during fetal brain development and which is dysregulated in hiPSC-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS/ERK, PI3K/AKT, and WNT/β-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.
PEPOP: new approaches to mimic non-continous epitopes
Authors: Demolombe Vincent , de Brevern Alexandre , Felicori Liza , NGuyen Christophe , de Avila Ricardo Andrez Machado , Valera Lionel , Jardin-Watelet Bénédicte , Lavigne Géraldine , Lebreton Aurélien , Molina Franck , Moreau Violaine
Published: October 2018

Bioinformatics methods are helpful to identify new molecules for diagnostic or therapeutic applications. For example, the use of peptides capable of mimicking binding sites has several benefits as replacing a protein difficult to produce, or toxic. Using peptides is less expensive. Peptides are easier to manipulate, and can be used as drugs. Continuous epitope predicted by bioinformatics tools are commonly used and these sequential epitopes are used as such in further experiments. Numerous discontinuous epitope predictors have been developed but only two bioinformatics tools proposed so far to predict peptide sequences: Superficial and PEPOP. PEPOP can generate series of peptide sequences that can replace continuous or discontinuous epitopes in their interaction with their cognate antibody. We have developed an improved version of PEPOP dedicated to answer to the experimentalists’ need for a tool able to handle proteins and to turn them into peptides. The PEPOP web site has been reorganized by peptide prediction category and is therefore better formulated to experimental designs. Since the first version of PEPOP, 32 new methods of peptide design were developed. In total, PEPOP proposes 35 methods in which 34 deal specifically with discontinuous epitopes, the most represented epitope type in nature.

We present the user-friendly, well-structured web-site of PEPOP and its validation through the use of predicted immunogenic or antigenic peptides mimicking discontinuous epitopes in different experimental ways. PEPOP proposes 35 methods of peptide design to guide experimentalists in using peptides potentially capable of replacing the cognate protein in its interaction with an Ab.
Benchmarking the PEPOP methods for mimicking discontinuous epitopes
Authors: Demolombe Vincent , de Brevern Alexandre G. , Molina Franck , Lavigne Géraldine , Granier Claude , Moreau Violaine
Published: October 2018

Computational methods provide approaches to identify epitopes in protein antigens to help characterizing potential biomarkers identified by high-throughput genomic or proteomic experiments. PEPOP version 1.0 was developed as an antigenic or immunogenic peptide prediction tool. We have now improved this tool by implementing 32 new methods (PEPOP version 2.0) to guide the choice of peptides that mimic discontinuous epitopes and thus potentially able to replace the cognate protein antigen in its interaction with an antibody. In the present work, we describe these new methods and the benchmarking of their performances.

Benchmarking was carried out by comparing the peptides predicted by the different methods and the corresponding epitopes determined by X-ray crystallography in a dataset of 75 antigen-antibody complexes. The Sensitivity (Se) and Positive Predictive Value (PPV) parameters were used to assess the performance of these methods. The results were compared to that of peptides obtained either by chance or by using the SUPERFICIAL tool, the only available comparable method.

The PEPOP methods were more efficient than, or as much as chance, and 33 of the 34 PEPOP methods performed better than SUPERFICIAL. Overall, “optimized” methods (tools that use the traveling salesman problem approach to design peptides) can predict peptides that best match true epitopes in most cases.
Gibberellin response in the embryo epidermis regulates germination uniformity in response to seed priming
Authors: Mitchell Jack , Mukhtar Nur K. , Skinner Isobel , Bassel George W.
Published: October 2018

Uniformity in seed germination remains a primary objective in plant-based food production systems, ensuring predictable and synchronized harvest dates, while suppressing weeds. Treatments including priming can be used to increase germination uniformity and increase the value of commercial seeds. Despite the economic and agronomic importance of seed enhancement treatments, little is known as to how they work at a mechanistic level. Using a combination of molecular genetics and microscopy, we established that hydropriming limits embryo growth genetic programs at an early stage of germination. Conversely, gibberellin (GA) and abscisic acid (ABA)-associated molecular processes progress to later stages of this developmental chronology. The response to GA was specifically affected in the epidermis of germinating embryos in response to hydropriming based on reporter gene expression. The reduction of GA response specifically in the embryo epidermis resulted in increased uniformity of seed germination following hydropriming relative to control seeds. This represents the identification of both a molecular signalling pathway and cell type that are acting to enhance the agronomic germination properties of seed populations. This provides molecular and cellular targets which may be genetically manipulated to enhance seed germination and food production in agronomic species.
Pre-operarative Multivariate Connectome Analysis for Glioma Patients
Authors: Crimi Alessandro , Wiestler Benedikt , Kirschke Jan S. , Krieg Sandro M.
Published: October 2018

Recent advances in neuroimaging have allowed the use of network analysis to study the brain in a system-based approach. A system-based analysis of gliomas can shed light on mechanisms underlying neuronal connectivity and plasticity and the recovery process, and it could support surgical decision-making. Surgery has been shifting from image-guided surgery to a functional mapping-guided resection where several structural and functional modalities are used. However, reliable identification of eloquent areas during planning of surgical resection is still a challenge. Pre-operative language mapping performed by navigated transcranial magnetic stimulation (nTMS) is of great value as it elucidates functional cortical organization, which might be different from patient to patient due to the heterogeneity of the lesions and individual plasticity. In this paper we propose the construction of an “effective” speech network used for surgical decision making. This is achieved by mapping functionally relevant areas identified by nTMS on tractography-based connectomics. Subsequently we compute graph metrics on the identified speech networks of patients who show preoperative aphasia aiming to identify relevant differences between graph metrics in patients with and without preoperative aphasia. Lastly, the validity of the speech networks is examined by checking the involved graph communities.
Defining the RNA Interactome by Total RNA-Associated Protein Purification
Authors: Shchepachev Vadim , Bresson Stefan , Spanos Christos , Petfalski Elisabeth , Fischer Lutz , Rappsilber Juri , Tollervey David
Published: October 2018

UV crosslinking can be used to identify precise RNA targets for individual proteins, transcriptome-wide. We sought to develop a technique to generate reciprocal data, identifying precise sites of RNA-binding proteome-wide. The resulting technique, total RNA-associated protein purification (TRAPP), was applied to yeast (S. cerevisiae) and bacteria (E. coli). In all analyses, SILAC labelling was used to quantify protein recovery in the presence and absence of irradiation. For S. cerevisiae, we also compared crosslinking using 254 nm (UVC) irradiation (TRAPP) with 4-thiouracil (4tU) labelling combined with ~350 nm (UVA) irradiation (PAR-TRAPP). Recovery of proteins not anticipated to show RNA-binding activity was substantially higher in TRAPP compared to PAR-TRAPP. As an example of preferential TRAPP-crosslinking, we tested enolase (Eno1) and demonstrated its binding to tRNA loops in vivo. We speculate that many protein-RNA interactions have biophysical effects on localization and/or accessibility, by opposing or promoting phase separation for highly abundant protein. Homologous metabolic enzymes showed RNA crosslinking in S. cerevisiae and E. coli, indicating conservation of this property. TRAPP allows alterations in RNA interactions to be followed and we initially analyzed the effects of weak acid stress. This revealed specific alterations in RNA-protein interactions; for example, during late 60S ribosome subunit maturation. Precise sites of crosslinking at the level of individual amino acids (iTRAPP) were identified in 395 peptides from 155 unique proteins, following phospho-peptide enrichment combined with a bioinformatics pipeline (Xi). TRAPP is quick, simple and scalable, allowing rapid characterization of the RNA-bound proteome in many systems.
Pore-scale hydrodynamics influence the spatial evolution of bacterial biofilms in a microfluidic porous network
Authors: Aufrecht Jayde A. , Fowlkes Jason , Bible Amber N. , Morrell-Falvey Jennifer , Doktycz Mitchel J. , Retterer Scott T.
Published: October 2018

Bacteria occupy heterogeneous environments, attaching and growing within pores in materials, living hosts, and matrices like soil. Systems that permit high-resolution visualization of dynamic bacterial processes within the physical confines of a realistic and tractable porous media environment are rare. Here we use microfluidics to replicate the particle shape and packing density of natural sands in a 2D platform to study the flow-induced spatial evolution of bacterial biofilms underground. We discover that initial bacterial dispersal and particle attachment is a stochastic process driven by bacterial rheotactic transport across pore space velocity gradients. Over time, we find that gravity-driven flow conditions activate different cell-clustering phentoypes in EPS producing and EPS defective bacteria strains, which subsequently changes the overall spatial distribution of cells across the porous media network as colonies grow and alter the fluid dynamics of their microenvironment.