bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing the effects of in utero exposure to valproic acid on murine fetal heart development
Authors: Philbrook Nicola A. , Nikolovska Ana , Maciver Rebecca D. , Belanger Christine L. , Winn Louise M. 
Published: October 2019

AbstractBackgroundRecently, the use of the antiepileptic drug valproic acid (VPA) for the treatment of psychiatric conditions has been on the rise. However, studies have shown that in utero VPA exposure can affect embryonic development, including being associated with congenital heart defects. One proposed mechanism of VPA‐initiated teratogenicity is the inhibition of histone deacetylase, which is involved in the regulation of transcription factors that regulate cardiogenesis. Myocyte enhancing factor 2C (Mef2c), a transcription factor involved in the development of cardiac structure and cardiomyocyte differentiation, has been shown to increase in response to in utero VPA exposure, associating with contractile dysfunction and myocardial disorganization.MethodsTo characterize the effects of VPA on murine heart development, pregnant CD‐1 mice were dosed with 400 mg/kg of VPA on gestational day (GD) 9. Using high‐resolution ultrasound, we examined the effects of VPA on cardiac contractile function on GD 14–18, with fetal hearts being harvested on GD 19 for histological analysis. Lastly, we conducted quantitative real‐time polymerase chain reaction to measure the relative Mef2c gene expression in GD 16 murine hearts.ResultsWe observed structural anomalies at GD 19 in the hearts of VPA‐treated mice. Additionally, our results showed alterations in measures of cardiac contractility, with a decrease or increase in cardiac contractile ability in VPA‐treated mice depending on the GD and measurement taken.ConclusionsThese results further characterize the effects of VPA on heart development and suggest that alterations in Mef2c gene expression, at least on GD 16, do not mediate VPA‐induced cardiotoxicity in CD‐1 mice.
Developing higher‐order reading skills in mainstream primary schools: A metacognitive and self‐regulatory approach
Authors: Moir Taryn , Boyle James , Woolfson Lisa M. 
Published: October 2019

The ability to read relies upon not just decoding, but also comprehending text. Being a good comprehender requires strategic reading and implies the use of comprehension strategies. Research indicates that readers who are taught several reading comprehension strategies have better reading skills than those only taught a single strategy. One multiple strategy reading comprehension intervention was evaluated using a mixed‐model quasi‐experimental design. Intervention and control conditions groups were assessed at pre‐ and post‐test points with standardised reading comprehension abilities, measured as the primary outcome measure. Implementation science principles were observed and evaluated. The schools all served areas of low socio‐economic status. 74 pupils (aged 9–10) in five classes in four primary‐level mainstream schools in a Scottish local authority were recruited as participants. Training was provided to participating schools by the first author and the programme was delivered in four sessions of 45 minutes per week for 8 weeks. An ANCOVA revealed a statistically significant effect of condition. Statistically significant scores were also evident in the secondary outcome measures of decoding of target word skills, children’s self‐reports of their reading strategy use and recreational reading frequency. Implementation tools indicated that the intervention was acceptable and feasible to implement. Implications of introducing this multiple strategy reading comprehension programme and of the evaluation of implementation are discussed.
The influence of feedback and awareness of consequences on the development of corporate sustainability action over time
Authors: Hörisch Jacob , Wulfsberg Isabell , Schaltegger Stefan 
Published: October 2019

AbstractThe current level of corporate sustainability is insufficient for overcoming pressing environmental and social issues. Research is therefore needed about processes that lead to increased corporate action that fosters sustainable development. This study investigates the influence of feedback and corporate awareness of consequences on the development of corporate sustainability action over time. It uses action regulation theory to quantitatively analyse data of 59 large German companies measured at two points in time. The results reveal a positive temporal development of corporate sustainability action, and awareness of consequences positively mediates the relationship between corporate sustainability actions in two different time periods. Feedback acts as a moderator between the positive effect of corporate sustainability action in the first period on corporate awareness of consequences in the second period. Based on these findings, recommendations for organisations include the importance of seeking and processing feedback.
Activation of Protic, Hydridic and Apolar E−H Bonds by a Boryl‐Substituted GeII Cation
Authors: Mangan Robert J. , Rit Arnab , Sindlinger Christian P. , Tirfoin Rémi , Campos Jesús , Hicks Jamie , Christensen Kirsten E. , Niu Haoyu , Aldridge Simon 
Published: October 2019

AbstractThe synthesis of a boryl‐substituted germanium(II) cation, [Ge{B(NDippCH)2}(IPrMe)]+, (Dipp=2,6‐diisopropylphenyl) featuring a supporting N‐heterocyclic carbene (NHC) donor, has been explored through chloride abstraction from the corresponding (boryl)(NHC)GeCl precursor. Crystallographic studies in the solid state and UV/Vis spectra in fluorobenzene solution show that this species dimerizes under such conditions to give [(IPrMe){(HCNDipp)2B}Ge=Ge{B(NDippCH)2}(IPrMe)]2+ (IPrMe = 1,3‐diisopropyl‐4,5‐dimethylimidazolin‐2‐ylidene), which can be viewed as an imidazolium‐functionalized digermene. The dimer is cleaved in the presence of donor solvents such as [D8]thf or [D5]pyridine, to give monomeric adducts of the type [Ge{B(NDippCH)2}(IPrMe)(L)]+. In the case of the thf adduct, the additional donor is shown to be sufficiently labile that it can act as a convenient in situ source of the monomeric complex [Ge{B(NDippCH)2}(IPrMe)]+ for oxidative bond‐activation chemistry. Thus, [Ge{B(NDippCH)2}(IPrMe)(thf)]+ reacts with silanes and dihydrogen, leading to the formation of GeIV products, whereas the cleavage of the N−H bond in ammonia ultimately yields products containing C−H and B−N bonds. The facile reactivity observed in E−H bond activation is in line with the very small calculated HOMO–LUMO gap (132 kJ mol−1).
Hydride Transfer Enables the Nickel‐Catalyzed ipso‐Borylation and Silylation of Aldehydes
Authors: Srimontree Watchara , Guo Lin , Rueping Magnus 
Published: October 2019

AbstractNickel‐catalyzed ipso‐borylations and silylations of aldehydes are described for the first time. The new functional‐group interconversion protocol is characterized by its scalability, functional‐group tolerance and wide substrate scope, including examples of late‐stage functionalization of complex molecules. The key for the successful reaction outcome is the use of a ketone as a hydride acceptor that intercepts the nickel hydride to undergo a reductive pathway, thus allowing formation of the desired C−B and C−Si bonds.
Design of Extractive Reaction Systems
Authors: Rathgeb Andrea , Palmtag Andreas , Kaminski Sebastian , Jupke Andreas 
Published: October 2019

AbstractProduct selectivity and yield in chemical reactions can be limited by side product formation or low conversions due to equilibrium limitations. Extractive reaction systems (ERS) employ an in situ liquid‐liquid extraction that separates the product from the reaction phase to overcome these difficulties. The design of ERS requires a broad knowledge of the discipline of process intensification and extraction and reaction engineering. Furthermore, specific knowledge about the interplay of reaction and extraction phenomena is unique to ERS. This review gives an overview of the design of ERS and enables their application to any suitable reaction.
Au(I)‐Catalyzed Annulation of Benzofurazan N‐oxides with Ynamides: From Predicting the Chemo‐Selectivity to the Synthesis of 7‐Nitroindole Derivatives
Authors: Zhu Changlei , Kou Luyao , Bao Xiaoguang 
Published: October 2019

Summary of main observation and conclusionIt could be proposed that gold(I)‐catalyzed reactions of ynamides with benzofurazan N‐oxides might proceed through either O‐attack or N‐attack to afford α‐oxo or α‐imino Au(I)‐carbenoid intermediates. Computational studies were performed to predict that benzofurazan N‐oxides are ready to undergo the chemoselective N‐attack to the Au(I)‐activated ynamides to generate the α‐imino Au(I)‐carbenoid intermediate. Experimental studies were carried out to confirm the computational results and the 7‐nitroindole derivatives were synthesized in a concise and efficient manner. The unfavored O‐attack for benzofurazan N‐oxides, which is in contrast to nitrones and pyridine/quinoline N‐oxides, in the Au(I)‐catalyzed reactions with ynamides is rationalized.
Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists
Authors: Sato Ayumu , Fukase Yoshiyuki , Kono Mitsunori , Ochida Atsuko , Oda Tsuneo , Sasaki Yusuke , Ishii Naoki , Tomata Yoshihide , Fukumoto Shoji , Imai Yumi N. , Uga Keiko , Shibata Akira , Yamasaki Masashi , Nakagawa Hideyuki , Shirasaki Mikio , Skene Robert , Hoffman Isaac , Sang Bi‐Ching , Snell Gyorgy , Shirai Junya , Yamamoto Satoshi 
Published: October 2019

AbstractRetinoic‐acid‐related orphan receptor γt (RORγt) inverse agonists could be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1 a with a flexible linear linker as a novel RORγt inverse agonist. A U‐shaped conformation in the complex structure of 1 a with RORγt protein was confirmed. Further improvement of the pharmacokinetic (PK) profiles was required because of the low drug exposure in mice upon oral administration (mouse AUC of 1 a: 27 ng ⋅ h ⋅ mL−1 at 1 mg ⋅ kg−1, p.o.). To improve the PK profiles, conformationally constrained U‐shaped scaffolds were investigated. As a result, morpholine analogues with improved PK profiles and high potency were successfully identified. The substituent at the N1 position of the quinazoline moiety was also modified, leading to an enhancement of reporter activity. Consequently, compound 43 (N2‐(3‐chloro‐4‐cyanophenyl)‐N4‐(3‐(cyclopropylmethyl)‐1‐isopropyl‐2,4‐dioxo‐1,2,3,4‐tetrahydroquinazolin‐6‐yl)morpholine‐2,4‐dicarboxamide) exhibited improved drug exposure (mouse AUC: 1289 ng ⋅ h ⋅ mL−1 at 1 mg ⋅ kg−1, p.o.). In addition, suppression of IL‐17A gene expression by IL‐23 stimulation in a mouse pharmacodynamics model was observed for 43. The conformation of 43 with RORγt protein was also confirmed as U‐shape by X‐ray co‐crystal structure analysis. The key interaction that boosts potency is also discussed.
Translating a Low‐Molecular‐Weight MRI Probe Sensitive to Amino Acid Neurotransmitters into a PAMAM Dendrimer Conjugate: The Impact of Conjugation
Authors: Toljić Đorđe , Angelovski Goran 
Published: October 2019

AbstractA novel nano‐sized MRI probe sensitive to zwitterionic amino acid neurotransmitters (ZNTs) was prepared by the conjugation of bismacrocyclic ZNT‐responsive units to a generation 4 (G4) polyamidoamine (PAMAM) dendrimer. In vitro evaluation through 1H NMR relaxometric titrations provided binding profiles revealing a surface morphology‐dependent interaction with the ZNTs. The positively charged dendrimeric periphery gave higher initial relaxivities and a milder decrease upon interaction with the target molecules. To improve solubility under physiologically relevant conditions, polyethylene glycol (PEG) units were additionally conjugated to the dendrimeric surface. The PEGylated conjugate displayed discrimination towards acetylcholine and a slightly increased binding affinity towards glutamate over the massively abundant competitive metabolite hydrogencarbonate.
Effects of size‐ and sex‐selective harvesting: An integral projection model approach
Authors: Stubberud Marlene Wæge , Vindenes Yngvild , Vøllestad Leif Asbjørn , Winfield Ian J. , Stenseth Nils Christian , Langangen Øystein 
Published: October 2019

AbstractHarvesting is often size‐selective, and in species with sexual size dimorphism, it may also be sex‐selective. A powerful approach to investigate potential consequences of size‐ and/or sex‐selective harvesting is to simulate it in a demographic population model. We developed a population‐based integral projection model for a size‐ and sex‐structured species, the commonly exploited pike (Esox lucius). The model allows reproductive success to be proportional to body size and potentially limited by both sexes. We ran all harvest simulations with both lower size limits and slot limits, and to quantify the effects of selective harvesting, we calculated sex ratios and the long‐term population growth rate (λ). In addition, we quantified to what degree purely size‐selective harvesting was sex‐selective, and determined when λ shifted from being female to male limited under size‐ and sex‐selective harvesting. We found that purely size‐selective harvest can be sex‐selective, and that it depends on the harvest limits and the size distributions of the sexes. For the size‐ and sex‐selective harvest simulations, λ increased with harvest intensity up to a threshold as females limited reproduction. Beyond this threshold, males became the limiting sex, and λ decreased as more males were harvested. The peak in λ, and the corresponding sex ratio in harvest, varied with both the selectivity and the intensity of the harvest simulation. Our model represents a useful extension of size‐structured population models as it includes both sexes, relaxes the assumption of female dominance, and accounts for size‐dependent fecundity. The consequences of selective harvesting presented here are especially relevant for size‐ and sex‐structured exploited species, such as commercial fisheries. Thus, our model provides a useful contribution toward the development of more sustainable harvesting regimes.
Using co‐occurrence network topology in assessing ecological stress in benthic macroinvertebrate communities
Authors: Simons Ariel Levi , Mazor Raphael , Theroux Susanna 
Published: October 2019

AbstractEcological monitoring of streams has often focused on assessing the biotic integrity of individual benthic macroinvertebrate (BMI) communities through local measures of diversity, such as taxonomic or functional richness. However, as individual BMI communities are frequently linked by a variety of ecological processes at a regional scale, there is a need to assess biotic integrity of groups of communities at the scale of watersheds. Using 4,619 sampled communities of streambed BMIs, we investigate this question using co‐occurrence networks generated from groups of communities selected within California watersheds under different levels of stress due to upstream land use. Building on a number of arguments in theoretical ecology and network theory, we propose a framework for the assessment of the biotic integrity of watershed‐scale groupings of BMI communities using measures of their co‐occurrence network topology. We found significant correlations between stress, as described by a mean measure of upstream land use within a watershed, and topological measures of co‐occurrence networks such as network size (r = −.81, p < 10–4), connectance (r = .31, p < 10–4), mean co‐occurrence strength (r = .25, p < 10–4), degree heterogeneity (r = −.10, p < 10–4), and modularity (r = .11, p < 10–4). Using these five topological measures, we constructed a linear model of biotic integrity, here a composite of taxonomic and functional diversity known as the California Stream Condition Index, of groups of BMI communities within a watershed. This model can account for 66% of among‐watershed variation in the mean biotic integrity of communities. These observations imply a role for co‐occurrence networks in assessing the current status of biotic integrity for BMI communities, as well as their potential use in assessing other ecological communities.
Intergenerational effects of CO2‐induced stream acidification in the Trinidadian guppy (Poecilia reticulata)
Authors: George Hartley C. P. H. , Miles George , Bemrose James , White Amelia , Bond Matthew N. , Cameron Tom C. 
Published: October 2019

AbstractRising atmospheric carbon dioxide levels are driving decreases in aquatic pH. As a result, there has been a surge in the number of studies examining the impact of acidification on aquatic fauna over the past decade. Thus far, both positive and negative impacts on the growth of fish have been reported, creating a disparity in results. Food availability and single‐generation exposure have been proposed as some of the reasons for these variable results, where unrealistically high food treatments lead to fish overcoming the energetic costs associated with acclimating to decreased pH. Likewise, exposure of fish to lower pH for only one generation may not capture the likely ecological response to acidification that wild populations might experience over two or more generations. Here we compare somatic growth rates of laboratory populations of the Trinidadian guppy (Poecilia reticulata) exposed to pH levels that represent the average and lowest levels observed in streams in its native range. Specifically, we test the role of maternal acclimation and resource availability on the response of freshwater fishes to acidification. Acidification had a negative impact on growth at more natural, low food treatments. With high food availability, fish whose mothers were acclimated to the acidified treatment showed no reduction in growth, compared to controls. Compensatory growth was observed in both control–acidified (maternal–natal environment) and acidified–control groups, where fish that did not experience intergenerational effects achieved the same size in response to acidification as those that did, after an initial period of stunted growth. These results suggest that future studies on the effects of shifting mean of aquatic pH on fishes should take account of intergenerational effects and compensatory growth, as otherwise effects of acidification may be overestimated.
Developing and applying a macroinvertebrate‐based multimetric index for urban rivers in the Niger Delta, Nigeria
Authors: Edegbene Augustine O. , Arimoro Francis O. , Odume Oghenekaro N. 
Published: October 2019

AbstractUrban pollution of riverine ecosystem is a serious concern in the Niger Delta region of Nigeria. No biomonitoring tool exists for the routine monitoring of effects of urban pollution on riverine systems within the region. Therefore, the aim of this study was to develop and apply a macroinvertebrate‐based multimetric index for assessing water quality condition of impacted urban river systems in the Niger Delta region of Nigeria. Macroinvertebrate and physicochemical samples were collected from 11 stations in eight river systems. Based on the physicochemical variables, the stations were categorized into three impact categories namely least impacted stations (LIS), moderately impacted stations (MIS) and heavily impacted stations (HIS). Seventy‐seven (77) candidate metrics were tested and only five: Hemiptera abundance, %Coleoptera + Hemiptera, %Chironomidae + Oligochaeta, Evenness index and Logarithm of relative abundance of very large body size (>40–80 mm) were retained and integrated into the final Niger Delta urban multimetric index (MINDU). The validation dataset showed a correspondence of 83.3% between the index result and the physicochemically‐based classification for the LIS and a 75% correspondence for the MIS. A performance of 22.2% was recorded for the HIS. The newly developed MINDU proved useful as a biomonitoring tool in the Niger Delta region of Nigeria and can thus be used by environmental managers and government officials for routine monitoring of rivers and streams subjected to urban pollution.
Ocean warming and tropical invaders erode the performance of a key herbivore
Authors: Yeruham E. , Shpigel M. , Abelson A. , Rilov G. 
Published: October 2019

AbstractClimate change and bioinvasions are two facets of global change that can act in tandem to impact native species and ecosystems. However, their combined effects on key species have rarely been studied. The Mediterranean Sea is a hot spot of both ocean warming and bioinvasions, where their impact can be tested together. In recent years, the population of a key herbivore, the European purple sea urchin (Paracentrotus lividus), has virtually collapsed along the Israeli Mediterranean coast (southeastern Levant). Here, we used field and lab experiments to test two complementary hypotheses that may explain the urchin population collapse: (1) resource competition that may lead to competitive exclusion by invasive grazers (two Red Sea rabbitfishes) and (2) reduced performance due to ocean warming. An inclusion–exclusion in situ caging experiment revealed a strong negative impact of fish grazing on algal cover and on the urchin’s gut content and gonado‐somatic index (GSI). Laboratory experiments revealed a considerable negative impact of both elevated temperature and food deficiency on sea urchin respiration and GSI, and consequently on its energy budget and reproductive potential and, potentially, fitness. Such reduced reproductive capacity must have greatly lowered the sea urchin’s population viability, contributing (and possibly even leading) to its collapse in the southeastern Levant in the past two decades. Urchin population declines are expected to spread to the west and north of the Mediterranean Sea following further warming and rabbitfish expansion. This study is the first to demonstrate the potential additive effects of ocean warming and implied competitive exclusion by an invader on a native species at its warm biogeographic distribution edge.
Efficacy and harms of long‐term opioid therapy in chronic non‐cancer pain: Systematic review and meta‐analysis of open‐label extension trials with a study duration ≥26 weeks
Authors: Bialas Patric , Maier Christoph , Klose Petra , Häuser Winfried 
Published: October 2019

AbstractBackground and ObjectiveThis updated systematic review evaluated the efficacy, acceptability and safety of long‐term opioid therapy (LTOT) for chronic non‐cancer pain (CNCP).Databases and Data TreatmentClinicaltrials.gov, CENTRAL and MEDLINE until June 2019. We included open‐label extension trials with a study duration ≥26 weeks of RCTs with ≥2 weeks duration. Pooled estimates of event rates of categorical data and standardized mean differences (SMD) of continuous variables were calculated using a random effects model.ResultsWe added four new studies with 1,154 participants for a total of 15 studies with 3,590 participants. Study duration ranged between 26 and 156 weeks. Studies included patients with low back, osteoarthritis and neuropathic pain. The quality of evidence for every outcome was very low. 31.1% (95% Confidence interval [CI] 23.0%–40.7%) of patients randomized at baseline finished the open label period. 14.1% (95% CI 10.9%–19.4%) of patients dropped out to due adverse events. In 6.3% (95 CI 3.9%–10.1%) of patients serious adverse events and in 2.7% (95% CI 1.5%–4.7%) aberrant drug behaviour were noted. 0.5% (95% CI 0.2%–1.4%) of patients died.ConclusionsWithin the context of open‐label extension studies, opioids maintain reduction of pain and disability and are rather well tolerated and safe. LTOT can be considered in carefully selected and monitored patients with low back, osteoarthritis and neuropathic pain who experience a clinically meaningful pain reduction with at least tolerable adverse events in short‐term opioid therapy.SignificanceThere is very low quality evidence of the long‐term efficacy, tolerability and safety of opioids for chronic low back, osteoarthritis and diabetic polyneuropathic pain within the context of open‐label extension studies of randomized controlled trials. Drop out rate due to adverse events and deaths increase with study duration. One‐third of patients profit from LTOT. Long‐term opioid therapy can be considered in some carefully selected and monitored patients.