bluuebunny/crossref_metadata_2025_split huggingface dataset:
A 3D brain unit model to further improve prediction of local drug distribution within the brain
Authors: Vendel Esmée , Rottschäfer Vivi , de Lange Elizabeth C. M. 
Published: July 2019

AbstractThe development of drugs targeting the brain still faces a high failure rate. One of the reasons is a lack of quantitative understanding of the complex processes that govern the pharmacokinetics (PK) of a drug within the brain. While a number of models on drug distribution into and within the brain is available, none of these addresses the combination of factors that affect local drug concentrations in brain extracellular fluid (brain ECF).Here, we develop a 3D brain unit model, which builds on our previous proof-of-concept 2D brain unit model, to understand the factors that govern local unbound and bound drug PK within the brain. The 3D brain unit is a cube, in which the brain capillaries surround the brain ECF. Drug concentration-time profiles are described in both a blood-plasma-domain and a brain-ECF-domain by a set of differential equations. The model includes descriptions of blood plasma PK, transport through the blood-brain barrier (BBB), by passive transport via paracellular and trancellular routes, and by active transport, and drug binding kinetics. The impact of all these factors on ultimate local brain ECF unbound and bound drug concentrations is assessed.In this article we show that all the above mentioned factors affect brain ECF PK in an interdependent manner. This indicates that for a quantitative understanding of local drug concentrations within the brain ECF, interdependencies of all transport and binding processes should be understood. To that end, the 3D brain unit model is an excellent tool, and can be used to build a larger network of 3D brain units, in which the properties for each unit can be defined independently to reflect local differences in characteristics of the brain.Author summaryInsights on how a drug distributes within the brain over both time and space are still limited. Here, we develop a ‘3D brain unit model’ in order to understand the factors that control drug concentrations within a small piece of brain tissue, the 3D brain unit. In one 3D brain unit, the brain capillaries, which are the smallest blood vessels of the brain, surround the brain extracellular fluid (ECF). The blood-brain barrier (BBB) is located between the brain capillaries and the brain ECF. The model describes the impact of brain capillary blood flow, transport across the BBB, diffusion, flow and drug binding on the distribution of a drug within the brain ECF. We distinguish between free (unbound) drug and drug that is bound to binding sites within the brain. We show that all of the above mentioned factors affect drug concentrations within brain ECF in an interdependent manner. The 3D brain unit model that we have developed is an excellent tool to increase our understanding of how local drug concentrations within the brain ECF are affected by brain transport and binding processes.
Closer to critical resting-state neural dynamics in individuals with higher fluid intelligence
Authors: Ezaki Takahiro , Reis Elohim Fonseca dos , Watanabe Takamitsu , Sakaki Michiko , Masuda Naoki 
Published: July 2019

ABSTRACTAccording to the critical brain hypothesis, the brain is considered to operate near criticality and realize efficient neural computations. Despite the prior theoretical and empirical evidence in favor of the hypothesis, no direct link has been provided between human cognitive performance and the neural criticality. Here we provide such a key link by analyzing resting-state dynamics of functional magnetic resonance imaging (fMRI) networks at a whole-brain level. We develop a data-driven analysis method, inspired from statistical physics theory of spin systems, to map out the whole-brain neural dynamics onto a phase diagram. Using this tool, we show evidence that neural dynamics of human participants with higher fluid intelligence quotient scores are closer to a critical state, i.e., the boundary between the paramagnetic phase and the spin-glass (SG) phase. The present results are consistent with the notion of “edge-of-chaos” neural computation.
A copy number variant is associated with a spectrum of pigmentation patterns in the rock pigeon (Columba livia)
Authors: Bruders Rebecca , Hollebeke Hannah Van , Osborne E.J. , Kronenberg Zev , Yandell Mark , Shapiro Michael D. 
Published: July 2019

ABSTRACTRock pigeons (Columba livia) display an extraordinary array of pigment pattern variation. One such pattern, Almond, is characterized by a variegated patchwork of plumage colors that are distributed in an apparently random manner. Almond is a sex-linked, semi-dominant trait controlled by the classicalStipper(St) locus. Heterozygous males (ZStZ+sex chromosomes) and hemizygous Almond females (ZStW) are favored by breeders for their attractive plumage. In contrast, homozygous Almond males (ZStZSt) develop severe eye defects and lack all plumage pigmentation, suggesting that higher dosage of the mutant allele is deleterious. To determine the molecular basis of Almond, we compared the genomes of Almond pigeons to non-Almond pigeons and identified a candidateStlocus on the Z chromosome. We found a copy number variant (CNV) within the differentiated region that captures complete or partial coding sequences of four genes, including the melanosome maturation geneMlana. We did not find fixed coding changes in genes within the CNV, but all genes are misexpressed in regenerating feather bud collar cells of Almond birds. Notably, six other alleles at theStlocus are associated with depigmentation phenotypes, and all exhibit expansion of the same CNV. Structural variation atStis linked to diversity in plumage pigmentation and gene expression, and thus provides a potential mode of rapid phenotypic evolution in pigeons.AUTHOR SUMMARYThe genetic changes responsible for different animal color patterns are poorly understood, due in part to a paucity of research organisms that are both genetically tractable and phenotypically diverse. Domestic pigeons (Columba livia) have been artificially selected for many traits, including an enormous variety of color patterns that are variable both within and among different breeds of this single species. We investigated the genetic basis of a sex-linked color pattern in pigeons called Almond that is characterized by a sprinkled pattern of plumage pigmentation. Pigeons with one copy of the Almond allele have desirable color pattern; however, male pigeons with two copies of the Almond mutation have severely depleted pigmentation and congenital eye defects. By comparing the genomes of Almond and non-Almond pigeons, we discovered that Almond pigeons have extra copies of a chromosome region that contains a gene that is critical for the formation of pigment granules. We also found that different numbers of copies of this region are associated with varying degrees of pigment reduction. The Almond phenotype in pigeons bears a remarkable resemblance to Merle coat color mutants in dogs, and our new results from pigeons suggest that similar genetic mechanisms underlie these traits in both species. Our work highlights the role of gene copy number variation as a potential driver of rapid phenotypic evolution.
The alarmone (p)ppGpp is part of the heat shock response ofBacillus subtilis
Authors: Schäfer Heinrich , Beckert Bertrand , Steinchen Wieland , Nuss Aaron , Beckstette Michael , Hantke Ingo , Sudzinová Petra , Krásný Libor , Kaever Volkhard , Dersch Petra , Bange Gert , Wilson Daniel , Turgay Kürşad 
Published: July 2019

AbstractHere,B. subtiliswas used as a model organism to investigate how cells respond and adapt to proteotoxic stress conditions. Our experiments suggested that the stringent response, caused by raised levels of the (p)ppGpp alarmone, plays a role during thermotolerance development and the heat shock response. Accordingly, our experiments revealed a rapid increase of cellular (p)ppGpp levels upon heat shock as well as salt- and oxidative stress. Strains lacking (p)ppGpp exhibited increased stress sensitivity, while raised (p)ppGpp levels conferred increased stress tolerance to heat- and oxidative stress. During thermotolerance development, stress response genes were highly up-regulated together with a concurrent transcriptional down-regulation of the rRNA, which was influenced by the second messenger (p)ppGpp and the transcription factor Spx. Remarkably, we observed that (p)ppGpp appeared to control the cellular translational capacity and that during heat stress the raised cellular levels of the alarmone were able to curb the rate of protein synthesis. Furthermore, (p)ppGpp controls the heat-induced expression of Hpf and thus the formation of translationally inactive 100S disomes. These results indicate thatB. subtiliscells respond to heat-mediated protein unfolding and aggregation, not only by raising the cellular repair capacity, but also by decreasing translation involving (p)ppGpp mediated stringent response to concurrently reduce the protein load for the cellular protein quality control system.Author SummaryHere we demonstrate that the bacterial stringent response, which is known to slow down translation upon sensing nutrient starvation, is also intricately involved in the stress response ofB. subtiliscells. The second messengers (p)ppGpp act as pleiotropic regulators during the adaptation to heat stress. (p)ppGpp slows down translation and is also involved in the transcriptional down-regulation of the translation machinery, together with the transcriptional stress regulator Spx. The stress-induced elevation of cellular (p)ppGpp levels confers increased stress tolerance and facilitates an improved protein homeostasis by reducing the load on the protein quality control system.
Development of equations for converting random-zero to automated oscillometric blood pressure values
Authors: Yan Li , Wen Xiaoxiao , Dyer Alan R , Chen Haiyan , Zhou Long , Elliott Paul , Wu Yangfeng , Chan Queenie , Zhao Liancheng 
Published: July 2019

AbstractObjectiveThis study aimed to collect data to compare blood pressure values between random-zero sphygmomanometers and automated oscillometric devices and generate equations to convert blood pressure values from one device to the other.MethodsOmron HEM-907, a widely used automated oscillometric device in many epidemiologic surveys and cohort studies, was compared here with random-zero sphygmomanometers. Two hundred and one participants aged 40-79 years (37% men) were enrolled and randomly assigned to one of two groups with blood pressure measurement first taken by automated oscillometric devices or by random-zero sphygmomanometers. The study design enabled comparisons of blood pressure values between random-zero sphygmomanometers and two modes of this automated oscillometric device – automated and manual, and assessment of effects of measurement order on blood pressure values.ResultsAmong all participants, mean blood pressure levels were lowest when measured with random-zero sphygmomanometers compared with both modes of automated oscillometric devices. Several variables, including age and gender, were found to contribute to the blood pressure differences between random-zero sphygmomanometers and automated oscillometric devices. Equations were developed using multiple linear regression after taking those variables into account to convert blood pressure values by random-zero sphygmomanometers to automated oscillometric devices.ConclusionEquations developed in this study could be used to compare blood pressure values between epidemiologic and clinical studies or identify shift of blood pressure distribution over time using different devices for blood pressure measurements.
Yield, nutritional quality, and fatty acid content of organic winter rye (Secale cereale) and winter wheat (Triticum aestivum) forages under cattle (Bos taurus) grazing conditions
Authors: Phillips Hannah N. , Heins Bradley J. , Delate Kathleen , Turnbull Robert 
Published: July 2019

AbstractThe objective of this study was to assess yield, nutritional quality, and fatty acid compositions of winter rye (Secale cereale) and winter wheat (Triticum aestivum) forages for grazing cattle (Bos taurus) in an organic system. The rye and wheat were established on two 4 ha plots in September 2015. Six groups of dairy steers rotationally grazed rye (n = 3) or wheat (n = 3) plots divided into seven paddocks (n = 14) from April to June 2016. Forage samples (n = 96) taken prior to paddock grazing were used to analyze forage characteristics. Mixed models with fixed factors of forage, date, and their interaction, a random subject factor of group nested in paddock, and a repeated effect of date were used for each outcome. The linear effect of date on fatty acids was obtained by substituting date as a continuous variable. The mean forage yield for rye was greater (P < 0.05) than wheat (mean ± standard error; 2840 and 2571 ± 82 kg ha-1, respectively). However, rye yielded less in the latter part of the grazing period. Wheat (19.3 ± 0.30% DM) had greater (P < 0.001) crude protein than rye (17.6 ± 0.30% DM). In general, crude protein, digestibility, and minerals decreased during the grazing period. Wheat (66.3 ± 0.54 g 100g-1) had greater (P < 0.001) alpha-linolenic acid (18:3n-3) concentration than rye (63.3 ± 0.54 g 100g-1). Although both forages decreased (P < 0.05) in alpha-linolenic acid concentration, wheat decreased 2.49 times more (P < 0.001) per d compared to rye forage. Winter rye and winter wheat forages are viable for cattle grazing. Producers should initiate early grazing to maximize protein, digestibility, and alpha-linolenic acid intake while the forages are immature.
Linkage disequilibrium and haplotype block patterns in popcorn populations
Authors: Andrade Andréa Carla Bastos , Viana José Marcelo Soriano , Pereira Helcio Duarte , Pinto Vitor Batista , Silva Fabyano Fonseca e 
Published: July 2019

AbstractLinkage disequilibrium (LD) analysis provides information on evolutionary aspects of the populations and allows selecting populations and single nucleotide polymorphisms (SNPs) for association studies. Recently, haplotype blocks have been used to increase the power of quantitative trait loci detection in genome-wide association studies and the prediction accuracy with genomic selection. The objectives of this study were to compare the degree of LD, the LD decay, the LD decay extent, and the number and length of haplotype blocks in the populations and to elaborate the first LD map for maize, for elucidating if the maize chromosomes also had a pattern of interspaced regions of high and low rates of recombination. We used a biparental temperate population, a tropical synthetic, and a tropical breeding population, genotyped for approximately 75,000 SNPs. The level of LD expressed by the r2values is surprisingly low (0.02, 0.04, and 0.04), but comparable to some non-isolated human populations. The general evidence is that the synthetic is the population with higher LD. It is not expected a significant advantage of haplotype-based association study and along generations genomic selection due to the reduced number of SNPs in the haplotype blocks (2 to 3). The results concerning LD decay (rapid decay after 5-10 kb) and LD decay extent (along up to 300 kb) are in the range observed with maize inbred line panels. Our most important result is that maize chromosomes had a pattern of regions of extensive LD interspaced with regions of low LD. However, our simple simulated LD map provides evidence that this pattern can reflect regions with differences of allele frequencies and LD level (expressed by D’) and not regions with high and low rates of recombination.
Preserving cultural heritage: Analyzing the antifungal potential of ionic liquids tested in paper restoration
Authors: Schmitz Kevin , Wagner Sebastian , Reppke Manfred , Maier Christian L. , Windeisen-Holzhauser Elisabeth , Benz J. Philipp 
Published: July 2019

AbstractEarly industrialization and the development of cheap production processes for paper have led to an exponential accumulation of paper-based documents during the last two centuries. Archives and libraries harbor vast amounts of ancient and modern documents and have to undertake extensive endeavors to protect them from abiotic and biotic deterioration. While services for mechanical preservation such asex postde-acidification of historic documents are already commercially available, the possibilities for long-term protection of paper-based documents against fungal attack (apart from temperature and humidity control) are very limited. Novel processes for mechanical enhancement of damaged cellulosic documents use Ionic Liquids (IL) as essential process components. With some of these ILs having azole-functionalities similar to well-known fungicides such as Clotrimazole, the possibility of antifungal activities of these ILs was proposed but has not yet been experimentally confirmed.We evaluated the potency of four ILs with potential application in paper restoration for suppression of fungal growth on five relevant paper-infesting molds. The results revealed a general antifungal activity of all ILs, which increased with the size of the non-polar group. Physiological experiments and ultimate elemental analysis allowed to determine the minimal inhibitory concentration of each IL as well as the residual IL concentration in process-treated paper. These results provide valuable guidelines for IL-applications in paper restoration processes with antifungal activity as an added benefit. With azoles remaining in the paper after the process, simultaneous repair and biotic protection in treated documents could be facilitated.
The origin of extracellular DNA in bacterial biofilm infectionsin vivo
Authors: Alhede Maria , Alhede Morten , Qvortrup Klaus , Kragh Kasper Nørskov , Jensen Peter Østrup , Stewart Philip Shook , Bjarnsholt Thomas 
Published: July 2019

AbstractExtracellular DNA (eDNA) plays an important role in both the aggregation of bacteria and in the interaction of the resulting biofilms with polymorphonuclear leukocytes (PMNs) during an inflammatory response. Here, transmission electron and confocal scanning laser microscopy were used to examine the interaction between biofilms ofPseudomonas aeruginosaand PMNs in a murine implant model and in lung tissue from chronically infected cystic fibrosis patients. PNA FISH, DNA staining, labeling of PMN DNA with a thymidine analogue, and immunohistochemistry were applied to localize bacteria, eDNA, PMN-derived eDNA, PMN-derived histone H3 (H3), neutrophil elastase (NE), and citrullinated H3 (citH3). Host-derived eDNA was observed surrounding bacterial aggregates but not within the biofilms. H3 localized to the lining of biofilms while NE was found throughout biofilms. CitH3, a marker for neutrophil extracellular traps (NETs) was detected only sporadically indicating that most host-derived eDNAin vivowas not a result of NETosis. Together these observations show that, in thesein vivobiofilm infections withP. aeruginosa, the majority of eDNA is found external to the biofilm and derives from the host.Author summaryThe role of extracellular DNA (eDNA) has been describedin vitroto play a major role in biofilm formation and antibiotic tolerance, but never for biofilm infectionsin vivo.Two important characteristics of human chronic bacterial infections are aggregated bacteria and white blood cells (WBC). Bacteria use eDNA to stabilize biofilms and WBC use eDNA to trap bacteria. Given the importance of eDNA for both bacteria and WBC we show here for the first time that bacterial biofilms do not co-localize with either bacterial or WBC-derived eDNA during chronic infections. Ourin vivofindings show eDNA is located outside biofilms as opposed to incorporated within the biofilm as commonly observedin vitro.We believe that understanding the interplay between biofilms and WBC during chronic infection is essential if we are to elucidate the mechanisms underlying persistent infection and ascertain why WBC fail to eradicate bacteria; this will enable us to develop new treatment strategies.
Peripartum interventions resulting in reduced perinatal mortality rates, and birth asphyxia rates, over 18 years in a tertiary centre in South India: a retrospective study
Authors: Ebenezer ED , Londhe V , Rathore S , Benjamin S , Ross B , Jeyaseelan L , Mathews JE 
Published: July 2019

ObjectiveTo study the changes in the rates of perinatal mortality, birth asphyxia, and caesarean sections in relation to interventions implemented over the past 18 years, in a tertiary centre in South India.DesignRetrospective study.SettingLabour and maternity unit of a tertiary centre in South India.Population or sampleWomen who gave birth between 2000 and 2018.MethodsInformation from perinatal audits, chart reviews, and data retrieved from the electronic database were used. Interventions implemented during this time period were audits and training, obstetric re‐organisation, and minor changes in staffing and infrastructure.Main outcome measuresMain outcome measures were perinatal mortality rate, birth asphyxia rate, and caesarean section rate.ResultsPerinatal mortality rate decreased from 44 per 1000 births in 2000 to 16.4 per 1000 births in 2018 (P < 0.001). The rates of babies born with birth asphyxia requiring admission to the neonatal unit decreased from 24 per 1000 births in 2001 to 0.7 per 1000 births in 2018 (P < 0.00001). The overall caesarean section rate was maintained close to 30%.ConclusionIn a large tertiary hospital in South India, with 14 000 deliveries per year, a policy of rigorous audits of stillbirths and birth asphyxia, electronic fetal monitoring, and the introduction of standardised criteria for trial of scar, reduced the perinatal mortality and the rate of babies born with birth asphyxia over the past 18 years, without an increase in the caesarean section rate.Tweetable abstractRigorous perinatal audits with training in fetal cardiotocography, decreased birth asphyxia, without a major increase in caesarean rates.