bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of oral administration of 1,3-1,6 β-glucans in DWV naturally infected newly emerged bees (Apis mellifera L.)
Authors: Antonio Felicioli , Mario Forzan , Simona Sagona , Paola D’agostino , Baido Diego , Baldassare Fronte , Maurizio Mazzei
Published: December 2019

Honeybee pathogens have an important role in honeybee colony mortality and colony losses, most of them are widely spread and necessitate worldwide solutions to contrast honeybee’s decline. Possible accepted solutions to cope with the spread of honeybee’s pathogen are focused on the study of experimental protocols to enhance the insect’s immune defences. Honeybee’s artificial diet capable to stimulate the immune system is a promising field of investigation as ascertained by the introduction of 1,3-1,6 β-glucans as a dietary supplement. In this work, by collecting faecal samples of honeybees exposed to different dietary conditions of 1,3-1,6 β-glucans (0.5% and 2% w/w), it has been possible to investigate the DWV viral load kinetic without harming the insects. Virological data obtained by a one-step TaqMan RT-PCR highlights the ability of 1,3-1,6 β-glucans to reduce the viral load at 24thday of rearing. Furthermore, results indicated that the diet supplemented with 1,3-1,6 β-glucans was associated with a dose-dependent activation of phenoloxidase. Control group showed a higher survival rate than honeybees exposed to different dietary conditions of 1,3-1,6 β-glucans while no differences have been observed concerning syrup daily consumption.
GCNG: Graph convolutional networks for inferring cell-cell interactions
Authors: Yuan Ye , Bar-Joseph Ziv
Published: December 2019

Several methods have been developed for inferring gene-gene interactions from expression data. To date, these methods mainly focused on intra-cellular interactions. The availability of high throughput spatial expression data opens the door to methods that can infer such interactions both within and between cells. However, the spatial data also raises several new challenges. These include issues related to the sparse, noisy expression vectors for each cell, the fact that several different cell types are often profiled, the definition of a neighborhood of cell and the relatively small number of extracellular interactions. To enable the identification of gene interactions between cells we extended a Graph Convolutional Neural network approach for Genes (GCNG). We encode the spatial information as a graph and use the network to combine it with the expression data using supervised training. Testing GCNG on spatial transcriptomics data we show that it improves upon prior methods suggested for this task and can propose novel pairs of extracellular interacting genes. Finally, we show that the output of GCNG can also be used for down-stream analysis including functional assignment.

Supporting website with software and data:https://github.com/xiaoyeye/GCNG.
Two distinct bacterial biofilm components trigger metamorphosis in the colonial hydrozoanHydractinia echinata
Authors: Guo Huijuan , Rischer Maja , Westermann Martin , Beemelmanns Christine
Published: December 2019

In the marine environment bacterial-induced metamorphosis of larvae is a widespread cross-kingdom communication phenomenon and critical for the persistence of many marine invertebrates. However, the identities of most inducing bacterial signals and the underlying cellular mechanisms remain enigmatic. Larvae ofHydractinia echinataprovide an excellent model for investigating bacteria-stimulated settlement as they transform upon detection of the signal into the colonial adult stage within 24 h. AlthoughH. echinataserved as cell biological model system for decades, the influence of bacterial signals on the morphogenic transition remained largely unexplored. Using a bioassay-guided analysis, we first identified that specific bacterial (lyso)phospholipids, naturally present in bacterial biofilms, elicit metamorphosis inHydractinialarvae in a dose-response matter. In particular, lysophospholipids as single compounds or in combinations at 50 µM concentrations induced metamorphosis in up to 50% of all larvae phospholipid within 48 h. By using fluorescence-labeled bacterial phospholipids, we demonstrated their incorporation into the larval membranes, where interactions with internal signaling cascades could occur. In addition, two structurally distinct exopolysaccharides, the newly identified Rha-Man polysaccharide fromPseudoalteromonassp. P1-9 and curdlan fromAlcaligenes faecaliscaused up to 75% of all larvae to transform within 24 h. We also found that combinations of (lyso)phospholipids and curdlan induced the transformation in almost all larvae within 24 h, thereby exceeding the morphogenic activity observed for single compounds and axenic bacterial biofilms. Our results demonstrate that multiple and structurally distinct bacterial-derived metabolites converge to induce high transformation rates ofHydractinialarvae, which might ensure optimal habitat selection despite the general widespread occurrence of both compound classes.

Significance Statement

Bacterial biofilms profoundly influence the recruitment and settlement of marine invertebrates, critical steps for diverse marine processes such as coral reef formation, marine fisheries and the fouling of submerged surfaces. Yet, the complex composition of biofilms often makes it challenging to characterize the individual signals and regulatory mechanisms. Developing tractable model systems to characterize these co-evolved interactions is the key to understand fundamental processes in evolutionary biology. Here, we characterized for the first time two types of bacterial signaling molecules that induce the morphogenic transition and analyzed their abundance and combinatorial activity. This study highlights the crucial role of the converging activity of multiple bacterial signals in development-related cross-kingdom signaling.

Areas

Major: Chemical Biology, Microbiology, Developmental Biology
A novel mouse model expressing human forms for complement receptorsCR1andCR2
Authors: Jackson Harriet M. , Foley Kate E. , O’Rourke Rita , Stearns Timothy M. , Fathalla Dina , Morgan B Paul , Howell Gareth R.
Published: December 2019

The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer’s disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, includingCR1andCR2. Genetic variation inCR1andCR2have been implicated in modifying disease states but the mechanisms are not known. To decipher the roles of humanCR1andCR2in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murineCr2with human complement receptors,CR1andCR2(B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frtandCre-loxP) two of the most common alleles (referred to asCR1longandCR1short) are replicated within this mouse model, along with a CR1 knockout allele (CR1KO). Transcriptional profiling of spleens and brains identifies genes and pathways differentially expressed between mice homozygous for eitherCR1long,CR1shortorCR1KO. Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated byCR1long, but notCR1shortorCR1KO. Therefore, this mouse model provides a novel tool for determining the relationship between human-relevantCR1alleles and disease.

Summary Statement

We present the creation and validation of a novel mouse model that expresses human forms of complement cascade regulators CR1 and CR2.
Identification of pathogenic variant enriched regions across genes and gene families
Authors: Pérez-Palma Eduardo , May Patrick , Iqbal Sumaiya , Niestroj Lisa-Marie , Du Juanjiangmeng , Heyne Henrike O. , Castrillon Jessica A. , O'Donnell-Luria Anne , Nürnberg Peter , Palotie Aarno , Daly Mark , Lal Dennis
Published: December 2019

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene-family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2871 gene-family protein sequence alignments involving 9990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 76,153 missense variants from patients. With this gene-family approach, we identified 465 regions enriched for patient variants spanning 41,463 amino acids in 1252 genes. As a comparison, by testing the same genes individually, we identified fewer patient variant enriched regions, involving only 2639 amino acids and 215 genes. Next, we selected de novo variants from 6753 patients with neurodevelopmental disorders and 1911 unaffected siblings and observed an 8.33-fold enrichment of patient variants in our identified regions (95% C.I. = 3.90-Inf, P-value = 2.72 × 10−11). By using the complete ClinVar variant set, we found that missense variants inside the identified regions are 106-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 106.15, 95% C.I = 70.66-Inf, P-value < 2.2 × 10−16). All pathogenic variant enriched regions (PERs) identified are available online through “PER viewer,” a user-friendly online platform for interactive data mining, visualization, and download. In summary, our gene-family burden analysis approach identified novel PERs in protein sequences. This annotation can empower variant interpretation.
Asymmetric repair of UV damage in nucleosomes imposes a DNA strand polarity on somatic mutations in skin cancer
Authors: Mao Peng , Smerdon Michael J. , Roberts Steven A. , Wyrick John J.
Published: December 2019

Nucleosomes inhibit excision repair of DNA damage caused by ultraviolet (UV) light, and it has been generally assumed that repair inhibition is equivalent on both sides of the nucleosome dyad. Here, we use genome-wide repair data to show that repair of UV damage in nucleosomes is asymmetric. In yeast, nucleosomes inhibit nucleotide excision repair (NER) of the nontranscribed strand (NTS) of genes in an asymmetric manner, with faster repair of UV damage occurring on the 5′ side of the nucleosomal DNA. Analysis of genomic repair data from UV-irradiated human cells indicates that NER activity along the NTS is also elevated on the 5′ side of nucleosomes, consistent with the repair asymmetry observed in yeast nucleosomes. Among intergenic nucleosomes, repair activity is elevated on the 5′ side of both DNA strands. The distribution of somatic mutations in nucleosomes shows the opposite asymmetry in NER-proficient skin cancers, but not in NER-deficient cancers, indicating that asymmetric repair of nucleosomal DNA imposes a strand polarity on UV mutagenesis. Somatic mutations are enriched on the relatively slow-repairing 3′ side of the nucleosomal DNA, particularly at positions where the DNA minor groove faces away from the histone octamer. Asymmetric repair and mutagenesis are likely caused by differential accessibility of the nucleosomal DNA, a consequence of its left-handed wrapping around the histone octamer.
Complexation of the nickel and cobalt transcriptional regulator RcnR with DNA
Authors: Li Chao , Vavra Joseph W. , Carr Carolyn E. , Huang Hsin-Ting , Maroney Michael J. , Wilmot Carrie M.
Published: December 2019

RcnR is a transcription factor that regulates the homeostasis of cobalt and nickel in bacterial cells. Escherichia coli RcnR was crystallized with DNA that encompasses the DNA-binding site. X-ray diffraction data were collected to 2.9 Å resolution. The crystal belonged to space group P6122 or P6522, with unit-cell parameters a = b = 73.59, c = 157.66 Å, α = β = 90, γ = 120°.
Crystal structure and Hirshfeld surface analysis of a copper(II) complex with ethylenediamine and non-coordinated benzoate
Authors: Qadir Adnan M. , Kansiz Sevgi , Rosair Georgina M. , Dege Necmi , Iskenderov Turganbay S.
Published: December 2019

In the title compound, diaquabis(ethylenediamine-κ2
N,N′)copper(II) bis(2-nitrobenzoate), [Cu(C2H8N2)2(H2O)2](C7H4NO4)2, two diaquabis(ethylenediamine)copper(II) cations and four nitrobenzoate anions are present in the asymmetric unit. All four anions are `whole-molecule' disordered over two sets of sites. The major components have refined occupancies of 0.572 (13), 0.591 (9), 0.601 (9) and 0.794 (10). The CuII ions exhibit slightly distorted octahedral geometries. In the crystal, cations and anions are connected to each other via N—H...O and O—H...O hydrogen bonds, forming a two-dimensional network parallel to (200). The intermolecular contacts in the crystal were further analysed using Hirshfeld surface analysis, which indicates that the most significant contacts are O...H/H...O (42.9%), followed by H...H (35.7%), C...H/H...C (14.2%), C...C (2.9%), C...O/O...C (2.2%), N...H/H...N (0.9%) and N...O/O...N (0.3%).
2-[4,5-Bis(4-bromophenyl)-1-(4-tert-butylphenyl)-1H-imidazol-2-yl]-4,6-dichlorophenol
Authors: Devika S. , Shraddha K. N. , Begum Noor Shahina
Published: December 2019

In the title compound, C31H24Br2Cl2N2O, the dihedral angles subtended by the tert-butyl-phenyl, 4,6-dichlorophenol and 4-bromophenyl (×2) rings are 70.7 (3), 8.1 (3), 28.1 (3) and 84.2 (3)°, respectively. The orientations of the pendant rings may be related to intramolecular O—H...N and C—H...π interactions. One of the tert-butyl methyl groups is disordered over two sets of sites in a 0.54 (3):0.46 (3) ratio. In the crystal, a weak C—H...π interaction generates inversion dimers.
Costs and benefits of multiple mating in a species with first‐male sperm precedence
Authors: Rodrigues Leonor R. , Figueiredo Alexandre R. T. , Van Leeuwen Thomas , Olivieri Isabelle , Magalhães Sara
Published: December 2019

Different patterns of sperm precedence are expected to entail different costs and benefits of mating for each sex that translate into distinct predictions regarding mating system evolution. Still, most studies addressing these costs and benefits have focused on species with mixed paternity or last male precedence, neglecting first‐male sperm precedence. We attempted to understand whether this latter pattern of sperm precedence translates into different costs and benefits for each sex in the haplodiploid spider mite Tetranychus urticae, a species in which female multiple mating is prevalent but most offspring are sired by first males.

First, we assessed the stability of the sperm precedence pattern. To do so, we measured offspring paternity after exposing females to a different number of matings and mating intervals. Next, to determine the potential costs or benefits of multiple mating for females under different contexts, we measured the fecundity and survival of females that re‐mated at different time points. To measure the potential costs of multiple mating for males, we analysed male survival in the presence of different numbers of virgin or mated females. We also tested whether males can reduce offspring production of their competitors, by reducing the production of fertilized offspring of mated females.

We found no change in the pattern of sperm precedence, independently of the mating interval between matings and the number of matings. Females paid a cost of mating, as multiply‐mated females laid fewer eggs than once‐mated females. However, while males had reduced survival when exposed to an intermediate number of virgin females, they paid no additional costs of mating with mated females. Moreover, females that mated multiple times produced fewer fertilized offspring than females that mated once. Thus, males that copulated with mated females reduced the fitness of other males, potentially leading to a relative fitness benefit for themselves.

Our results show that complex costs and benefits may arise in males in species with first‐male sperm precedence. How these costs and benefits affect the maintenance of selection for polyandry remains an open question.
Plant nutrient supply alters the magnitude of indirect interactions between insect herbivores: From foliar chemistry to community dynamics
Authors: Han Peng , Becker Christine , Le Bot Jacques , Larbat Romain , Lavoir Anne‐Violette , Desneux Nicolas
Published: December 2019

Density‐ and trait‐mediated indirect interactions (DMIIs and TMIIs respectively) are important drivers of community dynamics but how plant nutrients (bottom‐up effects) affect the magnitude of such indirect interactions has been scarcely addressed.

To assess the impact of bottom‐up forces on indirect interactions, we carried out laboratory and greenhouse experiments manipulating plant nutrient supplies in a four‐species diamond food web consisting of a plant (tomato), two phytophagous insects (a leafminer and an aphid) and a predator (a mirid bug) attacking both herbivores.

Multiple negative indirect effects of the leafminer occurred towards the aphid. The presence of its eggs negatively affected aphid population growth through increased predator abundance (DMIIs), and larval herbivory slowed down aphid development and negatively modulated aphid behaviours, for example they spent less time feeding (TMIIs), likely owing to enhanced plant chemical defences and/or decreased plant nutritional quality. Moreover, the low plant nutrient supply further magnified TMIIs.

Synthesis. Abiotic factors modulated predator‐ and plant‐mediated indirect interactions among herbivorous community members. Our study highlights the importance of using a holistic approach, from foliar chemistry to community dynamics, for disentangling interspecific interactions in a simple food web.
A systematic review of clinical practice guidelines on uncomplicated birth
Authors: Zhao Y , Lu H , Zang Y , Li X
Published: December 2019

Background

Clinical practice guidelines on uncomplicated birth provide clinical practice guidance and help to reduce unnecessary, non‐evidence‐based and potentially harmful intrapartum care practices. Little is known about the trustworthiness and consistency of these guidelines.

Objectives

To appraise guidelines relevant to uncomplicated birth, and summarise consensus and non‐consensus recommendations.

Search strategy

Eight literature databases and the websites of guideline development institutions and organisations of obstetricians, gynaecologists and midwives were searched from January 2008 to October 2018.

Selection criteria

Guidelines that: reported in Chinese or English; labelled guideline, or recommendation, or consensus, or practice parameter, or position paper/stand; with uncomplicated birth being the primary objectives or comprised chapter(s); and were the most recently published or updated versions.

Data collection and analysis

Two reviewers independently assessed guideline quality using the AGREE II instrument, and synthesised consensus and non‐consensus recommendations using the content analysis approach.

Main results

Eleven guidelines met the inclusion criteria. The WHO and NICE guidelines were deemed to have the highest methodological quality. Twenty‐three discrepant recommendations and 39 groups of unanimous recommendations (containing 113 individual ones) were identified, among which 14 recommendations including eating and drinking as desired, prophylactic uterotonics, routine amniotomy and episiotomy were included in five or more guidelines. Perineal massage, uterine massage, active or expectant management at the third stage and use of hands‐on or hands‐poised technique were identified as the main discrepant recommendations.

Conclusions

Two guidelines with higher methodological quality and key clinical guideline recommendations, including both consensus and non‐consensus ones, on uncomplicated birth were identified.

Tweetable abstract

Clinical guidelines of uncomplicated birth agree and disagree on several key recommendations.
Implementation of a Blind Quality Control Program in a Forensic Laboratory
Authors: Hundl Callan , Neuman Maddisen , Rairden Alicia , Rearden Preshious , Stout Peter
Published: December 2019

A blind quality control (QC) program was successfully developed and implemented in the Toxicology, Seized Drugs, Firearms, Latent Prints (Processing and Comparison), Forensic Biology, and Multimedia (Digital and Audio/Video) sections at the Houston Forensic Science Center (HFSC). The program was put into practice based on recommendations set forth in the 2009 National Academy of Sciences report and is conducted in addition to accreditation required annual proficiency tests. The blind QC program allows HFSC to test its entire quality management system and provides a real‐time assessment of the laboratory’s proficiency. To ensure the blind QC cases mimicked real casework, the workflow for each forensic discipline and their evidence submission processes were assessed prior to implementation. Samples are created and submitted by the HFSC Quality Division to whom the expected answer is known. Results from 2015 to 2018 show that of the 973 blind samples submitted, 901 were completed, and only 51 were discovered by analysts as being blind QC cases. Implementation data suggests that this type of program can be employed at other forensic laboratories.
Gender and the Preservation of Family Farming in Ireland
Authors: Balaine Lorraine
Published: December 2019

Family farming is the main model of European agriculture and is a means to promote rural development, agricultural sustainability and safeguarding of cultural heritage. Nevertheless, changes in modern societies and commodity markets lead to disruptions in the traditional family farming model and increasingly challenge its preservation. In this changing environment, many farmers strive to secure intergenerational farm transfer, but women are sometimes still disadvantaged in inheriting the family enterprise. In Ireland, farm succession patterns are dictated by patrilineal socio‐cultural values. This not only causes gender equality issues, but it also limits the poll of potential successors when willing candidates can be scarce. Men occupy the hegemonic position of the farmer and women are subordinated to the role of the farmer's wife. With these gender roles come societal expectations of what a traditional male farmer is. Problems arise from a disconnect between this traditional identity and the current reality of Irish farmers. Reliance on off‐farm income, social isolation and the high pace of societal change contribute to reduced well‐being of rural men. In this context, it is argued that evolution of patriarchal socio‐cultural norms underpinning family farming could lead to a redefinition of gender roles, thereby reducing the pressure on farm men and empowering farm women.
Comparative analysis of native and defatted flour from hard, extraordinarily soft, and medium‐hard wheat varieties for protein solvation, pasting, mixing, and dough rheological behavior
Authors: Katyal Mehak , Singh Narpinder , Virdi Amardeep Singh , Kaur Amritpal , Ahlawat Arvind Kumar , Singh Anju Mahendru , Bajaj Ritika
Published: December 2019

The effect of lipids extraction on protein salvation, pasting, and dough rheological behavior of flours dough from hard wheat (HW), extraordinarily soft wheat (Ex‐SW), and medium‐hard wheat (MHW) flour was analyzed. The varieties selected had wide variation in grain hardness index (17 to 95). Ex‐SW revealed lower tryptophan fluorescent emission and water absorption (WA) than MHW and HW varieties. The change in pasting parameters on defatting was the highest for Ex‐SW varieties. Native flour (NF) of HW varieties showed high protein content, pasting and dough strength, and fluorescence intensity in comparison to Ex‐SW varieties, while on defatting this was reversed. Protein pattern of defatted flour and NF did not differ significantly. Defatting of flours increased WA and decreased dough stability (DS). The decrease in DS on defatting was more for Ex‐SW varieties than others. DS for HW and MHW varieties reduced upon defatting. Defatting significantly increased all mixographic and rheological properties except peak time. Overall, results showed that defatting of flour improved paste and dough strength.

Practical Application

Higher gluten strength of defatted wheat flour of varied grain hardness has wide applications. Most of the Indian bread wheat varieties possess GluD1 high‐molecular‐weight glutenin subunit (HMW‐GS) allelic composition of (2 + 12), which is not suitable for bread making due to weak gluten strength. Defatting of flours improved the gluten strength of strong and weak flour dough of different wheat varieties irrespective of GluD1 allelic composition for HMW‐GS. Defatted flour may be used to improve the baking and cooking performance of dough made from weak wheat. These findings are highly suitable for wheat milling and baked product manufacturing industries.
Valorization of Euterpe edulis Mart. agroindustrial residues (pomace and seeds) as sources of unconventional starch and bioactive compounds
Authors: Carpiné Danielle , Dagostin João Luiz Andreotti , Mazon Elisa , Barbi Rafaela Cristina Turola , Alves Fillemon Edillyn da Silva Bambirra , Chaimsohn Francisco Paulo , Ribani Rosemary Hoffmann
Published: December 2019

Juçara fruit pomace is one of the most abundant byproducts of the pulp‐making process, generally discarded despite their attractive nutritional content. In this sense, this study aimed to investigate the potential of juçara fruit pomace as an alternative source of starch and natural dyes. Starch extracted from juçara seed (JS) was characterized in approximate composition, crystallinity, thermal profile, morphology, and equilibrium moisture data. Total phenolic content, anthocyanins content, and in vitro antioxidant capacity were assessed for the juçara seedless pomace (JSP). JSP is rich in monomeric anthocyanins (7.19 to 7.23 mg cyanidin 3‐O‐glycoside/g dry matter [dm]), presents high antioxidant potential, elevated dietary fibers (72.7% dm), considerable amount of lipids (12.8% dm), low protein content, and ash traces. JS is a rich carbon source (76.91% fibers [dm]; 12.21% amylaceous reserve). Being high in carbohydrates, mainly starch, it can be classified as high starch content flour (juçara seed starch‐flour [JSS‐F]). JSS‐F presented B‐type crystallinity and conventional starch‐like thermal stability. JSS‐F exhibited type III sorption isotherm behavior and the Gugghenheim–Anderson–DeBoer model adequately represented the moisture equilibrium data. As a nutritive source of bioactive compounds and starch, juçara pomace should be regarded as a coproduct to be explored as an alternative natural ingredient to food, pharmaceutical, and chemical industries.

Practical Application

Juçara agroindustrial residues (pomace and seeds) are a promising source of antioxidants and unconventional starch, which are usually discarded after depulping, representing approximately 74% of the fruits. Juçara pomace can be used to produce flour with marketing potential due to their functional properties and nutritional value. This flour can be incorporated directly into formulations or be used in extraction processes to obtain components of interest, for example, anthocyanins, to be used as a natural food dye. Starch can be extracted from juçara seeds, presenting adequate technological properties for partial replacement of conventional starches.
Investigating patterns of millennials' interest in gluten‐free beer in Poland: A question of beer price and alcohol content
Authors: Donadini Gianluca , Bertuzzi Terenzio , Kordialik‐Bogacka Edyta , Cywińska Dominika , Rossi Filippo , Spigno Giorgia , Porretta Sebastiano
Published: December 2019

The quality perception of gluten‐free beer was explored using conjoint analysis with a panel of Polish millennials (n = 200; aged 20 to 35), who were given 64 gluten‐free beer concepts to evaluate and score on a 9‐point scale of interest (1 = not interested at all; 9 = extremely interested). The constituent factors of the beer concepts were alcohol content, color, type of malt, price, drinking location and occasion, bottle size, label claims, type of farming, type of brewer, and bottle closure. Consumers judged price (38.4%) and alcohol (28.8%) five times more important than the other factors. Bottle size (5.3%), claims (4.8%), type of brewer (4.8%), malt type (4.6%), bottle closure (4.0%), beer color (3.6%), drinking location (2.3%), drinking occasion (2.0%), and type of farming (1.3%) were considered of little importance. The interest of Polish Millennials in gluten‐free beer resulted moderate and not linked to medical needs. Males were more interested in gluten‐free beers and gave more importance to alcohol content and less importance to price, compared to females. However, for both genders, interest and price were inversely correlated, while interest and alcohol content were directly correlated.

Practical Application

The identification of the product factors that are preferred by consumers is paramount to translate consumers’ needs and expectations into a beer designed to produce the best possible product in a relatively short period. Including information directly obtained from consumers before final design decisions are taken on the final beer output, helps ensuring development directions are on target and constitutes a cost‐competitive approach to product development.
Knock‐in Mice Expressing an Ethanol‐Resistant GluN2A NMDA Receptor Subunit Show Altered Responses to Ethanol
Authors: Zamudio Paula A. , Smothers Thetford C. , Homanics Gregg E. , Woodward John J.
Published: December 2019

Background

N‐methyl‐D‐aspartate receptors (NMDARs) are glutamate‐activated, heterotetrameric ligand‐gated ion channels critically important in virtually all aspects of glutamatergic signaling. Ethanol (EtOH) inhibition of NMDARs is thought to mediate specific actions of EtOH during acute and chronic exposure. Studies from our laboratory, and others, identified EtOH‐sensitive sites within specific transmembrane (TM) domains involved in channel gating as well as those in subdomains of extracellular and intracellular regions of GluN1 and GluN2 subunits that affect channel function. In this study, we characterize for the first time the physiological and behavioral effects of EtOH on knock‐in mice expressing a GluN2A subunit that shows reduced sensitivity to EtOH.

Methods

A battery of tests evaluating locomotion, anxiety, sedation, motor coordination, and voluntary alcohol intake were performed in wild‐type mice and those expressing the GluN2A A825W knock‐in mutation. Whole‐cell patch‐clamp electrophysiological recordings were used to confirm reduced EtOH sensitivity of NMDAR‐mediated currents in 2 separate brain regions (mPFC and the cerebellum) where the GluN2A subunit is known to contribute to NMDAR‐mediated responses.

Results

Male and female mice homozygous for the GluN2A(A825W) knock‐in mutation showed reduced EtOH inhibition of NMDAR‐mediated synaptic currents in mPFC and cerebellar neurons as compared to their wild‐type counterparts. GluN2A(A825W) male but not female mice were less sensitive to the sedative and motor‐incoordinating effects of EtOH and showed a rightward shift in locomotor‐stimulating effects of EtOH. There was no effect of the mutation on EtOH‐induced anxiolysis or voluntary EtOH consumption in either male or female mice.

Conclusions

These findings show that expression of EtOH‐resistant GluN2A NMDARs results in selective and sex‐specific changes in the behavioral sensitivity to EtOH.
Prenatal Ethanol Exposure and Postnatal Environmental Intervention Alter Dopaminergic Neuron and Microglia Morphology in the Ventral Tegmental Area During Adulthood
Authors: Aghaie Claudia I. , Hausknecht Kathryn A. , Wang Ruixiang , Dezfuli Parisa Halaji , Haj‐Dahmane Samir , Kane Cynthia J. M. , Sigurdson Wade J. , Shen Roh‐Yu
Published: December 2019

Background

Prenatal ethanol exposure (PE) impairs midbrain dopaminergic (DA) neuron function, which might contribute to various cognitive and behavioral deficits, including attention deficits and increased addiction risk, often observed in individuals with fetal alcohol spectrum disorders. Currently, the underlying mechanisms for PE‐induced deficits are unclear. PE could lead to neuroinflammation by activating microglia, which play an important role in synaptic function. In the present study, we investigated PE effects on microglial activation and DA neuron density and morphology in the ventral tegmental area (VTA). Since postnatal environmental enrichment can reduce neuroinflammation and ameliorate several PE‐induced behavioral deficits, we examined if a postnatal environmental intervention strategy using neonatal handling and postweaning complex housing could reverse PE effects on VTA DA neurons and microglia.

Methods

Pregnant rats received 0 or 6 g/kg/d ethanol by 2 intragastric intubations on gestation days 8 to 20. After birth, rats were reared in the standard laboratory or enriched condition. Male adult rats (8 to 12 weeks old) were used for immunocytochemistry.

Results

The results showed that PE decreased VTA DA neuron body size in standardly housed rats. Moreover, there was a significant decrease in numbers of VTA microglial branches and junctions in PE rats, suggesting morphological activation of microglia and possible neuroinflammation. The PE effects on microglia were normalized by postnatal environmental intervention, which also decreased the numbers of microglial branches and junctions in control animals, possibly via reduced stress.

Conclusions

Our findings show an association between PE‐induced morphological activation of microglia and impaired DA neuron morphology in the VTA. Importantly, postnatal environmental intervention rescues possible PE‐induced microglial activation. These data support that environmental intervention can be effective in ameliorating cognitive and behavioral deficits associated with VTA DA neuron dysfunctions, such as attention deficits and increased addiction risk.
Comparison of therapeutic interventions for recurrent pregnancy loss in association with antiphospholipid syndrome: A systematic review and network meta‐analysis
Authors: Liu Xiang , Qiu Yuxuan , Yu Esther Dawen , Xiang Shang , Meng Rui , Niu Kai fan , Zhu Huili
Published: December 2019

Antiphospholipid syndrome (APS) is one of the treatable causes for pregnant women with recurrent pregnancy loss (RPL). This review compares the efficacy of a few treatment interventions (low‐dose aspirin (LDA), aspirin plus low molecular weight heparin (LMWH), or unfractionated heparin (UFH)) in preventing complications during pregnancy and miscarriages for women with RPL and APS, and the potential differences in therapeutic effects of UFH and LMWH when combined with aspirin. We searched randomized controlled trials (RCTs) in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials and performed a systematic review and a Bayesian network meta‐analysis (NMA). Finally, we found aspirin alone had a lower live birth rate compared to LMWH plus aspirin (OR = 0.37; 95% CrI, 0.17, 0.71), and UFH plus aspirin showed a higher live birth rate than aspirin alone (OR = 2.63; 95% CrI, 1.04, 5.39) in NMA, treating with UFH plus aspirin or LMWH plus aspirin did not have difference on live birth. Furthermore, LDA alone resulted in a lower birthweight compared to heparin plus aspirin, while higher birthweight was found when compared UFH plus aspirin to LMWH plus aspirin (MD = 895.40; 95% CrI, 817.40, 988.57) in NMA. Additionally, in women with RPL and APS and without a prior thrombosis, heparin plus aspirin improved birthweight but could not promote live birth rate compared to aspirin alone. In conclusion, heparin plus aspirin is recommended for women with RPL and APS. Notably UFH plus aspirin demonstrates the most significant therapeutic efficacy among these interventions in improving birthweight.
Perspectives in allergen immunotherapy: 2019 and beyond
Authors: Pfaar Oliver , Agache Ioana , de Blay Frédéric , Bonini Sergio , Chaker Adam M. , Durham Stephen R. , Gawlik Radoslaw , Hellings Peter W. , Jutel Marek , Kleine‐Tebbe Jörg , Klimek Ludger , Kopp Matthias V. , Nandy Andreas , Rabin Ronald L. , van Ree Ronald , Renz Harald , Roberts Graham , Salapatek Anne‐Marie , Schmidt‐Weber Carsten B. , Shamji Mohamed H. , Sturm Gunter J. , Virchow J. Christian , Wahn Ulrich , Willers Christoph , Zieglmayer Petra , Akdis Cezmi A.
Published: December 2019

The seventh “Future of the Allergists and Specific Immunotherapy (FASIT)” workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the “Therapy Allergen Ordinance” in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.
In vivo hyperglycaemia exposure elicits distinct period‐dependent effects on human pancreatic progenitor differentiation, conveyed by oxidative stress
Authors: Legøy Thomas A. , Ghila Luiza , Vethe Heidrun , Abadpour Shadab , Mathisen Andreas F. , Paulo Joao A. , Scholz Hanne , Ræder Helge , Chera Simona
Published: December 2019

Aim

The loss of insulin‐secreting β‐cells, ultimately characterizing most diabetes forms, demands the development of cell replacement therapies. The common endpoint for all ex vivo strategies is transplantation into diabetic patients. However, the effects of hyperglycaemia environment on the transplanted cells were not yet properly assessed. Thus, the main goal of this study was to characterize global effect of brief and prolonged in vivo hyperglycaemia exposure on the cell fate acquisition and maintenance of transplanted human pancreatic progenitors.

Methods

To rigorously study the effect of hyperglycaemia, in vitro differentiated human‐induced pluripotent stem cells (hiPSC)‐derived pancreatic progenitors were xenotransplanted in normoglycaemic and diabetic NSG rat insulin promoter (RIP)‐diphtheria toxin receptor (DTR) mice. The transplants were retrieved after 1‐week or 1‐month exposure to overt hyperglycaemia and analysed by large‐scale microscopy or global proteomics. For this study we pioneer the use of the NSG RIP‐DTR system in the transplantation of hiPSC, making use of its highly reproducible specific and absolute β‐cell ablation property in the absence of inflammation or other organ toxicity.

Results

Here we show for the first time that besides the presence of an induced oxidative stress signature, the cell fate and proteome landscape response to hyperglycaemia was different, involving largely different mechanisms, according to the period spent in the hyperglycaemic environment. Surprisingly, brief hyperglycaemia exposure increased the bihormonal cell number by impeding the activity of specific islet lineage determinants. Moreover, it activated antioxidant and inflammation protection mechanisms signatures in the transplanted cells. In contrast, the prolonged exposure was characterized by decreased numbers of hormone + cells, low/absent detoxification signature, augmented production of oxygen reactive species and increased apoptosis.

Conclusion

Hyperglycaemia exposure induced distinct, period‐dependent, negative effects on xenotransplanted human pancreatic progenitor, affecting their energy homeostasis, cell fate acquisition and survival.
Adaptation of the cardiovascular system to weightlessness: Surprises, paradoxes and implications for deep space missions
Authors: Norsk Peter
Published: December 2019

Weightlessness in space induces a fluid shift from the dependent to the cephalad parts of the body leading to distension of the cardiac chambers and an accumulation of blood in the veins of the head and neck. Surprisingly, central venous pressure (CVP) during the initial hours of spaceflight decreases compared to being horizontal supine on the ground. The explanation is that the thorax is expanded by weightlessness leading to a decrease in inter‐pleural pressure (IPP), which exceeds the measured decrease in CVP. Thus, transmural CVP (TCVP = CVP − IPP) is increased indicating an augmented cardiac preload. Simultaneously, stroke volume and cardiac output (CO) are increased by 18%‐26% within the initial weeks and more so by 35%‐56% during the subsequent months of flight relative to in the upright posture on the ground. Mean arterial pressure (MAP) is decreased indicating a lower systemic vascular resistance (MAP/CO). It is therefore a surprise that sympathetic nerve activity is not suppressed in space and thus cannot be a mechanism for the systemic vasodilation, which still needs to be explored. Recent observations indicate that the fluid shift during long duration (months) flights is associated with increased retinal thickness that sometimes leads to optical disc oedema. Ocular and cerebral structural changes, increases in left atrial size and decreased flows with thrombi formation in the left internal jugular vein have also been observed. This is of concern for future long duration deep space missions because the health implications are unknown.
Use of proton pump inhibitors and mortality among Icelandic patients with prostate cancer
Authors: Hálfdánarson Óskar Ö. , Pottegård Anton , Lund Sigrún H. , Ogmundsdottir Margret H. , Ogmundsdottir Helga M. , Zoega Helga
Published: December 2019

Proton pump inhibitors (PPIs) are commonly used drugs among cancer patients. Due to conflicting reports on their safety, we aimed to determine whether PPI use is associated with mortality among prostate cancer patients. In this population‐based cohort study, we identified incident diagnoses of prostate cancer between 2007 and 2012 (n = 1058). Follow‐up was from 12 months after diagnosis until death, emigration or end the of study. Post‐diagnosis use was defined as ≥2 filled prescriptions following diagnosis. We used time‐dependent Cox proportional hazard regression models to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer‐specific and all‐cause mortality associated with post‐diagnosis use of PPIs. We identified 347 (32.8%) post‐diagnosis PPI users and 711 (67.2%) non‐users after diagnosis. Of the 347 patients using PPIs after diagnosis, 59 (17.0%) died due to any cause and 22 (6.3%) due to prostate cancer, compared with 144 (20.3%) and 76 (10.7%) among non‐users after diagnosis, respectively. Post‐diagnosis PPI use was not associated with prostate cancer‐specific mortality (HR 0.88; 95% CI: 0.52‐1.48) or all‐cause mortality (HR 1.02; 95% CI: 0.73‐1.43). Contrary to a previous report, this study did not find evidence of an association between post‐diagnosis PPI use and mortality among prostate cancer patients.
Impact of out‐of‐pocket costs on patient initiation, adherence and persistence rates for patients treated with anti‐vascular endothelial growth factor medicines
Authors: Jackson Shaun , Stokes John P.
Published: December 2019

Importance

Out‐of‐pocket costs are a key driver of patient decisions to access, adhere and persist with anti‐vascular endothelial growth factor (VEGF) therapy. The Medicare Benefits Schedule Review Taskforce proposes a 69% reduction in the scheduled fee for intravitreal injections (item 42 738) which risks increasing out‐of‐pocket costs for patients and worsening visual outcomes.

Background

To determine the impact of out‐of‐pocket costs on current anti‐VEGF utilization rates in patients with neovascular age‐related macular degeneration (nAMD) and diabetic macular oedema (DMO).

Design

This is a retrospective cohort drug‐utilization analysis.

Participants

This study involved 11 592 patients in Australia diagnosed with nAMD or DMO.

Methods

A retrospective analysis of electronic, de‐identified dispensing records of patients diagnosed with nAMD or DMO who initiated anti‐VEGF therapy between January 1, 2016 and December 2018 across Australia. Patients were categorized by treatment facility type: bulk‐billing clinics (BBCs) and “rest of market” clinics (ROMCs).

Main Outcome Measures

Dispensing quantities, intervals and persistence rates.

Results

For patients with nAMD who initiated therapy between 2016 and 2018 the mean number of medicines dispensed up to September 30, 2019 was 17.0 for BBC and 13.8 for ROMC patients. For patients with DMO, the mean number of medicines dispensed was 16.5 for BBC patients and 12.5 for ROMC patients. Patients treated at BBCs had higher persistence rates than those treated at ROMCs. DMO patients had higher initiation rates BBCs (46%) vs ROMCs (25%).

Conclusions and Relevance

Lower out‐of‐pocket costs are associated with higher adherence and persistence rates for anti‐VEGF therapy in patients with AMD and DMO and higher initiation rates for DMO patients.
Low retinal toxicity of intravitreal carboplatin associated with good retinal tumour control in transgenic murine retinoblastoma
Authors: Lemaître Stéphanie , Poyer Florent , Fréneaux Paul , Leboucher Sophie , Doz François , Cassoux Nathalie , Thomas Carole D.
Published: December 2019

Background

Retinoblastoma is a rare intraocular malignancy in children. Current treatments have many adverse effects. New therapeutic approaches like intravitreal injections of chemotherapies are currently being developed but their toxicities need to be evaluated on animal models. This study compares the efficacy and toxicity of intravitreal melphalan, topotecan and carboplatin, alone or in combination (sequential administration), in the LHBetaTag retinoblastoma mice.

Methods

Mice were divided into nine groups: control, carboplatin 1.5 and 4 μg, melphalan 0.1 and 1 μg, topotecan 0.1 and 1 μg, carboplatin 4 μg/topotecan 0.1 μg and melphalan 1 μg/topotecan 0.1 μg. The follow‐up was performed using fundus imaging and optical coherence tomography combined with histopathological analysis. Absence of tumour and presence of calcified tumours were the criteria for therapeutic response assessment. Ocular complications were assessed after four weekly injections. Retinal toxicity was defined by the decrease of retinal thickness and of the number of retinal layers.

Results

Topotecan was inactive on retinal tumours. Melphalan (1 μg) led to a complete tumour control in 91.7% of eyes. Carboplatin strongly decreased the tumour burden (85.7‐93.8% of eyes without retinal tumour). The intravitreal injection itself led to ocular complications (25% of media opacities and 45.7% of retinal detachment). Only melphalan at 1 μg showed a strong retinal toxicity. The two combinations showed a good efficacy in reducing the number of eyes with retinal tumours with a reduced retinal toxicity.

Conclusions

This preclinical study suggests that intravitreal injection of carboplatin has a low toxicity and could be evaluated in clinical practice to treat patients suffering from retinoblastoma.
The Meaning and Content of the Concept of the Social in the Scientific Discourse on Urban Social Sustainability
Authors: Barrado–Timón Diego A.
Published: December 2019

The introduction and progressive consolidation of the paradigm of sustainability, and specifically that of social sustainability, has led to changes in the content attributed to the idea of the social in scientific discourse on the city and urban contexts. In this article, discourse analysis methods are used to assess these changes quantitatively and qualitatively as well as to highlight the new scientific, political, and ideological content that the concept is acquiring. The conclusion is that two discourses currently compete in redefining the idea of the social in relation to the city: one that we may term traditional or “hard,” linked to ideological positions of the left, and another “soft” or emerging meaning that connects to a great extent with discursive neoliberal logic.