bluuebunny/crossref_metadata_2025 huggingface dataset:
Coblopasvir and sofosbuvir for treatment of chronic hepatitis C virus infection in China: A single‐arm, open‐label, phase 3 trial
Authors: Gao Yanhang , Kong Fei , Li Guangming , Li Cheng , Zheng Sujun , Lin Jianmei , Wen Xiaofeng , Hu Jinghua , Wang Xiaozhong , Wu Xiaofeng , Xing Huichun , Jia Jidong , Jia Zhansheng , Guan Yujuan , Li Chenghao , Wu Guicheng , Gao Zhiliang , Mou Zhuangbo , Ning Qin , Mao Qing , Yang Yongfeng , Ning Jing , Li Li , Pan Hai , Zhou Desheng , Ding Yanhua , Qin Hong , Niu Junqi
Published: August 2020

Background & Aim

An affordable, pangenotypic regimen remains as an unmet medical need for chronic hepatitis C patients in China. This single‐arm, open‐label, multicenter, phase 3 trial evaluated the efficacy and safety of coblopasvir, a pangenotypic non‐structural protein 5A (NS5A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic hepatitis C virus (HCV) infection.

Methods

Treatment‐naïve and interferon‐experienced adult patients, including those with advanced fibrosis (F3) or compensated cirrhosis (F4), were treated with a universal, combinational regimen of coblopasvir 60 mg and sofosbuvir 400 mg, once daily, for 12 weeks. The primary efficacy endpoint was sustained virological response at post‐treatment week 12 (SVR12).

Results

Overall, 371 patients (men, 51%; age, 47 ± 11 years; genotype 1a < 1%, 1b 48%, 2a 26%, 3a 6%, 3b 7% and 6 12%) were enrolled from 19 sites. Fifty‐one patients (14%) had F3, 39 patients (11%) had F4 and 39 patients (11%) were interferon experienced. The overall SVR12 was 97% (95% CI, [94%, 98%]) for the full analysis set and was equal to or above 90% for all predefined subsets. Ten patients (3%) experienced virological relapse and two patients did not complete follow‐up. No adverse events (AEs) occurred at a frequency ≥5%, and the most often reported AEs (≥1%) were neutropenia and fatigue. The majority of AEs were mild to moderate and transient without specific medical intervention.

Conclusions

The universal, pangenotypic combo of coblopasvir plus sofosbuvir is an efficacious and safe treatment for Chinese patients monoinfected with HCV of genotype 1, 2, 3 and 6, including those with compensated cirrhosis.

Lay summary

The regimen of coblopasvir and sofosbuvir is a safe and effective treatment for Chinese patients with genotype 1, 2, 3 and 6 HCV infection, including those with compensated cirrhosis. Therefore, this regimen would be a novel choice of treatment for this patient population.
Substantial direct fitness gains of workers in a highly eusocial ant
Authors: Giehr Julia , Wallner Jennifer , Senninger Lisa , Ruhland Katja , Krüger Theresa , Heinze Jürgen
Published: August 2020

Hamilton's theory of inclusive fitness suggests that helpers in animal societies gain fitness indirectly by increasing the reproductive performance of a related beneficiary. Helpers in cooperatively breeding birds, mammals and primitively eusocial wasps may additionally obtain direct fitness through inheriting the nest or mating partner of the former reproductive. Here, we show that also workers of a highly eusocial ant may achieve considerable direct fitness by producing males in both queenless and queenright colonies. We investigated the reproductive success of workers of the ant Temnothorax crassispinus in nature and the laboratory by dissecting workers and determining the origin of males by microsatellite analysis. We show that workers are capable of activating their ovaries and successfully producing their sons independently of the presence of a queen. Genotypes revealed that at least one fifth of the males in natural queenright colonies were not offspring of the queen. Most worker‐produced males could be assigned to workers that were unrelated to the queen, suggesting egg‐laying by drifting workers.
Genomic evidence for parallel adaptation to cities
Authors: Garroway Colin J. , Schmidt Chloé
Published: August 2020

Urban evolutionary biology is the study of rapid evolutionary change in response to humans and our uses of land to support city dwellers. Because cities are relatively modern additions to the natural world, research on urban evolution tends to focus on microevolutionary change that has happened across a few to many hundreds of generations. These questions still fall under the broad purview of evolutionary ecology. However, the severity, rapidity and replication of environmental changes that drive evolution in this context make it worthy of specific attention. Urban evolution provides the opportunity to study the earliest stages of evolution in a context that is scientifically interesting and societally important. The newness of urban populations and their proximity to natural populations also creates challenges when trying to detect population genetic change. In a From the Cover article in this issue of Molecular Ecology, Mueller et al. use whole genome resequencing data to address some of these challenges while exploring genetic changes associated with urbanization in three replicate urban‐rural burrowing owl (Athene cunicularia) populations. Combining multiple approaches across these sample sites Mueller et al. find evidence for selection on genes whose function is related to synapses, neuron projections, brain connectivity and cognitive function in general. That selection was parallel suggests that phenotypes related to brain processes were probably particularly important for urban adaptation.
The limited spatial scale of dispersal in soil arthropods revealed with whole‐community haplotype‐level metabarcoding
Authors: Arribas Paula , Andújar Carmelo , Salces‐Castellano Antonia , Emerson Brent C. , Vogler Alfried P.
Published: August 2020

Soil arthropod communities are highly diverse and critical for ecosystem functioning. However, our knowledge of spatial structure and the underlying processes of community assembly are scarce, hampered by limited empirical data on species diversity and turnover. We implement a high‐throughput sequencing approach to generate comparative data for thousands of arthropods at three hierarchical levels: genetic, species and supra‐specific lineages. A joint analysis of the spatial arrangement across these levels can reveal the predominant processes driving the variation in biological assemblages at the local scale. This multihierarchical approach was performed using haplotype‐level COI metabarcoding of entire communities of mites, springtails and beetles from three Iberian mountain regions. Tens of thousands of specimens were extracted from deep and superficial soil layers and produced comparative phylogeographic data for >1,000 codistributed species and nearly 3,000 haplotypes. Local assemblage composition differed greatly between grasslands and forests and, within each habitat, showed strong spatial structure and high endemicity. Distance decay was high at all levels, even at the scale of a few kilometres or less. The local distance decay patterns were self‐similar for the haplotypes and higher hierarchical entities, and this fractal structure was similar in all regions, suggesting that uniform processes of limited dispersal determine local‐scale community assembly. Our results from whole‐community metabarcoding provide insight into how dispersal limitations constrain mesofauna community structure within local spatial settings over evolutionary timescales. If generalized across wider areas, the high turnover and endemicity in the soil locally may indicate extremely high richness globally, challenging our current estimations of total arthropod diversity on Earth.
Medical trainees as job crafters: Looking at identity formation through another lens
Authors: Bochatay Naike , van Schaik Sandrijn , O’Brien Bridget
Published: August 2020

Trying to understand how professional identity evolves through training transitions? The concept of job crafting provides a useful lens for analysis.
Affirmative action programmes in postgraduate medical and surgical training—A narrative review
Authors: Koea Jonathan , Rahiri Jamie‐Lee , Ronald Maxine
Published: August 2020

Objective

This review aims to identify and summarise the literature pertaining to the implementation of affirmative action programmes (AAP) for selection of ethnic minorities and Indigenous peoples into selective specialist medical and surgical training programmes.

Methods

A systematic literature search was conducted to identify relevant studies reporting on the background, implementation and results of AAP for ethnic minorities and Indigenous peoples into medical and surgical training. MEDLINE, EMBASE, PubMed, Scopus and Google Scholar databases were queried from inception through to 1 February 2020. All included studies were subjected to inductive thematic analysis in order to systematically collate study findings. Articles were read through several times in an iterative manner to allow the identification of themes across the included studies. The themes were cross‐compared among the authors to establish their interconnectedness.

Results

Forty‐five articles described AAP pertaining to ethnic minorities in the United States of America (African‐Americans and Hispanic Americans), women and ethnic minorities, Indigenous peoples (New Zealand Māori) and people with low socio‐economic status. Four themes were identified. These included the need for social responsiveness in clinical training organisations, justification and criticism of AAP, how clinical training agencies should participate in AAP and what constitutes an effective AAP for specialist medical and surgical training.

Conclusions

Affirmative action programmes have been effective at increasing numbers of ethnic minority medical school graduates but have not been used for specialist medical or surgical training selection. AAP achieve the best results when they are associated with a comprehensive programme of candidate preparation, support and mentorship beginning prior to application, and support and mentorship extending through training and subsequently into the post‐training period as an independent professional. The overall aim of any AAP in medical or surgical training must be graduation of significant numbers of minority and Indigenous trainees into successful practice with appointment to faculty member and leadership positions.
Antifungal drugs: An updated review of central nervous system pharmacokinetics
Authors: Wirth Fernanda , Ishida Kelly
Published: August 2020

Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Four chemical classes of systemic antifungal agents are used for the treatment of IFIs (eg meningitis), including polyenes, triazoles, pyrimidine analogues and echinocandins. This review will address all of these classes and discuss their penetration and accumulation in the CNS. Treatment of fungal meningitis is based on the antifungal that shows good penetration and accumulation in the CNS. Pharmacokinetic data concerning the entry of antifungal agents into the intracranial compartments are faulty. This review will provide an overview of the ability of systemic antifungals to penetrate the CNS, based on previously published drug physicochemical properties and pharmacokinetic data, for evaluation of the most promising antifungal drugs for the treatment of fungal CNS infections. The studies selected and discussed in this review are from 1990 to 2019.
Targeted plant hologenome editing for plant trait enhancement
Authors: Ravanbakhsh Mohammadhossein , Kowalchuk George A. , Jousset Alexandre
Published: August 2020

Breeding better crops is a cornerstone of global food security. While efforts in plant genetic improvement show promise, it is increasingly becoming apparent that the plant phenotype should be treated as a function of the holobiont, in which plant and microbial traits are deeply intertwined.

Using a minimal holobiont model, we track ethylene production and plant nutritional value in response to alterations in plant ethylene synthesis (KO mutation in ETO1), which induces 1‐aminocyclopropane‐1‐carboxylic acid (ACC) synthase 5 (ACS5), or microbial degradation of ACC (KO mutation in microbial acdS), preventing the breakdown of the plant ACC pool, the product of ACS5.

We demonstrate that similar plant phenotypes can be generated by either specific mutations of plant‐associated microbes or alterations in the plant genome. Specifically, we could equally increase plant nutritional value by either altering the plant ethylene synthesis gene ETO1, or the microbial gene acdS. Both mutations yielded a similar plant phenotype with increased ethylene production and higher shoot micronutrient concentrations. Restoring bacterial AcdS enzyme activity also rescued the plant wild‐t8yp phenotype in an eto1 background.

Plant and bacterial genes build an integrated plant–microbe regulatory network amenable to genetic improvement from both the plant and microbial sides.
Skeletally anchored forsus fatigue resistant device for correction of Class II malocclusions—A systematic review and meta‐analysis
Authors: Arvind Prasanna , Jain Ravindra Kumar
Published: August 2020

The use of skeletal anchorage with fixed functional appliances (FFA) has been proposed by various authors to produce skeletal changes and reduce lower incisor proclination. To compare the skeletal and dentoalveolar effects of Forsus Fatigue Resistant Device (FFRD) with or without skeletal anchorage (miniplates and mini‐implants). The electronic database PubMed, Cochrane Library, Medline, Embase and Google Scholar along with a manual search of orthodontic journals till the year 2019. Only randomized control trials (RCTs) were included in the systematic review. One controlled clinical trial (CCT) which involved FFRD was included in the review since it was a continuation of an RCT which was expanded to a CCT. Skeletal and dentoalveolar outcome data were extracted to collect study characteristics. After evaluating risk of bias, the standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated. Three RCTs and one prospective CCT were evaluated. The analysis included data from 116 Class II subjects [(58) treated with FFA along with skeletal anchorage and (58) treated with FFA]. There were no significant difference between the two groups with respect to mandibular length changes (P value = .10) and SNB angle changes (P value = .22). With respect to lower incisor inclination however, there was a significant difference between the two groups (P value = .005) signifying better results with respect to skeletal anchorage. The studies reviewed provide insufficient evidence to form a conclusion regarding the effects of the use of skeletal anchorage with FFRD. The available weak evidence suggests that the use of skeletal anchorage with FFRD has no superior skeletal effects but is able to reduce proclination of the lower incisors. Control of lower incisor proclination remains the most significant advantage of skeletal reinforcement, and miniplate‐anchored FFRD showed more promising results in preventing lower incisor proclination than miniscrew‐anchored FFRD.
Deregulation of desmosomal proteins and extracellular matrix proteases in odontogenic keratocyst
Authors: Diniz Marina Gonçalves , Duarte‐Andrade Filipe Fideles , Stussi Fernanda , Vitório Jéssica Gardone , Fonseca Felipe Paiva , Ramos Domingues Romênia , Paes Leme Adriana F. , Gomes Carolina Cavaliéri , Gomez Ricardo Santiago
Published: August 2020

Objective

Odontogenic keratocyst (OKC) is a benign lesion that tends to recur after surgical treatment. In an attempt to clarify the molecular basis underlining the OKC pathobiology, we aimed to analyze its proteomic profile.

Materials and Methods

We compared the proteomic profiles of five OKC and matched normal oral mucosa by using liquid chromatography–tandem mass spectrometry (LC‐MS/MS). Then, we performed enrichment analysis and a literature search for the immunoexpression of the proteomics targets.

Results

We identified 1,150 proteins and 72 differently expressed proteins (log2 fold change ≥ 1.5; p < .05). Twenty‐seven peptides were exclusively detected in the OKC samples. We found 35 enriched pathways related to cell differentiation and tissue architecture, including keratinocyte differentiation, keratinization, desmosome, and extracellular matrix (ECM) organization and degradation. The immunoexpression information of 11 out of 50 proteins identified in the enriched pathways was obtained. We found the downregulation of four desmosomal proteins (JUP, PKP1, PKP3, and PPL) and upregulation of ECM proteases (MMP‐2, MMP‐9, and cathepsins).

Conclusions

Proteomic analysis strengthened the notion that OKC cells have a similar proteomic profile to oral keratinocytes. Contextual investigation of the differentially expressed proteins revealed the deregulation of desmosome proteins and ECM degradation as important alterations in OKC pathobiology.
Shifting as a key executive function underlying cognitive restructuring for individuals with elevated social anxiety
Authors: Holder Lauren J. , Prasad Ashni , Han Jin , Torok Michelle , Wong Quincy J. J.
Published: August 2020

Objectives

Previous studies have examined the relationship between executive functions and performance on cognitive behavioural therapy (CBT) tasks, such as cognitive restructuring. However, previous studies have used samples of older adults and only traditional measures of executive functions involving non‐emotional stimuli. This study extends previous research to examine the specific executive function of shifting with regard to non‐emotional and emotional stimuli and its relationship with cognitive restructuring, in a sample of young to middle‐aged adults with elevated social anxiety.

Design

Cross‐sectional study.

Methods

Participants (N = 49) completed a standard Wisconsin Card Sorting Test (WCST), an emotional version of the WCST (eWCST), and a cognitive restructuring task prior to an impromptu speech task. Per cent perseverative errors (an indicator of shifting) from the WCST and eWCST, along with planned covariates, were used to predict three indicators of cognitive restructuring task performance: task response quality (production of helpful alternative thoughts), change in belief in negative thought, and peak anxiety during speech.

Results

As expected, higher per cent perseverative errors (i.e., poorer shifting) on the WCST predicted poorer ability during the cognitive restructuring task to produce helpful alternative thoughts to a negative thought about the impending speech task. However, WCST per cent perseverative errors did not predict the other indicators of cognitive restructuring task performance. eWCST per cent perseverative errors did not predict any of the indicators of cognitive restructuring task performance.

Conclusions

The standard WCST may be sensitive to capturing the type of mental flexibility which is important for producing helpful alternative thinking during cognitive restructuring.

Practitioner points

Poorer shifting ability with regard to non‐emotional stimuli in clients with elevated social anxiety may be related to poorer ability to produce helpful alternative thoughts during cognitive restructuring.

For clinicians whose clients with elevated social anxiety are having difficulty with generating alternative thoughts during cognitive restructuring, clinicians should consider poor shifting ability as a potential contributing factor.

Clinicians may need to provide further support for such clients during cognitive restructuring (e.g., greater emphasis on Socratic questioning to better facilitate alternative thinking).
The miR156/SPL module regulates apple salt stress tolerance by activating MdWRKY100 expression
Authors: Ma Yue , Xue Hao , Zhang Feng , Jiang Qiu , Yang Shuang , Yue Pengtao , Wang Feng , Zhang Yuanyan , Li Linguang , He Ping , Zhang Zhihong
Published: August 2020

Salt stress dramatically impedes plant growth and development as well as crop yield. The apple production regions are reduced every year, because of the secondary salt damage by improper fertilization and irrigation. To expand the cultivation area of apple (Malus domestica) and select salt‐resistant varieties, the mechanism of salt tolerance in apple is necessary to be clarified. The miR156/SPL regulatory module plays key roles in embryogenesis, morphogenesis, life cycle stage transformation, flower formation and other processes. However, its roles in the mechanisms of salt tolerance are unknown. In order to elucidate the mechanism of 156/SPL regulating salt stress in apple, we performed RLM‐5’ RACE and stable genetic transformation technology to verify that both mdm‐MIR156a and MdSPL13 responded to salt stress in apple and that the latter was the target of the former. MIR156a overexpression weakened salt resistance in apple whereas MdSPL13 overexpression strengthened it. A total of 6094 differentially expressed genes relative to nontransgenic apple plants were found by RNA‐Seq analysis of MdSPL13OE. Further verification indicated that MdSPL13 targeted the MdWRKY100 gene promoter. Moreover, MdWRKY100 overexpression enhanced salt tolerance in apple. Our results revealed that the miR156/SPL module regulates salt tolerance by up‐regulating MdWRKY100 in apple. This study is the first to elucidate the mechanism underlying the miRNA network response to salt stress in apple and provides theoretical and empirical bases and genetic resources for the molecular breeding of salt tolerance in apple.
Qualitative analysis and functional classification of the uterine proteome of mares in oestrus and dioestrus
Authors: Khan Firdous A. , Diel de Amorim Mariana , Chenier Tracey S.
Published: August 2020

Quantitative analysis of the uterine flush fluid proteome of mares in oestrus and dioestrus has been previously reported. The objectives of this study were to: a) evaluate qualitative differences in the uterine flush fluid proteome between mares in oestrus and mares in dioestrus and b) perform a functional classification of proteins either unique to each stage or common between the two stages. Uterine flush fluid samples were collected from 8 light breed mares in either oestrus (n = 5) or dioestrus (n = 3). Proteomic analysis of the samples was conducted using liquid chromatography–tandem mass spectrometry. Proteins exclusively detected in oestrus or dioestrus and those common to both stages were identified using the Scaffold software (version 4.4.8, Proteome Software Inc., Portland, OR). The identified proteins were classified into gene ontology (GO) categories (cellular component [CC], molecular function [MF] and biological process [BP]) using the PANTHER (www.pantherdb.org) classification system version 14.0. Of 172 proteins identified, 51 and 28 were exclusively detected in mares in oestrus and dioestrus, respectively, and 93 proteins were common to both stages. The most represented terms in various GO categories were similar among the three subsets of proteins. The most represented CC terms were extracellular region and cell, the most represented MF terms were catalytic activity and binding, and the most represented BP terms were metabolic process and cellular process. In conclusion, proteomic analysis of the uterine flush fluid enabled the identification of subsets of proteins unique to oestrus or dioestrus, or common to both stages. The results of this study can serve as a baseline for future research focused on finding stage‐specific protein markers or evaluating differences in the uterine flush fluid proteome between normal mares and those with uterine disease.
Spillovers of the Conventional and Unconventional Monetary Policy from the US to South Africa
Authors: Kabundi Alain , Loate Tumisang , Viegi Nicola
Published: August 2020

This paper assesses the effect of US monetary policy on South Africa during the period 1990–2018. We separately analyse and compare the effect of conventional monetary policy, before the Global Financial Crisis, and unconventional monetary policy, after the US monetary policy reached the zero‐lower bound. Our impulse response function results indicate that monetary policy in South Africa responds mainly to local inflation, economic activity and financial conditions. While there is strong correlation between the global and South African financial cycle, the financial cycle is not transmitted to the real economy because of the sluggish response of industrial production and domestic credit, especially after the global financial crisis. We see this as an indication of the effects of structural issues to the real economy and constrained households’ balance sheet which has prevented the local economy to take advantage of low local interest rates and the global economic recovery after the crisis.
Natural and anthropogenic compaction in North Germany (Schleswig‐Holstein): Verification of harmful subsoil compactions
Authors: Mordhorst Anneka , Fleige Heiner , Burbaum Bernd , Filipinski Marek , Horn Rainer
Published: August 2020

Many soil types in the federal state of Schleswig‐Holstein (North Germany) are naturally compacted in the subsoil due to pedo‐ or geogenic processes (42% of the area) but, due to anthropogenic impacts, the percentage of subsoil compaction has increased further. To determine the overall subsoil compaction status of seven representative soil types in Schleswig‐Holstein (≤ 60 cm depth), air capacity (AC), saturated hydraulic conductivity (Ks) and effective bulk density (ρBeff) of 342 soil profiles from the database of the State Agency for Agriculture, Environment and Rural Areas of Schleswig‐Holstein (LLUR) were evaluated with respect to critical threshold values (AC < 5 Vol.‐%, Ks < 10 cm day−1, ρBeff > 1.7 g cm−3). The compaction status was classified into Classes I–IV, where a harmful subsoil compaction was assumed if both values of AC and Ks simultaneously exceeded (are smaller than) their threshold value (Class IV). Subsoils of (Stagnic) Luvisols and Stagnosols derived from glacial till, as well as those of Fluvic Gleyic Stagnosols of the marshlands, showed a high degree of natural compaction (46%–65% in Class IV). In contrast, sandy subsoil horizons of Podzols and Brunic Arenosols derived from glacifluvial sediments were rarely compacted (< 13% in Class IV), and possessed the lowest ρBeff, which were similar to Anthrosols. Only 5%–18% of their subsoil horizons exceeded the critical value of 1.7 g cm−3. Additionally, anthropogenic subsoil compaction of at least 6%–10% was verified for (Stagnic) Luvisols and Stagnosols.
Identification of the novel HLA‐A*30:171 allele in a volunteer donor from the China Marrow Donor Program
Authors: Zhang Li‐Qun , Xiao Yao , Zhou Xiao‐Yang , Cui Ju , Cai Jian‐Ping
Published: August 2020

HLA‐A*30:171 differs from HLA‐A*30:01:01:01 by one nucleotide substitution at position 821 in exon 4.
Characterization of the novel HLA‐A*11:349 allele by next‐generation sequencing
Authors: Genebrier Steve , Elsermans Vincent , Texeraud Emeric , Bertrand Gerald , Renac Virginie
Published: August 2020

A*11:349 differs from A*11:01:01:01 by one nucleotide substitution at position 688 in exon 4.
Very late‐onset cytomegalovirus disease with ganciclovir resistance >15 years following renal transplantation
Authors: Khan Sadid F. , Yong Michelle K. , Slavin Monica A. , Hughes Peter , Sasadeusz Joseph
Published: August 2020

Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality after solid organ transplantation. There has been a significant shift in disease epidemiology with the introduction of antiviral prophylaxis, with CMV disease occurring later and clinical presentations more atypical. We describe two cases of very late‐onset CMV disease where first disease occurred 15 and 18 years post–renal transplantation, with both cases complicated by antiviral drug resistance. We subsequently review the published cases and literature of very late‐onset CMV disease (onset > 10 years post–solid organ transplantation) as an increasingly recognized phenomenon which is emerging as an important aspect in improving long‐term patient outcomes in the current era of renal transplantation.
Dissection of the domestication‐shaped genetic architecture of lettuce primary metabolism
Authors: Zhang Weiyi , Alseekh Saleh , Zhu Xiang , Zhang Qinghua , Fernie Alisdair R. , Kuang Hanhui , Wen Weiwei
Published: August 2020

Lettuce (Lactuca sativa L.) is an important vegetable crop species worldwide. The primary metabolism of this species is essential for its growth, development and reproduction as well as providing a considerable direct source of energy and nutrition for humans. Here, through investigating 77 primary metabolites in 189 accessions including all major horticultural types and wild lettuce L. serriola we showed that the metabolites in L. serriola were different from those in cultivated lettuce. The findings were consistent with the demographic model of lettuce and supported a single domestication event for this species. Selection signals among these metabolic traits were detected. Specifically, galactinol, malate, quinate and threonate were significantly affected by the domestication process and cultivar differentiation of lettuce. Galactinol and raffinose might have been selected during stem lettuce cultivation as an adaption to the local environments in China. Furthermore, we identified 154 loci significantly associated with the level of 51 primary metabolites. Three genes (LG8749721, LG8763094 and LG5482522) responsible for the levels of galactinol, raffinose, quinate and chlorogenic acid were further dissected, which may have been the target of domestication and/or affected by local adaptation. Additionally, our findings strongly suggest that human selection resulted in reduced quinate and chlorogenic acid levels in cultivated lettuce. Our study thus provides beneficial genetic resources for lettuce quality improvement and sheds light on the domestication and evolution of this important leafy green.
Precision transcriptomics of viral foci reveals the spatial regulation of immune‐signaling genes and identifies RBOHD as an important player in the incompatible interaction between potato virus Y and potato
Authors: Lukan Tjaša , Pompe‐Novak Maruša , Baebler Špela , Tušek‐Žnidarič Magda , Kladnik Aleš , Križnik Maja , Blejec Andrej , Zagorščak Maja , Stare Katja , Dušak Barbara , Coll Anna , Pollmann Stephan , Morgiewicz Karolina , Hennig Jacek , Gruden Kristina
Published: August 2020

Whereas the activation of resistance (R) proteins has been intensively studied, the downstream signaling mechanisms leading to the restriction of the pathogen remain mostly unknown. We studied the immunity network response conditioned by the potato Ny‐1 gene against potato virus Y. We analyzed the processes in the cell death zone and surrounding tissue on the biochemical and gene expression levels in order to reveal the spatiotemporal regulation of the immune response. We show that the transcriptional response in the cell death zone and surrounding tissue is dependent on salicylic acid (SA). For some genes the spatiotemporal regulation is completely lost in the SA‐deficient line, whereas other genes show a different response, indicating multiple connections between hormonal signaling modules. The induction of NADPH oxidase RBOHD expression occurs specifically on the lesion border during the resistance response. In plants with silenced RBOHD, the functionality of the resistance response is perturbed and the spread of the virus is not arrested at the site of infection. RBOHD is required for the spatial accumulation of SA, and conversely RBOHD is under the transcriptional regulation of SA. Using spatially resolved RNA‐seq, we also identified spatial regulation of an UDP‐glucosyltransferase, another component in feedback activation of SA biosynthesis, thus deciphering a novel aspect of resistance signaling.
The Acer truncatum genome provides insights into nervonic acid biosynthesis
Authors: Ma Qiuyue , Sun Tianlin , Li Shushun , Wen Jing , Zhu Lu , Yin Tongming , Yan Kunyuan , Xu Xiao , Li Shuxian , Mao Jianfeng , Wang Ya‐nan , Jin Shuangxia , Zhao Xing , Li Qianzhong
Published: August 2020

Acer truncatum (purpleblow maple) is a woody tree species that produces seeds with high levels of valuable fatty acids (especially nervonic acid). However, the lack of a complete genome sequence has limited both basic and applied research on A. truncatum. We describe a high‐quality draft genome assembly comprising 633.28 Mb (contig N50 = 773.17 kb; scaffold N50 = 46.36 Mb) with at least 28 438 predicted genes. The genome underwent an ancient triplication, similar to the core eudicots, but there have been no recent whole‐genome duplication events. Acer yangbiense and A. truncatum are estimated to have diverged about 9.4 million years ago. A combined genomic, transcriptomic, metabonomic, and cell ultrastructural analysis provided new insights into the biosynthesis of very long‐chain monounsaturated fatty acids. In addition, three KCS genes were found that may contribute to regulating nervonic acid biosynthesis. The KCS paralogous gene family expanded to 28 members, with 10 genes clustered together and distributed in the 0.27‐Mb region of pseudochromosome 4. Our chromosome‐scale genomic characterization may facilitate the discovery of agronomically important genes and stimulate functional genetic research on A. truncatum. Furthermore, the data presented also offer important foundations from which to study the molecular mechanisms influencing the production of nervonic acids.
Two chloroplast thioredoxin systems differentially modulate photosynthesis in Arabidopsis depending on light intensity and leaf age
Authors: Guinea Diaz Manuel , Nikkanen Lauri , Himanen Kristiina , Toivola Jouni , Rintamäki Eevi
Published: August 2020

Various regulatory mechanisms have evolved in plants to optimize photosynthetic activity under fluctuating light. Thioredoxins (TRX) are members of the regulatory network balancing activities of light and carbon fixation reactions in chloroplasts. We have studied the impact of two chloroplast TRX systems, the ferredoxin‐dependent TRX reductase (FTR) and the NADPH‐dependent TRX reductase C (NTRC) on regulation of photosynthesis by mutants lacking or overexpressing a component of either system. Plants were subjected to image‐based phenotyping and chlorophyll fluorescence measurements that allow long‐term monitoring of the development and photosynthetic activity of the rosettes, respectively. Our experiments demonstrate that NTRC and FTR systems respond differently to variation of light intensity. NTRC was an indispensable regulator of photosynthesis in young leaves, at light‐intensity transitions and under low light intensities limiting photosynthesis, whereas steady‐state exposure of plants to growth or higher light intensities diminished the need of NTRC in regulation of photosynthesis. In fluctuating light, overexpression of NTRC increased the quantum yield of Photosystem II (YII) at low light and stimulated the relaxation of non‐photochemical quenching (NPQ) after high light exposure, indicating that overexpression of NTRC improves leaf capacity to convert light energy to chemical energy under these conditions. Overexpression of chimeric protein (NTR‐TRXf) containing both the thioredoxin reductase and TRXf activity on an ntrc mutant background, did not completely recover either growth or steady‐state photosynthetic activity, whereas OE‐NTR‐TRXf plants exposed to fluctuating light regained the wild‐type level of Y(II) and NPQ.
Soybean BARCSoySNP6K: An assay for soybean genetics and breeding research
Authors: Song Qijian , Yan Long , Quigley Charles , Fickus Edward , Wei He , Chen Linfeng , Dong Faming , Araya Susan , Liu Jinlong , Hyten David , Pantalone Vincent , Nelson Randall L.
Published: August 2020

The limited number of recombinant events in recombinant inbred lines suggests that for a biparental population with a limited number of recombinant inbred lines, it is unnecessary to genotype the lines with many markers. For genomic prediction and selection, previous studies have demonstrated that only 1000–2000 genome‐wide common markers across all lines/accessions are needed to reach maximum efficiency of genomic prediction in populations. Evaluation of too many markers will not only increase the cost but also generate redundant information. We developed a soybean (Glycine max) assay, BARCSoySNP6K, containing 6000 markers, which were carefully chosen from the SoySNP50K assay based on their position in the soybean genome and haplotype block, polymorphism among accessions and genotyping quality. The assay includes 5000 single nucleotide polymorphisms (SNPs) from euchromatic and 1000 from heterochromatic regions. The percentage of SNPs with minor allele frequency >0.10 was 95% and 91% in the euchromatic and heterochromatic regions, respectively. Analysis of progeny from two large families genotyped with SoySNP50K versus BARCSoySNP6K showed that the position of the common markers and number of unique bins along linkage maps were consistent based on the SNPs genotyped with the two assays; however, the rate of redundant markers was dramatically reduced with the BARCSoySNP6K. The BARCSoySNP6K assay is proven as an excellent tool for detecting quantitative trait loci, genomic selection and assessing genetic relationships. The assay is commercialized by Illumina Inc. and being used by soybean breeders and geneticists and the list of SNPs in the assay is an ideal resource for SNP genotyping by targeted amplicon sequencing.
Serosurvey of pandemic H1N1 influenza A virus in dogs in Andalusia (southern Spain)
Authors: Jurado‐Tarifa Estefanía , Cano‐Terriza David , Daly Janet M. , Arenas Antonio , García‐Bocanegra Ignacio
Published: August 2020

In April 2009, a new influenza A virus (IAV) subtype (A(H1N1)pdm09) spread worldwide and triggered the first human influenza pandemic of the 21st century. Since then, exposure to the pandemic H1N1 IAV has been confirmed in different animal species. Serological evidence and clinical infection with A(H1N1)pdm09 have been reported in canines, but the information available about the role of dogs in the epidemiology of this IAV subtype is still very limited in Europe. A cross‐sectional study was carried out to determine the seroprevalence of A(H1N1)pdm09 in dogs in southern Spain, a region with endemic seasonal circulation in human. Sera from 750 companion dogs were collected during the period 2013–2016. Antibodies against pandemic H1N1 IAV were analysed using the haemagglutination inhibition test. Positive samples were also tested by single radial haemolysis assay. Seropositivity was only confirmed by both methods in one (0.13%; 95% CI: 0.00–0.38) adult animal sampled in 2013. To the best of the authors’ knowledge, this is the first report of A(H1N1)pdm09 exposure in dogs in Spain. The low seroprevalence obtained indicates a limited exposure history to A(H1N1)pdm09 IAV in dogs in this country and suggests a low risk of transmission of this zoonotic IAV subtype between humans and dogs.
Randomised clinical trial of a gastrointestinal care bundle to reduce symptoms in patients with pelvic cancer undergoing chemoradiotherapy
Authors: White Katherine L , Henson Caroline C , Hann Mark , Eden Martin , Burden Sorrel T , Lal Simon , Davidson Susan E , McLaughlin John T
Published: August 2020

Objective

Pelvic radiotherapy is used to treat 17 000 people in the UK each year. Eight in 10 develop difficult bowel problems during pelvic treatment, especially diarrhoea, urgency and incontinence. Some cannot complete treatment, reducing the chance of cancer cure. Undertaking gastroenterologist-led investigation and management during pelvic radiotherapy has never been evaluated. In this study, we aimed to assess whether patients could successfully receive a novel gastrointestinal (GI) care bundle during chemoradiotherapy (feasibility aim) and would experience reduced symptom severity (clinical impact aim).

Design

This randomised controlled trial recruited patients with cervical and bladder cancers undergoing radical chemoradiotherapy. Participants were randomised to intervention or control groups. Questionnaire and anthropometric data were collected. All intervention group patients received individualised dietary counselling weekly throughout treatment, and if bowel symptoms developed they were offered rapid-access investigation and treatment for any identified pathology: lactose intolerance, bacterial overgrowth or bile acid malabsorption.

Results

Feasibility: 50 participants were recruited, 24 were randomised to the intervention group and 26 to the control group. All completed 20 fractions of external beam pelvic radiotherapy. It was possible to perform 57/72 (79%) of proposed intervention tests with no disruption of oncological management.

Clinical impact

All participants developed GI symptoms during radiotherapy. The median symptom score for each group increased from baseline at 6 weeks. This was from 0.156 (0.000–0.333) to 0.600 (0.250–1.286) in the control group, and from 0.00 (0.000–0.300) to 0.402 (0.000–0.667) in the intervention group.

Conclusion

It was feasible to recruit to and deliver a randomised controlled trial of interventions in patients undergoing pelvic chemoradiotherapy. Lower median bowel scores were reported in the intervention group at 6 weeks, with fewer patients experiencing symptoms overall.

Trial registration number

ISRCTN783488.
Potentially addictive drugs dispensing to patients receiving opioid agonist therapy: a register-based prospective cohort study in Norway and Sweden from 2015 to 2017
Authors: Vold Jørn Henrik , Aas Christer , Skurtveit Svetlana , Odsbu Ingvild , Chalabianloo Fatemeh , Reutfors Johan , Halmøy Anne , Johansson Kjell Arne , Fadnes Lars Thore
Published: August 2020

Objectives

To compare the use of benzodiazepines, z-hypnotics, gabapentinoids, opioids and centrally acting stimulants (CAS) among patients who had received opioid agonist therapy (OAT) in Norway and Sweden during the period 2015 - 2017.

Design

A register-based prospective cohort study using information about dispensed drugs from the Norwegian Prescription Database and Swedish Prescribed Drug Register.

Setting

Patients who were dispensed OAT opioids from pharmacies.

Participants

A total of 7176 Norwegian and 3591 Swedish patients on OAT were included.

Outcome measures

The number and frequency of potentially addictive drugs dispensed were calculated for the two countries. The mean daily doses of dispensed benzodiazepines and z-hypnotics were summarised by calculating benzodiazepines in diazepam equivalents and z-hypnotics in zopiclone equivalents.

Results

In 2017, 46% of patients in Norway, and 15% in Sweden, were dispensed a benzodiazepine. Moreover, 14% in Norway and 26% in Sweden received z-hypnotics. Gabapentinoids were dispensed to 10% of patients in Norway and 19% of patients in Sweden. In Norway, 6% and 12% of the patients received strong and weak non-OAT opioids, respectively, whereas in Sweden 10% were dispensed strong non-OAT opioids and 5% weak non-OAT opioids . CAS were dispensed to 4% in Norway and 18% in Sweden. The mean daily doses of benzodiazepines were 16 and 17 mg diazepam equivalents in Norway and Sweden, respectively. For z-hypnotics, the mean daily dose was 8 mg zopiclone equivalents in both countries. ‘Benzodiazepines and z-hypnotics’ was the most dispensed drug combination in 2017. Similar results were found in 2015 and 2016.

Conclusions

Nearly half of those patients who were dispensed an OAT opioid in Norway and Sweden were dispensed potentially addictive drugs. The differences identified between Norway and Sweden might be related to differences in eligibility guidelines and restrictions with respect to OAT.
Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells
Authors: Chen Heyu , Chen Yuanzhi , Deng Mi , John Samuel , Gui Xun , Kansagra Ankit , Chen Weina , Kim Jaehyup , Lewis Cheryl , Wu Guojin , Xie Jingjing , Zhang Lingbo , Huang Ryan , Liu Xiaoye , Arase Hisashi , Huang Yang , Yu Hai , Luo Wenxin , Xia Ningshao , Zhang Ningyan , An Zhiqiang , Zhang Cheng Cheng
Published: August 2020

Background

Current immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment.

Methods

First, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models,in vitroandin vivoxenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice.

Results

We demonstrate that percentage of LILRB1+NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors,in vitroandin vivo.

Conclusions

Our results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.