bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Social Isolation on Subsequent Peptic Ulcer Recurrence in Older Adults With Mild Cognitive Impairment: The Role of Change in Severity of Depression
Authors: Fang Boye , Liu Huiying , Yang Shuyan , Xu Ruirui , Chen Gengzhen
Published: December 2019

Objective

This study aimed to examine the association between social isolation, change in severity of depression, and subsequent recurrence of peptic ulcer disease (PUD) in older adults with mild cognitive impairment.

Methods

Older adults (≥55 years) with mild cognitive impairment and Helicobacter pylori–infected PUD (N = 2208) were recruited between 2010 and 2014 from 12 hospitals in the People’s Republic of China. H. pylori was eradicated and PUD was cleared in 2015 participants by the end of 2014; 1900 of these were followed up for up to 36 months. The Kaplan-Meier method was used to assess how PUD recurrence varied with social engagement levels and changes in depression severity. Multivariate Cox proportional hazard models were used to examine associations between social isolation, changes in depression severity, and PUD recurrence.

Results

PUD recurrence was more prevalent in socially isolated (10.8%) than in socially engaged participants (5.5%). However, the rates of PUD were lower in socially isolated individuals without (absence of) depression (7.2%) and those with decreased depression (8.2%), whereas socially isolated individuals with unchanged and increased depression had substantially higher rates of PUD (16.3% and 17.8%, respectively; the social isolation by depression group for PUD recurrence was significant (p < .001). Specifically, although social isolation was associated with PUD recurrence during the 36-month follow-up period (hazard ratio [HR] = 2.665 [1.602–4.518]), it did not increase PUD recurrence risk in participants without depression or with reduced depression. However, in participants with unchanged or increased depression, PUD recurrence was more likely to occur in socially isolated (HR = 1.587 [1.125–2.588]; HR = 1.886 [1.012, 3.522] respectively) than in socially engaged participants.

Conclusions

Social isolation is associated with a greater risk of PUD recurrence; however, the absence of or decreased severity of depression may alter this relationship.
The impact of localized implementation: determining the cost-effectiveness of HIV prevention and care interventions across six United States cities
Authors: Krebs Emanuel , Zang Xiao , Enns Benjamin , Min Jeong E. , Behrends Czarina N. , del Rio Carlos , Dombrowski Julia C. , Feaster Daniel J. , Gebo Kelly A. , Golden Matthew , Marshall Brandon D.L. , Metsch Lisa R. , Schackman Bruce R. , Shoptaw Steven , Strathdee Steffanie A. , Nosyk Bohdan
Published: December 2019

Objective:

Effective interventions to reduce the public health burden of HIV/AIDS can vary in their ability to deliver value at different levels of scale and in different epidemiological contexts. Our objective was to determine the cost-effectiveness of HIV treatment and prevention interventions implemented at previously documented scales of delivery in six US cities with diverse HIV microepidemics.

Design:

Dynamic HIV transmission model-based cost-effectiveness analysis.

Methods:

We identified and estimated previously documented scale of delivery and costs for 16 evidence-based interventions from the US CDC's Compendium of Evidence-Based Interventions and Best Practices for HIV Prevention. Using a model calibrated for Atlanta, Baltimore, Los Angeles, Miami, New York City and Seattle, we estimated averted HIV infections, quality-adjusted life years (QALY) gained and incremental cost-effectiveness ratios (healthcare perspective; 3% discount rate, 2018$US), for each intervention and city (10-year implementation) compared with the status quo over a 20-year time horizon.

Results:

Increased HIV testing was cost-saving or cost-effective across cities. Targeted preexposure prophylaxis for high-risk MSM was cost-saving in Miami and cost-effective in Atlanta ($6123/QALY), Baltimore ($18 333/QALY) and Los Angeles ($86 117/QALY). Interventions designed to improve antiretroviral therapy initiation provided greater value than other treatment engagement interventions. No single intervention was projected to reduce HIV incidence by more than 10.1% in any city.

Conclusion:

Combination implementation strategies should be tailored to local epidemiological contexts to provide the most value. Complementary strategies addressing factors hindering access to HIV care will be necessary to meet targets for HIV elimination in the United States.
On generative models of T-cell receptor sequences
Authors: Isacchini Giulio , Sethna Zachary , Elhanati Yuval , Nourmohammad Armita , Walczak Aleksandra M. , Mora Thierry
Published: December 2019

T-cell receptors (TCR) are key proteins of the adaptive immune system, generated randomly in each individual, whose diversity underlies our ability to recognize infections and malignancies. Modeling the distribution of TCR sequences is of key importance for immunology and medical applications. Here, we compare two inference methods trained on high-throughput sequencing data: a knowledge-guided approach, which accounts for the details of sequence generation, supplemented by a physics-inspired model of selection; and a knowledge-free Variational Auto-Encoder based on deep artificial neural networks. We show that the knowledge-guided model outperforms the deep network approach at predicting TCR probabilities, while being more interpretable, at a lower computational cost.
Implicit bias is strongest when assessing top candidates
Authors: Andersson Emma R , Hagberg Carolina , Hägg Sara
Published: December 2019

Background

Academic life is highly competitive and expectations of fair competition underlie the assumption that academia is a meritocracy. However, implicit bias reinforces gender inequality in all peer review processes, unfairly eliminating outstanding individuals and depleting academia of diversity. Here, we ask whether applicant gender biases reviewer assessments of merit in Sweden, a country that is top ranked for gender equality.

Methods

We analyzed the peer review procedure for positions awarded at a Swedish medical University, Karolinska Institutet (KI), during four consecutive years (2014-2017) for Assistant Professor (n=207) and Senior Researcher (n=153). We derived a composite bibliometric score to compute productivity, and compared this to subjective external (non-KI) peer reviewer scores on applicants’ merits to test their association for men and women, separately.

Results

Men and women with equal merits are not scored equally by reviewers. Men generally have stronger associations (steeper slopes) between computed productivity and subjective external scores, meaning that peer reviewers suitably “reward” men’s productivity with increased merit scores. However, for each additional composite bibliometric score point, women applying for Assistant Professor positions only receive 58% (79% for Senior Researcher) of the external reviewer score that men received, confirming that implicit bias affects external reviewers’ assessments. As productivity increases, the difference in merit scores between men and women increases.

Conclusions

Accumulating bias impacts most strongly in the highest tier of competition, the pool from which successful candidates are ultimately chosen. Gender bias is apparent in external peer review processes of applications for academic positions in Sweden, and is likely to reinforce the unbalanced numbers of professorships in Sweden.
Processing of the SARS-CoV pp1a/ab nsp7-10 region
Authors: Krichel Boris , Falke Sven , Hilgenfeld Rolf , Redecke Lars , Uetrecht Charlotte
Published: December 2019

1.1.

Severe acute respiratory syndrome coronavirus (SARS-CoV) is the causative agent of a respiratory disease with a high case fatality rate. During the formation of the coronaviral replication/transcription complex (RTC), essential steps include processing of the conserved polyprotein nsp7-10 region by the main protease Mproand subsequent complex formation of the released nsp’s. Here, we analyzed processing of the coronavirus nsp7-10 region using native mass spectrometry showing consumption of substrate, rise and fall of intermediate products and complexation. Importantly, there is a clear order of cleavage efficiencies, which is influenced by the polyprotein tertiary structure. Furthermore, the predominant product is an nsp7+8(2:2) hetero-tetramer with nsp8 scaffold. In conclusion, native MS, opposed to other methods, can expose the processing dynamics of viral polyproteins and the landscape of protein interactions in one set of experiments. Thereby, new insights into protein interactions, essential for generation of viral progeny, were provided, with relevance for development of antivirals.
Individual differences in dopamine function underlying the balance between model-based and model-free control
Authors: Lee Ying , Deserno Lorenz , Kroemer Nils B. , Pooseh Shakoor , Oehme Liane , Müller Dirk K. , Goschke Thomas , Huys Quentin J.M. , Smolka Michael N.
Published: December 2019

Reinforcement learning involves a balance between model-free (MF) and model-based (MB) systems. Recent studies suggest that individuals with either pharmacologically enhanced levels of dopamine (DA) or higher baseline levels of DA exhibit more MB control. However, it remains unknown whether such pharmacological effects depend on baseline DA.

Here, we investigated whether effects of L-DOPA on the balance of MB/MF control depend on ventral striatal baseline DA. Sixty participants had two functional magnetic resonance imaging (fMRI) scans while performing a two-stage sequential decision-making task under 150 mg L-DOPA or placebo (counterbalanced), followed by a 4-hour18F-DOPA positron emission tomography (PET) scan (on a separate occasion).

We found an interaction between baseline DA levels and L-DOPA induced changes in MB control. Individuals with higher baseline DA levels showed a greater L-DOPA induced enhancement in MB control. Surprisingly, we found a corresponding drug-by-baseline DA interaction on MF, but not MB learning signals in the ventromedial prefrontal cortex. We did not find a significant interaction between baseline DA levels and L-DOPA effects on MF control or MB/MF balance.

In sum, our findings point to a baseline dependency of L-DOPA effects on differential aspects of MB and MF control. Individual differences in DA washout may be an important moderator of L-DOPA effects. Overall, our findings complement the general notion where higher DA levels is related to a greater reliance on MB control. Although the relationship between phasic DA firing and MF learning is conventionally assumed in the animal literature, the relationship between DA and MF control is not as straightforward and requires further clarification.
The Multispecies Coalescent Model Outperforms Concatenation across Diverse Phylogenomic Data Sets
Authors: Jian Xiaodong , Edwards Scott V. , Liu Liang
Published: December 2019

A statistical framework of model comparison and model validation is essential to resolving the debates over concatenation and coalescent models in phylogenomic data analysis. A set of statistical tests are here applied and developed to evaluate and compare the adequacy of substitution, concatenation, and multispecies coalescent (MSC) models across 47 phylogenomic data sets collected across tree of life. Tests for substitution models and the concatenation assumption of topologically concordant gene trees suggest that a poor fit of substitution models (44% of loci rejecting the substitution model) and concatenation models (38% of loci rejecting the hypothesis of topologically congruent gene trees) is widespread. Logistic regression shows that the proportions of GC content and informative sites are both negatively correlated with the fit of substitution models across loci. Moreover, a substantial violation of the concatenation assumption of congruent gene trees is consistently observed across 6 major groups (birds, mammals, fish, insects, reptiles, and others, including other invertebrates). In contrast, among those loci adequately described by a given substitution model, the proportion of loci rejecting the MSC model is 11%, significantly lower than those rejecting the substitution and concatenation models, and Bayesian model comparison strongly favors the MSC over concatenation across all data sets. Species tree inference suggests that loci rejecting the MSC have little effect on species tree estimation. Due to computational constraints, the Bayesian model validation and comparison analyses were conducted on the reduced data sets. A complete analysis of phylogenomic data requires the development of efficient algorithms for phylogenetic inference. Nevertheless, the concatenation assumption of congruent gene trees rarely holds for phylogenomic data with more than 10 loci. Thus, for large phylogenomic data sets, model comparison analyses are expected to consistently and more strongly favor the coalescent model over the concatenation model. Our analysis reveals the value of model validation and comparison in phylogenomic data analysis, as well as the need for further improvements of multilocus models and computational tools for phylogenetic inference.
Structure-guided molecular grafting of a complex broadly neutralizing viral epitope
Authors: Bajic Goran , Maron Max J. , Tian Ming , Kelsoe Garnett , Kuraoka Masayuki , Schmidt Aaron G.
Published: December 2019

Antigenic variation and viral evolution have thwarted traditional influenza vaccination strategies. The broad protection afforded by a “universal” influenza vaccine will come from immunogens that elicit humoral immune responses targeting conserved epitopes on the viral hemagglutinin (HA), such as the receptor-binding site (RBS). Here, we engineered candidate immunogens that use non-circulating, avian influenza HAs as molecular scaffolds to present the broadly neutralizing RBS epitope from historical, circulating H1 influenzas. These “resurfaced” HAs (rsHAs) remove epitopes potentially targeted by strain-specific responses in immune-experienced individuals. Through structure-guided optimization we improved two antigenically different scaffolds to bind a diverse panel of pan-H1 and H1/H3 cross-reactive bnAbs with high affinity. Subsequent serological analyses from murine prime-boost immunizations show that the rsHAs are both immunogenic and can enrich for RBS-directed antibodies. Our structure-guided, RBS grafting approach provides candidate immunogens for selectively presenting a conserved viral epitope.
Paralogs in the PKA regulon traveled different evolutionary routes to divergent expression in budding yeast
Authors: Heineike Benjamin Murray , El-Samad Hana
Published: December 2019

Functional divergence of duplicate genes, or paralogs, is an important driver of novelty in evolution. In the model yeast Saccharomyces cerevisiae, there are 547 paralog gene pairs that survive from an interspecies Whole Genome Hybridization (WGH) that occurred ∼100MYA. Many WGH paralogs (or ohnologs) are known to have differential expression during the yeast Environmental Stress Response (ESR), of which Protein Kinase A (PKA) is a major regulator. While investigating the transcriptional response to PKA inhibition in S. cerevisiae, we discovered that approximately 1/6th (91) of all ohnolog pairs were differentially expressed with a striking pattern. One member of each pair tended to have low basal expression that increased upon PKA inhibition, while the other tended to have high but unchanging expression. Examination of PKA inhibition data in the pre-WGH species K. lactis and PKA-related stresses in other budding yeasts indicated that unchanging expression in response to PKA inhibition is likely to be the ancestral phenotype prior to duplication. Analysis of promoter sequences of orthologs of gene pairs that are differentially expressed in S. cerevisiae further revealed that the emergence of PKA-dependence took different evolutionary routes. In some examples, regulation by PKA and differential expression appears to have arisen following the WGH, while in others, regulation by PKA appears to have arisen in one of the two parental lineages prior to the WGH. More broadly, our results illustrate the unique opportunities presented by a WGH event for generating functional divergence by bringing together two parental lineages with separately evolved regulation into one species. We propose that functional divergence of two ohnologs can be facilitated through such regulatory divergence, which can persist even when functional differences are erased by gene conversion.
Ex-situ cultivation of Isoetes cangae and Isoetes serracarajensis (Isoetaceae) two endemic species from Brazilian Amazon
Authors: Zandonadi Daniel Basílio , Martins Rodrigo Lemes , dos Santos Prado Luis Alfredo , Duarte Heitor Monteiro , Santos Mirella Pupo , Calderon Emiliano , Fernandes Ana Carolina Almeida , Santos Quézia Souza , Nunes Filipe Junior Gonçalves , Ribeiro Luis Carlos Felisberto , Fernandes Taís Nogueira , Castilho Alexandre , de Assis Esteves Francisco
Published: December 2019

Isoetes L. is a genus of lycophytes widely distributed around the world that has a large number of endemic species. Here we document the first successful large scale ex-situ cultivation of the new endemic species from Brazilian Amazon quillworts Isoetes cangae and Isoetes serracarajensis. These isoetids are endemic of an iron mining site and grow on a superficial iron crust that occurs over ferriferous rocks. This study aimed to develop the cultivation methods of the threatened species I. cangae and monitoring its unique physiology. Plants from both species brought from Amazon lagoons were cultivated through a year in a low-cost system at a different site during different seasons. The survival rate of plants was higher as 98% and both species developed well under cultivation but showed different patterns during linear growth: I. cangae showed faster leaf development but was slower on sprout production than I. serracarajensis. The mechanism of leaf expansion is related to plasma membrane H+-ATPase activation, near to 2-fold higher in I. cangae. On the other hand, the effective quantum yield of photosystem II was higher in I. serracarajensis than in I. cangae. During the cultivation, new sporophytes of I. cangae were produced, confirming its reproductive status. We have also tested elevated iron levels on the growth of plants, but no interference of iron concentration was observed. The results of this work have broad applicability, assisting other low-cost cultivation studies, which are very important in ecosystem recovery of mining areas and conservation strategies.
Biosynthesis of Iron Oxide Nanoparticles via Crocus sativus and their Antifungal Efficacy against Verticillium Wilt Pathogen Verticillium dahliae
Authors: Alam Tariq , Akbar Fazal , Ali Mohammad , Munis Muhammad Farooq Hussain , Khan Jafar
Published: December 2019

Plant diseases pose threat to global food security. The excessive use of synthetic agro-chemical engender pesticide resistance. The exploration of alternative sustainable diseases management practices are crucial to overcome the devastative plant diseases. In this study, a facile innocuous approach was adopted for biogenic synthesis of Fe2O3-CsNPs via Crocus sativus corm aqueous extract and was evaluated for their antifungal efficacy against the Verticillium wilt pathogen Verticillium dahliae. The physico-chemical characterization of biosynthesized nanoparticles were performed through UV-visible Spectroscopy, Fourier Transform Infrared Spectroscopy, Energy Dispersive X-ray Spectroscopy, X-Ray Diffraction, and Scanning Electron Microscopy. The fungus mycelium growth was significantly inhibited in the media containing 3mg/mL Fe2O3-CsNPs. Degenerated, concentrated and shriveled hyphae were revealed in Scanning Electron Microscopy. The overall results demonstrated that the biogenic Fe2O3-CsNPs have the efficacy to control devastative phytopathogens.
Design and analysis of CRISPR-based underdominance toxin-antidote gene drives
Authors: Champer Jackson , Champer Samuel E. , Kim Isabel , Clark Andrew G. , Messer Philipp W.
Published: December 2019

CRISPR gene drive systems offer a mechanism for transmitting a desirable transgene throughout a population for purposes ranging from vector-borne disease control to invasive species suppression. In this simulation study, we assess the performance of several CRISPR-based underdominance gene drive constructs employing toxin-antidote principles. These drives disrupt the wild-type version of an essential gene using a CRISPR nuclease (the toxin) while simultaneously carrying a recoded version of the gene (the antidote). Drives of this nature allow for releases that could be potentially confined to a desired geographic location. This is because such drives have a nonzero invasion threshold frequency, referring to the critical frequency required for the drive to spread through the population. We model drives which target essential genes that are either haplosufficient or haplolethal, using nuclease promoters with expression restricted to the germline, promoters that additionally result in cleavage activity in the early embryo from maternal deposition, and promoters that have ubiquitous somatic expression. We also study several possible drive architectures, considering both “same-site” and “distant-site” systems, as well as several reciprocally targeting drives. Together, these drive variants provide a wide range of invasion threshold frequencies and options for both population modification and suppression. Our results suggest that CRISPR toxin-antidote underdominance drive systems could allow for the design of highly flexible and potentially confinable gene drive strategies.
Emergence of a novel immune-evasion strategy from an ancestral protein fold in bacteriophage Mu
Authors: Karambelkar Shweta , Udupa Shubha , Gowthami Vykuntham Naga , Ramachandra Sharmila Giliyaru , Swapna Ganduri , Nagaraja Valakunja
Published: December 2019

The broad host range bacteriophage Mu employs a novel ‘methylcarbamoyl’ modification to protect its DNA from diverse host restriction systems. Biosynthesis of the unusual modification is a longstanding mystery. Moreover, isolation of Mom, the phage protein involved in the modification has remained elusive to date. Here, we characterized the co-factor and metal binding properties of Mom and provide a molecular mechanism to explain ‘methylcarbamoyl’ation by Mom. Our computational analyses revealed a conserved GNAT (GCN5-related N-acetyltransferase) fold in Mom, predicting acetyl CoA as its co-factor. We demonstrate that Mom binds to acetyl CoA and identify the active site. Puzzlingly, none of the > 309,000 GNAT members identified so far catalyze Mom-like modification of their respective substrates. Besides, conventional acid-base catalysis deployed by typical acetyltransferases cannot support methylcarbamoylation of adenine seen in Mu phage. In contrast, free radical-chemistry, catalyzed by Fe-S cluster or transition metal ions can explain the seemingly challenging reaction between acetyl CoA and DNA. We discovered that Mom is an iron-binding protein, with the Fe2+/3+ion colocalized with acetyl CoA in the active site of Mom. Mutants defective for binding Fe2+/3+or acetyl CoA demonstrated compromised activity, indicating their importance in the DNA modification reaction. Iron-binding in the GNAT active site is unprecedented and represents a small step in the evolution of Mom from the ancestral acetyltransferase fold. Yet, the tiny step allows a giant chemical leap from usual acetylation to a novel methylcarbamoylation function, while conserving the overall protein architecture.

Studying the arms race between bacteria and their viruses (bacteriophages or phages) is key to understanding microbial life and its complexity. An unprecedented DNA modification shields phage Mu from bacterial restriction endonucleases that destroy incoming phage DNA. Nothing is known of how the modification is brought about, except that a phage protein Mom is involved. Here, we discover acetyl CoA and iron as key requirements for the modification. We explain how by evolving the ability to bind iron - a transition metal capable of generating highly reactive free radicals, a well-studied scaffold like the acetyltransferase fold can gain novel catalytic prowess in Mom. These findings have broad implications for gene editing technologies and therapeutic application of phages.
An optimized acetylcholine sensor for monitoring in vivo cholinergic activity
Authors: Jing Miao , Li Yuexuan , Zeng Jianzhi , Huang Pengcheng , Skirzewski Miguel , Kljakic Ornela , Peng Wanling , Qian Tongrui , Tan Ke , Wu Runlong , Zhang Shichen , Pan Sunlei , Xu Min , Li Haohong , Saksida Lisa M. , Prado Vania F. , Bussey Tim , Prado Marco A.M. , Chen Liangyi , Cheng Heping , Li Yulong
Published: December 2019

The ability to directly measure acetylcholine (ACh) release is an essential first step towards understanding its physiological function. Here we optimized the GRABACh (GPCR-Activation–Based-ACh) sensor with significantly improved sensitivity and minimal downstream coupling. Using this sensor, we measured in-vivo cholinergic activity in both Drosophila and mice, revealing compartmental ACh signals in fly olfactory center and single-trial ACh dynamics in multiple regions of the mice brain under a variety of different behaviors
Assessing the impacts of agriculture and its trade on Philippine biodiversity
Authors: Ortiz Andrea Monica D. , Torres Justine Nicole V.
Published: December 2019

The Philippines is home to a high number of unique species that can be found nowhere else in the world. However, its unique species and ecosystems are at high risk because of habitat loss and degradation. Agricultural land use and land use change are major drivers of biodiversity loss in the Philippines.

In the Philippines, an important area that requires focus is plantation agriculture (monocropping) for high-value crops such as banana and pineapple, which are grown widely in the country, particularly in the island of Mindanao. The intensive nature of plantation agriculture means that it has many adverse effects on the environment while producing goods and commodities that are typically for trade and export with international partners. This means that local biodiversity losses may be driven by countries thousands of kilometers away.

While many global studies have attempted to understand how biodiversity impacts are embodied within agricultural goods, there are few studies that have investigated the Philippines specifically. In this study, local and national-scale data are investigated to better characterize the nexus between agriculture, biodiversity, and trade in the Philippine context. Based on geographical data, many banana and pineapple plantations and their buffer zones interact and overlap with areas that are high in biodiversity, such as Protected Areas and Important Bird Areas. In this study, data shows that 82 threatened species, including the critically endangered Philippine eagle, are at risk of exposure to agricultural activities from high-value crops banana and pineapple. An additional and important political and legal analysis is also undertaken in the study to reveal key legislation and enabling environments relevant to the interactions between land use and biodiversity. More stringent definitions and protections for biodiversity are recommended to recognize the increasing role that agricultural production, and importantly, its global trade, has on threatened Philippine species and habitats.
Nature protection across countries: Do size and power matter?
Authors: Baldi Germán
Published: December 2019

Protected areas are one of the most effective tools for nature conservation. Consequently, almost all countries have agreed to set increasingly demanding goals for the expansion of their protected area systems. However, there is a large disparity among countries, and research on the cultural drivers of differences remains quite unexplored. Here, we explore the relationship between protected extent and a limited spectrum of socio-economic characteristics, making focus on size and power features. Protected areas under strict conservation categories (I to IV, IUCN) were considered for 195 countries, and relationships were modeled by means of LOESS regressions, violin plots, and a random forest ensemble learning method. Larger and more powerful countries (in terms of land area, gross domestic product, or military expenditure) protect less and in relatively smaller units than smaller and less powerful countries. Out of the twenty most extensive countries of the world, only two exceed 10% of protection. This situation is problematic since an effective growth of the global protected area network depends on the willingness of larger and more powerful countries. We propose different hypothesesa posteriorithat explain the role of size and power driving protection. These hypotheses involve direct mechanisms (e.g., the persuasive capacity of large countries) or mechanisms that mediate the interactions of some others (e.g., tourism contribution to GDP and insularity). Independently of mechanisms, our results emphasize the conservation responsibilities of large and powerful countries and contribute to envision conservation scenarios in the face of changes in the number and size of countries.
Tuning antiviral CD8 T-cell response via proline-altered peptide ligand vaccination
Authors: Duru Adil Doganay , Sun Renhua , Allerbring Eva B. , Chadderton Jesseka , Kadri Nadir , Han Xiao , Uchtenhagen Hannes , Madhurantakam Chaithanya , Pellegrino Sara , Sandalova Tatyana , Nygren Per-Åke , Turner Stephen J. , Achour Adnane
Published: December 2019

Viral escape from CD8+cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+T cell recognition of the naturally occurring MHC-I-restricted LCMV-associated immune escape variant Y4F is restored following vaccination with a proline-altered peptide ligand (APL). The APL increases MHC/peptide (pMHC) complex stability, rigidifies the peptide and facilitates T cell receptor (TCR) recognition through reduced entropy costs. Structural analyses of pMHC complexes before and after TCR binding, combined with biophysical analyses, revealed that although the TCR binds similarly to all complexes, the p3P modification alters the conformations of a very limited amount of specific MHC and peptide residues, facilitating efficient TCR recognition. This approach can be easily introduced in peptides restricted to other MHC alleles, and can be combined with currently available and future vaccination protocols in order to prevent viral immune escape.

Author Summary

Viral escape mutagenesis correlates often with disease progression and represents a major hurdle for vaccination-based therapies. Here, we have designed and developed a novel generation of altered epitopes that re-establish and enhance significantly CD8+T cell recognition of a naturally occurring viral immune escape variant. Biophysical and structural analyses provide a clear understanding of the molecular mechanisms underlying this reestablished recognition. We believe that this approach can be implemented to currently available or novel vaccination approaches to efficiently restore T cell recognition of virus escape variants to control disease progression.
Assigning a role for chemosensory signal transduction inCampylobacter jejunibiofilms using a combined omics approach
Authors: Tram Greg , Klare William P. , Cain Joel A. , Mourad Basem , Cordwell Stuart J. , Korolik Victoria , Day Christopher J.
Published: December 2019

Biofilms serve as a protective mechanism for bacteria to cope with environmental stress. Whilst ordinarily a fastidious organism, it has been long suggested thatC. jejuniis able to utilise this mode of growth as a way to transmit infection from the avian host to humans. Herein, we undertook a combinatorial approach to examine differential expression ofC. jejunigenes and protein abundance during biofilm formation. RNA sequencing and proteomicsviaquantitative liquid chromatography – tandem mass spectrometry (LC-MS/MS) revealed biofilm growth induced a substantial rearrangement of theC. jejunitranscriptome and proteome, with ∼600 genes differentially expressed in biofilms compared to planktonic cells. Biofilm-induced genes / proteins were those involved in iron metabolism and acquisition, cell division, glycan production and attachment, while those repressed were associated with metabolism, amino acid uptake and utilisation, and large tracts of the chemotaxis pathway.

We further examined the role of chemotaxis inC. jejunibiofilm formation by assessing the behaviour of isogenic strains with deletions of thecheVandcheWgenes. Both ΔcheVand ΔcheWexhibited a significant decrease in directed motility when compared to wild-typeC. jejuni. Both mutants also demonstrated an increase in autoagglutination ability and increased biofilm formation. A subtle difference was also observed between the phenotypes of ΔcheVand ΔcheWmutants, both in motility and biofilm formation. This suggests roles for the CheV and CheW signal transduction proteins and may present signal transduction as a potential method for modulatingC. jejunibiofilm formation.

Author summary

Campylobacter jejuniis a gastroenteric bacterium that is responsible for most cases of bacterial food poisoning in the developed world. The organism commonly resides in avian reservoirs and is passed to humans through contaminated poultry and animal products. Ordinarily,C. jejunirequires a strict set of conditions in order to survive and cause infections in humans. Biofilms are a method of bacterial growth that may provide shielding from harsh environments and provide an important link between reservoirs and human hosts. In this study, we have utilised a multi-platform approach to compare gene expression and protein abundance in planktonicC. jejunicells and those growing as a biofilm. We subsequently focused on the chemosensory system ofC. jejuniand demonstrated that signal transduction proteins play a role in biofilm formation. Our work has provided a broad profile of which genes are important toC. jejunibiofilms and that the chemosensory pathway has an influence on biofilm formation.
Prediction of fruit texture with training population optimization for efficient genomic selection in apple
Authors: Roth Morgane , Di Guardo Mario , Guerra Walter , Muranty Hélène , Patocchi Andrea , Costa Fabrizio
Published: December 2019

Texture plays a major role in the determination of fruit quality in apple. Due to its physiological and economic relevance, this trait has been largely investigated, leading to the fixation of the major gene PG1 controlling firmness in elite cultivars. To further improve fruit texture, the targeting of an undisclosed reservoir of loci with minor effects is compelling. In this work, we aimed to unlock this potential with a genomic selection approach by predicting fruit acoustic and mechanical features as obtained with a TA.XTplus texture analyzer in 537 individuals genotyped with 8,294 SNP markers. The best prediction accuracies following cross-validations within the training set (TRS) of 259 individuals were obtained for the acoustic linear distance (0.64). Prediction accuracy was further improved through the optimization of TRS size and composition according to the test set. With this strategy, a maximal accuracy of 0.81 was obtained when predicting the synthetic trait PC1 in the family ‘Gala × Pink Lady’. We discuss the impact of genetic relatedness and clustering on trait variability and predictability. Moreover, we demonstrated the need for a comprehensive dissection of the complex texture phenotype and the potentiality of using genomic selection to improve fruit quality in apple.

Highlight

A genomic selection study, together with the optimization of the training set, demonstrated the possibility to accurately predict texture sub-traits valuable for the amelioration of fruit quality in apple.
Lizard colour plasticity tracks background seasonal changes
Authors: Pellitteri-Rosa Daniele , Gazzola Andrea , Todisco Simone , Mastropasqua Fabio , Liuzzi Cristiano
Published: December 2019

Environmental heterogeneity on spatial and temporal scale fosters organism’s capacity to plastically alter coloration. Predation risk might favour the evolution of phenotypic plasticity in colour patterns, as individuals, which change colour throughout the year, could be able to improve their fitness. Here we explored the change in dorsal pigmentation of the Italian wall lizard (Podarcis siculus campestris) along three time points (March, July and October) during the period of activity. Lizard dorsal pictures were collected on the field, with the support of a reference chart to quantitatively estimate chromatic variables (hue, saturation and value, HSV). At the same time, pictures of grassy coverings (the most representative portion of the environment subjected to normal seasonal change), were collected. Our findings show that lizards are capable of altering dorsal coloration during seasonal change. They vary from green, at the onset of spring, to brownish in the middle of summer, and greyish colour in October. This modification closely followed environmental background colour variation and enhanced lizard crypsis during each season.
SLC2A knockout mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects
Authors: Boel Annekatrien , Burger Joyce , Vanhomwegen Marine , Beyens Aude , Renard Marjolijn , Barnhoorn Sander , Casteleyn Christophe , Reinhardt Dieter P. , Descamps Benedicte , Vanhove Christian , van der Pluijm Ingrid , Coucke Paul , Willaert Andy , Essers Jeroen , Callewaert Bert
Published: December 2019

Arterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-of-function mutations inSLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicate GLUT10 in transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygousSlc2a10missense mutations do not recapitulate the human phenotype. Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient forSlc2a10as well asGulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in rodents.Gulo;Slc2a10knock-out mice show mild phenotypic anomalies, which were absent in single knock-out controls. WhileGulo;Slc2a10knock-out mice do not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. TGFβ signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived fromGulo;Slc2a10knock-out mice. Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.
Flavor-specific enhancement of electronic cigarette liquid consumption and preference in mice
Authors: Wong AL , McElroy SM , Robinson JM , Mulloy SM , El Banna FK , Harris AC , LeSage MG , Lee AM
Published: December 2019

Background

The use of electronic cigarettes has increased over the past decade. To determine how the abuse liability of electronic cigarette liquids (e-liquids) differs from nicotine alone, and to determine the impact of flavor, we compared nicotine-containing fruit- and tobacco-flavored e-liquids, and their nicotine-free versions, to nicotine alone in mouse models of oral consumption, reward and aversion.

Methods

Adult male C57BL/6J mice voluntarily consumed oral nicotine, equivalent nicotine concentrations of fruit- and tobacco-flavored e-liquid, and equivalent dilutions of the nicotine-free versions in 2-bottle choice tests. Conditioned place preference and place aversion were assessed with peripherally administered e-liquids or nicotine. Serum nicotine and cotinine levels were measured after subcutaneous injections of e-liquid or nicotine.

Results

Mice showed higher consumption and preference for the fruit-flavored e-liquid compared with nicotine alone. This increase was not due to the flavor itself as consumption of the nicotine-free fruit-flavored e-liquid was not elevated until the highest concentration tested. The increased consumption and preference were not observed with the tobacco-flavored e-liquid. The conditioned place preference, place aversion and nicotine pharmacokinetics of the fruit-flavored e-liquid were not significantly different from nicotine alone.

Conclusions

Our data suggest that fruit, but not tobacco flavor, increased the oral consumption of e-liquid compared with nicotine alone. Moreover, this enhancement was not due to increased consumption of the flavor itself, altered rewarding or aversive properties after peripheral administration, or altered pharmacokinetics. This flavor-specific enhancement suggests that some flavors may lead to higher nicotine intake and increased use of e-liquids compared with nicotine alone.

Highlights

Fruit flavor, but not tobacco flavor, enhances e-liquid consumption and preference

The nicotine-free flavored e-liquid is not preferred over nicotine alone

Conditioning rewarding and aversive effects are equal between nicotine and e-liquid
First isolation and characterisation of Alongshan virus in Russia
Authors: Kholodilov Ivan S. , Litov Alexander G. , Klimentov Alexander S. , Belova Oxana A. , Polienko Alexandra E. , Nikitin Nikolai A. , Shchetinin Alexey M. , Ivannikova Anna Y. , Bell-Sakyi Lesley , Yakovlev Alexander S. , Bugmyrin Sergey V. , Bespyatova Liubov A. , Gmyl Larissa V. , Luchinina Svetlana V. , Gmyl Anatoly P. , Gushchin Vladimir A. , Karganova Galina G.
Published: December 2019

In recent decades, many new flavi-like viruses have been discovered predominantly in different invertebrates and, as was recently shown, some of them may cause disease in humans. The Jingmen tick virus (JMTV) group holds a special place among flavi-like viruses because, in contrast to the “classic” flaviviruses and other flavi-like viruses, they have a segmented ssRNA(+) genome. Two segments of the JMTV genome have homology with regions of the flavivirus genome encoding polymerase and helicase-protease proteins. JMTVs have several open reading frames (ORF) in segments encoding glycoprotein(s) and capsid protein and these ORF are specific only to them. JMTVs greatly differ in virion size.

We isolated three strains of Alongshan virus (ALSV), which is a representative of the JMTV group, from adultIxodes persulcatusticks collected in two geographically-separated Russian regions in the tick cell line IRE/CTVM19. One of the strains persisted in the IRE/CTVM19 cells without cytopathic effect for three years. Most virions purified from tick cells were spherical with a diameter of approximately 40.5 nm. In addition, we found smaller particles of approximately 13.1 nm in diameter. We obtained full genome sequences of all four segments of two of the isolated ALSV strains, and partial sequences of one segment from the third strain. Phylogenetic analysis on genome segment 2 of the JMTV group clustered our novel strains with other ALSV strains. We found evidence for the existence of a novel upstream ORF in the glycoprotein-coding segment of ALSV and other members of the JMTV group.

Significance Statement

We isolated three strains of Alongshan virus (ALSV) from adultIxodes persulcatusticks from two geographically separate areas of Russia in theIxodes ricinustick cell line IRE/CTVM19. One of the strains persisted in the IRE/CTVM19 cells without cytopathic effect for three years. Our study confirmed the value of tick cell lines in virus isolation and maintenance of persistent infection. The majority of virions of the ALSV strain Miass527 were enveloped spherical particles with a diameter of 40.5±3.7 nm. We found evidence for the existence of a novel upstream ORF in the glycoprotein-coding segment of ALSV and other members of the Jingmen tick virus group.
A synthetic Calvin cycle enables autotrophic growth in yeast
Authors: Gassler Thomas , Sauer Michael , Gasser Brigitte , Mattanovich Diethard , Steiger Matthias G.
Published: December 2019

The methylotrophic yeast Pichia pastoris is frequently used for heterologous protein production and it assimilates methanol efficiently via the xylulose-5-phosphate pathway. This pathway is entirely localized in the peroxisomes and has striking similarities to the Calvin-Benson-Bassham (CBB) cycle, which is used by a plethora of organisms like plants to assimilate CO2 and is likewise compartmentalized in chloroplasts. By metabolic engineering the methanol assimilation pathway of P. pastoris was re-wired to a CO2 fixation pathway resembling the CBB cycle. This new yeast strain efficiently assimilates CO2 into biomass and utilizes it as its sole carbon source, which changes the lifestyle from heterotrophic to autotrophic.

In total eight genes, including genes encoding for RuBisCO and phosphoribulokinase, were integrated into the genome of P. pastoris, while three endogenous genes were deleted to block methanol assimilation. The enzymes necessary for the synthetic CBB cycle were targeted to the peroxisome. Methanol oxidation, which yields NADH, is employed for energy generation defining the lifestyle as chemoorganoautotrophic. This work demonstrates that the lifestyle of an organism can be changed from chemoorganoheterotrophic to chemoorganoautotrophic by metabolic engineering. The resulting strain can grow exponentially and perform multiple cell doublings on CO2 as sole carbon source with a µmax of 0.008 h−1.

Graphical Abstract
Arabidopsis ROOT PHOTOTROPISM2 is a Light-Dependent Dynamic Modulator of Phototropin1
Authors: Kimura Taro , Tsuchida-Mayama Tomoko , Imai Hirotatsu , Okajima Koji , Ito Kosuke , Sakai Tatsuya
Published: December 2019

Arabidopsis thaliana phototropin1 (phot1) is a blue-light photoreceptor, i.e. a blue-light-activated Ser/Thr-protein kinase that mediates various light responses including phototropism. Phot1 functions in hypocotyl phototropism dependent on the light induction of ROOT PHOTOTROPISM2 (RPT2) proteins within a broad range of blue light intensities. It is not yet known however how RPT2 contributes to the photosensory adaptation of phot1 to high intensity blue light and the second positive phototropism. We here show that RPT2 suppresses the activity of phot1. Yeast two-hybrid analysis indicated RPT2 binding to the LOV1 (light, oxygen or voltage sensing 1) domain of phot1 required for its high photosensitivity. Our biochemical analyses revealed that RPT2 inhibits the autophosphorylation of phot1, suggesting that it suppresses the photosensitivity and/or kinase activity of phot1 through the inhibition of LOV1 function. We found for the first time that RPT2 proteins are degraded via a ubiquitin-proteasome pathway when phot1 is inactive and stabilized under blue-light conditions in a phot1-dependent manner. We propose that RPT2 is a molecular rheostat that maintains a moderate activation level of phot1 under any light intensity conditions.