bluuebunny/crossref_metadata_2025 huggingface dataset:
Seed ecology of European mesic meadows
Authors: Fernández-Pascual Eduardo , Vaz Madalena , Morais Beatriz , Reiné Ramón , Ascaso Joaquín , Afif Khouri Elías , Carta Angelino
Published: October 2021

Background and Aims

European mesic meadows are semi-natural open habitats of high biodiversity and an essential part of European landscapes. These species-rich communities can be a source of seed mixes for ecological restoration, urban greening and rewilding. However, limited knowledge of species germination traits is a bottleneck to the development of a competitive native seed industry. Here, we synthesize the seed ecology of mesic meadows.

Methods

We combined our own experimental data with data obtained from databases to create a combined dataset containing 2005 germination records of 90 plant species from 31 European countries. We performed a Bayesian meta-analysis of this dataset to test the seed germination response to environmental cues including scarification, stratification, temperature, alternating temperature and light. We also used multivariate ordination to check the relationship between seed traits (germination and morphology) and species ecological preferences, and to compare the seed ecology of mesic meadows with that of other herbaceous plant communities from the same geographic area.

Key Results

The seed ecology of mesic meadows is characterized by (1) high seed germinability when compared with other herbaceous plant communities; (2) low correspondence between seed traits and species ecological preferences; and (3) a deep phylogenetic separation between the two major families, Poaceae and Fabaceae. Poaceae produce many light seeds that respond to gap-detecting germination cues (alternating temperatures and light); Fabaceae produce fewer heavy seeds, which need scarification to break their physical dormancy.

Conclusions

High germinability of meadow seeds will reduce their capacity to form persistent seed banks, resulting in dispersal limitations to passive regeneration. For centuries, human activities have shaped the regeneration of meadows, leading to a loss of seed dormancy and decoupling seeds from seasonal cycles, as has been found in many domesticated species. The same anthropic processes that have shaped semi-natural mesic meadows have left them dependent on continued human intervention for their regeneration, highlighting the importance of active restoration via seed supply.
The power of word-frequency-based alignment-free functions: a comprehensive large-scale experimental analysis
Authors: Cattaneo Giuseppe , Ferraro Petrillo Umberto , Giancarlo Raffaele , Palini Francesco , Romualdi Chiara
Published: October 2021

Motivation

Alignment-free (AF) distance/similarity functions are a key tool for sequence analysis. Experimental studies on real datasets abound and, to some extent, there are also studies regarding their control of false positive rate (Type I error). However, assessment of their power, i.e. their ability to identify true similarity, has been limited to some members of the D2 family. The corresponding experimental studies have concentrated on short sequences, a scenario no longer adequate for current applications, where sequence lengths may vary considerably. Such a State of the Art is methodologically problematic, since information regarding a key feature such as power is either missing or limited.

Results

By concentrating on a representative set of word-frequency-based AF functions, we perform the first coherent and uniform evaluation of the power, involving also Type I error for completeness. Two alternative models of important genomic features (CIS Regulatory Modules and Horizontal Gene Transfer), a wide range of sequence lengths from a few thousand to millions, and different values of k have been used. As a result, we provide a characterization of those AF functions that is novel and informative. Indeed, we identify weak and strong points of each function considered, which may be used as a guide to choose one for analysis tasks. Remarkably, of the 15 functions that we have considered, only four stand out, with small differences between small and short sequence length scenarios. Finally, to encourage the use of our methodology for validation of future AF functions, the Big Data platform supporting it is public.

Availability and implementation

The software is available at: https://github.com/pipp8/power_statistics.

Supplementary information

Supplementary data are available at Bioinformatics online.
Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain
Authors: Dedek Annemarie , Xu Jian , Lorenzo Louis-Étienne , Godin Antoine G , Kandegedara Chaya M , Glavina Geneviève , Landrigan Jeffrey A , Lombroso Paul J , De Koninck Yves , Tsai Eve C , Hildebrand Michael E
Published: October 2021

The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking.

Here, we discovered that in the Freund’s adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females.

This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.
Subcortical–cortical functional connectivity as a potential biomarker for identifying patients with functional dyspepsia
Authors: Yin Tao , Sun Ruirui , He Zhaoxuan , Chen Yuan , Yin Shuai , Liu Xiaoyan , Lu Jin , Ma Peihong , Zhang Tingting , Huang Liuyang , Qu Yuzhu , Suo Xueling , Lei Du , Gong Qiyong , Liang Fanrong , Li Shenghong , Zeng Fang
Published: October 2021

The diagnosis of functional dyspepsia (FD) presently relies on the self-reported symptoms. This study aimed to determine the potential of functional brain network features as biomarkers for the identification of FD patients. Firstly, the functional brain Magnetic Resonance Imaging data were collected from 100 FD patients and 100 healthy subjects, and the functional brain network features were extracted by the independent component analysis. Then, a support vector machine classifier was established based on these functional brain network features to discriminate FD patients from healthy subjects. Features that contributed substantially to the classification were finally identified as the classifying features. The results demonstrated that the classifier performed pretty well in discriminating FD patients. Namely, the accuracy of classification was 0.84 ± 0.03 in cross-validation set and 0.80 ± 0.07 in independent test set, respectively. A total of 15 connections between the subcortical nucleus (the thalamus and caudate) and sensorimotor cortex, parahippocampus, orbitofrontal cortex were finally determined as the classifying features. Furthermore, the results of cross-brain atlas validation showed that these classifying features were quite robust in the identification of FD patients. In summary, the current findings suggested the potential of using machine learning method and functional brain network biomarkers to identify FD patients.
Occurrence of Sexual Reproduction ofDaktulosphaira vitifoliae(Hemiptera: Phylloxeridae) in Southern Brazil and Biology and Fertility Life Table in Grapevine Cultivars
Authors: Andzeiewski S , Oliveira D C , Bernardi D , Botton M
Published: October 2021

The grapevine phylloxera Daktulosphaira vitifoliae (Fitch) is the pest insect of greatest importance in grapevine. The objective of study was to evaluate the occurrence of overwintering eggs in seedlings of ‘Paulsen 1103’ (Vitis berlandieri × Vitis rupestris) and evaluate the biology and fertility life table of D. vitifoliae on five grape cultivars: ‘Bordô’ (Vitis labrusca), ‘Cabernet Sauvignon’ (Vitis vinifera), ‘BRS Lorena’ (Vitis vinifera × Seyval [Seibell 5656-Rayon d’Or]), ‘Magnolia’ (Vitis rotundifolia), and ‘Paulsen 1103’. In the field, overwintering eggs were found to be present in 78% of ‘Paulsen 1103’ seedlings, on the trunk of the seedlings. In the laboratory, phylloxera was found to complete the biological cycle (egg to adult) in roots of ‘BRS Lorena’, ‘Bordô’, and ‘Cabernet Sauvignon’. Nymphs did not complete development on roots of ‘Paulsen 1103’ and ‘Magnolia’, with 100% first instar mortality. Adult females feeding on ‘Bordô’ roots showed the lowest total fecundity (20.9 eggs per female), differing from insects feeding on ‘Cabernet Sauvignon’ roots (207.8 eggs per female). Based on the fertility life table, roots of ‘Cabernet Sauvignon’ provided the best reproduction rate (Ro = 219), intrinsic rate of increase (rm = 0.197 d) and time between generations (T = 21.5 d). The presence of overwintering eggs on the trunk of the rootstock ‘Paulsen 1103’ may promote the survival and dispersal of the insect. Lignified roots of the rootstock ‘Paulsen 1103’ and the cultivar ‘Magnolia’ do not allow the development of D. vitifoliae, with ‘Cabernet Sauvignon’ being the most suitable for the development of the insect.
A pragmatic evaluation of the primary school Be Active After-School Activity Programme (Be Active ASAP)
Authors: Murtagh Elaine , Mulhare Brian , Woods Catherine , Corr Méabh , Belton Sarahjane
Published: October 2021

The period after school represents an opportunity to engage children in physical activity (PA) programmes in schools. The purpose of this study was to evaluate the effect of an afterschool programme, delivered in schools, on children’s participation in and attitudes to PA. Ten schools took part in this non-randomized controlled trial (five experimental and five control schools). Experimental schools participated in an after-school programme delivered by teachers and parents for 50 min per week. Outcome measures included device-measured PA, self-report youth PA behaviour and parental perceptions of the school environment. Measurements took place at baseline, and mean follow-up was at 10 weeks. Data were collected from 196 participants, with a mean age of 8.1 ± 0.8 years. Mean daily minutes of moderate-to-vigorous physical activity (MVPA) for the entire sample at baseline was 69.9 ± 23.3. While both groups presented a decline in MVPA levels, there was a significant difference in the change from baseline to follow-up (P = 0.043) of min/day MVPA between the control group (−13.2 ± 23.9) and the experimental group (−0.9 ± 25.2). This programme may help maintain MVPA levels, with children exposed to the intervention experiencing a significantly lower decline in MVPA than their control counterparts.
Clinical, pathological and genetic features and follow-up of 110 patients with late-onset MADD: a single-center retrospective study
Authors: Wen Bing , Tang Shuyao , Lv Xiaoqing , Li Duoling , Xu Jingwen , Olsen Rikke Katrine Jentoft , Zhao Yuying , Li Wei , Wang Tan , Shao Kai , Zhao Dandan , Yan Chuanzhu
Published: October 2021

To observe a long-term prognosis in late-onset multiple acyl-coenzyme-A dehydrogenation deficiency (MADD) patients and to determine whether riboflavin should be administrated in the long-term and high-dosage manner, we studied the clinical, pathological and genetic features of 110 patients with late-onset MADD in a single neuromuscular center. The plasma riboflavin levels and a long-term follow-up study were performed. We showed that fluctuating proximal muscle weakness, exercise intolerance and dramatic responsiveness to riboflavin treatment were essential clinical features for all 110 MADD patients. Among them, we identified 106 cases with ETFDH variants, 1 case with FLAD1 variants and 3 cases without causal variants. On muscle pathology, fibers with cracks, atypical ragged red fibers (aRRFs) and diffuse decrease of SDH activity were the distinctive features of these MADD patients. The plasma riboflavin levels before treatment were significantly decreased in these patients as compared to healthy controls. Among 48 MADD patients with a follow-up of 6.1 years on average, 31 patients were free of muscle weakness recurrence, while 17 patients had episodes of slight muscle weakness upon riboflavin withdrawal, but recovered after retaking a small-dose of riboflavin for a short-term. Multivariate Cox regression analysis showed vegetarian diet and masseter weakness were independent risk factors for muscle weakness recurrence. In conclusion, fibers with cracks, aRRFs and diffuse decreased SDH activity could distinguish MADD from other genotypes of lipid storage myopathy. For late-onset MADD, increased fatty acid oxidation and reduced riboflavin levels can induce episodes of muscle symptoms, which can be treated by short-term and small-dose of riboflavin therapy.
The underrepresentation of palliative care in global guidelines for responding to infectious disease outbreaks: a systematic narrative review
Authors: de Boer Meghan , Coghlan Rachel J , Russell Bethany , Philip Jennifer A M
Published: October 2021

Background

The importance of palliative care provision has been highlighted in previous humanitarian emergencies. This review aimed to examine the breadth and depth of palliative care inclusion within global guidelines for responding to infectious disease outbreaks.

Methods

The review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Electronic searches of MEDLINE, Embase, Cumulative Index to Nursing and Allied Health, PsychInfo and grey literature were performed. Inclusion criteria were guidelines (recommendations for clinical practice or public health policy) for responding to infectious disease outbreaks in the general adult population. Results were limited to the English language, between 1 January 2010 and 17 August 2020. Analysis of the included articles involved assessing the breadth (number of palliative care domains covered) and depth (detail with which the domains were addressed) of palliative care inclusion.

Results

A total of 584 articles were retrieved and 43 met the inclusion criteria. Two additional articles were identified through handsearching. There was limited inclusion of palliative care in the guidelines examined.

Conclusions

There is an opportunity for the development of guidelines that include information on palliative care implementation in the context of infectious disease outbreaks in order to reduce the suffering of key vulnerable populations worldwide.
GlcNAc-Asn is a biomarker for NGLY1 deficiency
Authors: Mueller William F , Zhu Lei , Tan Brandon , Dwight Selina , Beahm Brendan , Wilsey Matt , Wechsler Thomas , Mak Justin , Cowan Tina , Pritchett Jake , Taylor Eric , Crawford Brett E
Published: October 2021

Substrate-derived biomarkers are necessary in slowly progressing monogenetic diseases caused by single-enzyme deficiencies to identify affected patients and serve as surrogate markers for therapy response. N-glycanase 1 (NGLY1) deficiency is an ultra-rare autosomal recessive disorder characterized by developmental delay, peripheral neuropathy, elevated liver transaminases, hyperkinetic movement disorder and (hypo)-alacrima. We demonstrate that N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA), is the analyte most closely associated with NGLY1 deficiency, showing consistent separation in levels between patients and controls. GNA accumulation is directly linked to the absence of functional NGLY1, presenting strong potential for its use as a biomarker. In agreement, a quantitative liquid chromatography with tandem mass spectrometry assay, developed to assess GNA from 3 to 3000 ng/ml, showed that it is conserved as a marker for loss of NGLY1 function in NGLY1-deficient cell lines, rodents (urine, cerebrospinal fluid, plasma and tissues) and patients (plasma and urine). Elevated GNA levels differentiate patients from controls, are stable over time and correlate with changes in NGLY1 activity. GNA as a biomarker has the potential to identify and validate patients with NGLY1 deficiency, act as a direct pharmacodynamic marker and serve as a potential surrogate endpoint in clinical trials.
MRI in the Setting of Neoadjuvant Treatment of Breast Cancer
Authors: Mercado Cecilia , Chhor Chloe , Scheel John R
Published: October 2021

Neoadjuvant therapy may reduce tumor burden preoperatively, allowing breast conservation treatment for tumors previously unresectable or requiring mastectomy without reducing disease-free survival. Oncologists can also use the response of the tumor to neoadjuvant chemotherapy (NAC) to identify treatment likely to be successful against any unknown potential distant metastasis. Accurate preoperative estimations of tumor size are necessary to guide appropriate treatment with minimal delays and can provide prognostic information. Clinical breast examination and mammography are inaccurate methods for measuring tumor size after NAC and can over- and underestimate residual disease. While US is commonly used to measure changes in tumor size during NAC due to its availability and low cost, MRI remains more accurate and simultaneously images the entire breast and axilla. No method is sufficiently accurate at predicting complete pathological response that would obviate the need for surgery. Diffusion-weighted MRI, MR spectroscopy, and MRI-based radiomics are emerging fields that potentially increase the predictive accuracy of tumor response to NAC.
Actin nucleator formins regulate the tension-buffering function of caveolin-1
Authors: Shi Xuemeng , Tang Daijiao , Xing Yifan , Zhao Shuangshuang , Fan Changyuan , Zhong Jin , Cui Yanqin , Shi Kun , Jiu Yaming
Published: October 2021

Both the mechanosensitive actin cytoskeleton and caveolae contribute to active processes such as cell migration, morphogenesis, and vesicular trafficking. Although distinct actin components are well studied, how they contribute to cytoplasmic caveolae, especially in the context of mechano-stress, has remained elusive. Here, we identify two actin-associated mobility stereotypes of caveolin-1 (CAV-1)-marked intracellular vesicles, which are characterized as ‘dwelling’ and ‘go and dwelling’. In order to exploit the reason for their distinct dynamics, elongated actin-associated formin functions are perturbed. We find drastically decreased density, increased clustering, and compromised motility of cytoplasmic CAV-1 vesicles resulting from lacking actin nucleator formins by both chemical treatment and RNA silencing of formin genes. Furthermore, hypo-osmosis-stimulated diminishing of CAV-1 is dramatically intensified upon blocking formins. The clustering of CAV-1 vesicles when cells are cultured on soft substrate is also aggravated under formin inhibition condition. Together, we reveal that actin-associated formins are essential for maintaining the dynamic organization of cytoplasmic CAV-1 and importantly its sensitivity upon mechanical challenge. We conclude that tension-controlled actin formins act as a safety valve dampening excessive tension on CAV-1 and safeguarding CAV-1 against mechanical damage.
Limitation of C4 photosynthesis by low carbonic anhydrase activity increases with temperature but does not influence mesophyll CO2 conductance
Authors: Crawford Joseph D , Cousins Asaph B
Published: October 2021

The CO2-concentrating mechanism (CCM) in C4 plants is initiated by the uptake of bicarbonate (HCO3−) via phosphoenolpyruvate carboxylase (PEPC). Generation of HCO3− for PEPC is determined by the interaction between mesophyll CO2 conductance and the hydration of CO2 to HCO3− by carbonic anhydrase (CA). Genetic reduction of CA was previously shown not to limit C4 photosynthesis under ambient atmospheric partial pressures of CO2 (pCO2). However, CA activity varies widely across C4 species and it is unknown if there are specific environmental conditions (e.g. high temperature) where CA may limit HCO3− production for C4 photosynthesis. Additionally, CA activity has been suggested to influence mesophyll conductance, but this has not been experimentally tested. We hypothesize that CA activity can limit PEPC at high temperatures, particularly at low pCO2, but does not directly influence gm. Here we tested the influence of genetically reduced CA activity on photosynthesis and gm in the C4 plant Zea mays under a range of pCO2 and temperatures. Reduced CA activity limited HCO3− production for C4 photosynthesis at low pCO2 as temperatures increased, but did not influence mesophyll conductance. Therefore, high leaf CA activity may enhance C4 photosynthesis under high temperature when stomatal conductance restricts the availability of atmospheric CO2.
A birth-death-migration model for life in astrophysical environments
Authors: Lingam Manasvi , Grimaldi Claudio , Balbi Amedeo
Published: October 2021

To assess the number of life-bearing worlds in astrophysical environments, it is necessary to take the intertwined processes of abiogenesis (birth), extinction (death), and transfer of life (migration) into account. We construct a mathematical model that incorporates this trio of mechanisms and accordingly derive the probability distribution function and other statistical properties (e.g. mean) for the number of worlds with biospheres. We show that a given astrophysical setting may become eventually saturated with life if the rate of successful transfers of organisms is higher than the extinction rate of biospheres. Based on the available data, we suggest that this criterion might be fulfilled for star-forming clusters (and perhaps the Galactic bulge under optimal circumstances), thereby indicating that such regions could constitute promising abodes for hosting and detecting life.
Isocratic HPLC analysis for the simultaneous determination of dNTPs, rNTPs and ADP in biological samples
Authors: Ranjbarian Farahnaz , Sharma Sushma , Falappa Giulia , Taruschio Walter , Chabes Andrei , Hofer Anders
Published: October 2021

Information about the cellular concentrations of deoxyribonucleoside triphosphates (dNTPs) is instrumental for mechanistic studies of DNA replication and for understanding diseases caused by defects in dNTP metabolism. The dNTPs are measured by methods based on either HPLC or DNA polymerization. An advantage with the HPLC-based techniques is that the parallel analysis of ribonucleoside triphosphates (rNTPs) can serve as an internal quality control of nucleotide integrity and extraction efficiency. We have developed a Freon-free trichloroacetic acid-based method to extract cellular nucleotides and an isocratic reverse phase HPLC-based technique that is able to separate dNTPs, rNTPs and ADP in a single run. The ability to measure the ADP levels improves the control of nucleotide integrity, and the use of an isocratic elution overcomes the shifting baseline problems in previously developed gradient-based reversed phase protocols for simultaneously measuring dNTPs and rNTPs. An optional DNA-polymerase-dependent step is used for confirmation that the dNTP peaks do not overlap with other components of the extracts, further increasing the reliability of the analysis. The method is compatible with a wide range of biological samples and has a sensitivity better than other UV-based HPLC protocols, closely matching that of mass spectrometry-based detection.
An integrative NMR-SAXS approach for structural determination of large RNAs defines the substrate-free state of a trans-cleaving Neurospora Varkud Satellite ribozyme
Authors: Dagenais Pierre , Desjardins Geneviève , Legault Pascale
Published: October 2021

The divide-and-conquer strategy is commonly used for protein structure determination, but its applications to high-resolution structure determination of RNAs have been limited. Here, we introduce an integrative approach based on the divide-and-conquer strategy that was undertaken to determine the solution structure of an RNA model system, the Neurospora VS ribozyme. NMR and SAXS studies were conducted on a minimal trans VS ribozyme as well as several isolated subdomains. A multi-step procedure was used for structure determination that first involved pairing refined NMR structures with SAXS data to obtain structural subensembles of the various subdomains. These subdomain structures were then assembled to build a large set of structural models of the ribozyme, which was subsequently filtered using SAXS data. The resulting NMR-SAXS structural ensemble shares several similarities with the reported crystal structures of the VS ribozyme. However, a local structural difference is observed that affects the global fold by shifting the relative orientation of the two three-way junctions. Thus, this finding highlights a global conformational change associated with substrate binding in the VS ribozyme that is likely critical for its enzymatic activity. Structural studies of other large RNAs should benefit from similar integrative approaches that allow conformational sampling of assembled fragments.
Examining Truth and State-Sponsored Media Campaigns as a Means of Decreasing Youth Smoking and Related Disparities in the United States
Authors: Colston David C , Xie Yanmei , Thrasher James F , Patrick Megan E , Titus Andrea R , Emery Sherry , McLeod M Chandler , Elliott Michael R , Fleischer Nancy L
Published: October 2021

Introduction

To analyze the impact of Truth and state-sponsored anti-tobacco media campaigns on youth smoking in the United States, and their potential to reduce tobacco-related health disparities.

Aims and Methods

Our study included data from the 2000–2015 Monitoring the Future study, an annual nationally representative survey of youth in 8th (n = 201 913), 10th (n = 194 468), and 12th grades (n = 178 379). Our primary exposure was Gross Rating Points (GRPs) of Truth or state-sponsored anti-tobacco advertisements, from Nielsen Media Research. Modified Poisson regression was used to assess the impact of a respondent’s GRPs on smoking intentions, past 30-day smoking participation, and first and daily smoking initiation. Additive interactions with sex, parental education, college plans, and race/ethnicity were used to test for differential effects of campaign exposure on each outcome.

Results

Greater campaign exposure (80th vs. 20th GRP percentile) was associated with lower probabilities of smoking intentions among 8th graders, smoking participation among 8th and 12th graders, and initiation among 8th graders. Greater exposure was associated with a greater reduction in the likelihood of smoking participation among 10th and 12th grade males than females; 10th and 12th graders with parents of lower education versus those with a college degree; and 12th graders who did not definitely plan to go to college relative to those who did.

Conclusions

Media campaign exposure was associated with a lower likelihood of youth smoking behaviors. Associations were more pronounced for groups disproportionately affected by smoking, including youth of lower socioeconomic status. Media campaigns may be useful in reducing smoking disparities and improving health equity.

Implications

Few recent studies have investigated the impact of anti-tobacco media campaigns on youth smoking and their potential to reduce tobacco-related health disparities in the United States. We found media campaigns—specifically state-sponsored media campaigns—reduced the likelihood of several smoking outcomes among youth, with some evidence that they mitigate disparities for disproportionately affected groups.
Intracellular Life Cycle of ‘CandidatusLiberibacter asiaticus’ Inside Psyllid Gut Cells
Authors: Lin Chun-Yi , Achor Diann , Levy Amit
Published: October 2021

‘Candidatus Liberibacter asiaticus’ (CLas), the devastating pathogen related to Huanglongbing (HLB), is a phloem-limited, fastidious, insect-borne bacterium. Rapid spread of HLB disease relies on CLas-efficient propagation in the vector, the Asian citrus psyllid Diaphorina citri, in a circulative manner. Understanding the intracellular lifecycle of CLas in psyllid midgut, the major organ for CLas transmission, is fundamental to improving current management strategies. Using a microscopic approach within CLas-infected insect midgut, we observed the entry of CLas into gut cells inside vesicles, termed Liberibacter-containing vacuoles (LCVs), by endocytosis. Endocytosis is followed by the formation of endoplasmic reticulum-related and replication permissive vacuoles (rLCVs). Additionally, we observed the formation of double membrane autophagosome-like structure, termed autophagy-related vacuole (aLCV). Vesicles containing CLas egress from aLCV and fuse with the cell membrane. Immunolocalization studies showed that CLas uses endocytosis- and exocytosis-like mechanisms that mediates bacterial invasion and egress. Upregulation of autophagy-related genes indicated subversion of host autophagy by CLas in psyllid vector to promote infection. These results indicate that CLas interacts with host cellular machineries to undergo a multistage intracellular cycle through endocytic, secretory, autophagic, and exocytic pathways via complex machineries. Potential tactics for HLB control can be made depending on further investigations on the knowledge of the molecular mechanisms of CLas intracellular cycle.
Goal-directed graph construction using reinforcement learning
Authors: Darvariu Victor-Alexandru , Hailes Stephen , Musolesi Mirco
Published: October 2021

Graphs can be used to represent and reason about systems and a variety of metrics have been devised to quantify their global characteristics. However, little is currently known about how to construct a graph or improve an existing one given a target objective. In this work, we formulate the construction of a graph as a decision-making process in which a central agent creates topologies by trial and error and receives rewards proportional to the value of the target objective. By means of this conceptual framework, we propose an algorithm based on reinforcement learning and graph neural networks to learn graph construction and improvement strategies. Our core case study focuses on robustness to failures and attacks, a property relevant for the infrastructure and communication networks that power modern society. Experiments on synthetic and real-world graphs show that this approach can outperform existing methods while being cheaper to evaluate. It also allows generalization to out-of-sample graphs, as well as to larger out-of-distribution graphs in some cases. The approach is applicable to the optimization of other global structural properties of graphs.
Bayesian uncertainty quantification for data-driven equation learning
Authors: Martina-Perez Simon , Simpson Matthew J. , Baker Ruth E.
Published: October 2021

Equation learning aims to infer differential equation models from data. While a number of studies have shown that differential equation models can be successfully identified when the data are sufficiently detailed and corrupted with relatively small amounts of noise, the relationship between observation noise and uncertainty in the learned differential equation models remains unexplored. We demonstrate that for noisy datasets there exists great variation in both the structure of the learned differential equation models and their parameter values. We explore how to exploit multiple datasets to quantify uncertainty in the learned models, and at the same time draw mechanistic conclusions about the target differential equations. We showcase our results using simulation data from a relatively straightforward agent-based model (ABM) which has a well-characterized partial differential equation description that provides highly accurate predictions of averaged ABM behaviours in relevant regions of parameter space. Our approach combines equation learning methods with Bayesian inference approaches so that a quantification of uncertainty can be given by the posterior parameter distribution of the learned model.
EFFECTS OF HAZARDOUS ALCOHOL AND DRUG USE ON ANTIRETROVIRAL ADHERENCE AND HIV VIRAL SUPPRESSION: A MEDIATION ANALYSIS
Authors: Moges Tesfaye S. , Cachay Edward R. , Qin Huifang , Bamford Laura , Grelotti David J. , Mathews Wm. Christopher
Published: October 2021

Background

Little is known regarding the degree to which substance and alcohol use effects on HIV viral suppression are mediated through medication adherence. We hypothesized that the total effects of such use are mediated through adherence.

Methods

We included patients with HIV (PWH) receiving care at an urban academic HIV clinic between 2014 and 2018. Eligible patients were those prescribed antiretroviral therapy who completed both patient reported outcome (PRO) questionnaires, and had subsequent plasma viral load (pVL) measurements. Measures included assessments of alcohol use (AUDIT-C), drug use (ASSIST), and self-reported adherence. Substances found in bivariate analysis to predict detectable pVL were modeled separately for mediation effects through adherence. We report natural direct (NDE) and indirect effect (NIE), marginal total effect (MTE) and percentage mediated.

Results

Among 3125 Patients who met eligibility criteria, percentages of current use by category were: hazardous alcohol 25.8%, cannabis 27.1%, amphetamines 13.1%, inhalants 11.9%, cocaine 5.3%, sedative-hypnotics 4.5%, opioids 2.9%, and hallucinogens 2.3%. Excellent adherence was reported in 58% and 10% had detectable pVL. Except for sedatives use of other ascertained substances was significantly associated with worse adherence. Bivariate predictors of detectable pVL were [OR(95% CI)]: amphetamine use 2.4 (1.8 -3.2) and opioid use 2.3 (1.3 - 4.0). The percentage mediated by adherence was 36% for amphetamine use, 26.5% for opioid use, and 39% for multiple substance use.

Conclusion

Use of amphetamines, opioids, and multiple substances predicted detectable pVL. However, less than 40% of effects were mediated by self-reported adherence.

We examined adherence-mediated effects of hazardous alcohol and substance use on HIV viral suppression. Use of amphetamines, opioids, and multiple substance predicted detectable viral load, however, less than 40% of effects were mediated by self-reported antiretroviral adherence.
A monogenean parasite reveals the widespread translocation of the African Clawed Frog in its native range
Authors: Schoeman Anneke L , du Preez Louis H , Kmentová Nikol , Vanhove Maarten PM
Published: October 2021

The management of bio-invasions relies upon the development of methods to trace their origin and expansion. Co-introduced parasites, especially monogenean flatworms, are ideal tags for the movement of their hosts due to their short generations, direct life cycles and host specificity. However, they are yet to be applied to trace the intraspecific movement of host lineages in their native ranges.

As proof of this concept, we conducted a comparative phylogeographic analysis based upon two mitochondrial markers of a globally invasive frog Xenopus laevis and its monogenean parasite Protopolystoma xenopodis in its native range in southern Africa and invasive range in Europe.

Translocation of lineages was largely masked in the frog’s phylogeography. However, incongruent links between host and parasite phylogeography indicated host switches from one host lineage to another after these were brought into contact in the native range. Thus, past translocation of host lineages is revealed by the invasion success of its co-introduced parasite lineage.

This study demonstrates that parasite data can serve as an independent line of evidence in invasion biology, also on the intraspecific level, shedding light on previously undetected invasion dynamics. Based upon the distribution of these invasive parasite lineages, we infer that there is widespread anthropogenic translocation of this frog, not only via official export routes, but also facilitated by the frog’s use as live bait by angling communities.

Synthesis and applications. Data from co-introduced, host-specific parasites, as tags for translocation, can add value to investigations in invasion biology and conservation. A better understanding of the translocation history and resulting genetic mixing of host and parasite lineages in the native range can shed light on the genetic make-up of parasite assemblages co-introduced to the invasive range. Knowledge of the intraspecific movement of different lineages of animals in their native ranges also has conservation implications, since contact between divergent lineages of hosts and parasites can facilitate host switches and altered parasite dynamics in both native and invasive populations. Therefore, we recommend the inclusion of parasite data as a more holistic approach to the invasion ecology of animals on the intraspecific level.
Kinetic principles underlying pioneer function of GAGA transcription factor in live cells
Authors: Tang Xiaona , Li Taibo , Liu Sheng , Wisniewski Jan , Zheng Qinsi , Rong Yikang , Lavis Luke D. , Wu Carl
Published: October 2021

How pioneer factors interface with chromatin to promote accessibility for transcription control is poorly understood in vivo. Here, we directly visualize chromatin association by the prototypical GAGA pioneer factor (GAF) in live Drosophila hemocytes. Single-particle tracking reveals that the majority of GAF is chromatin-bound, with a stable-binding fraction showing nucleosome-like confinement residing on chromatin for over 2 minutes, far longer than the dynamic range of most transcription factors. These kinetic properties require the full complement of GAF’s DNA-binding, multimerization and intrinsically disordered domains, and are autonomous from recruited chromatin remodelers NURF and PBAP, whose activities primarily benefit GAF’s neighbors such as HSF. Evaluation of GAF kinetics together with its endogenous abundance indicates that despite on-off dynamics, GAF constitutively and fully occupies chromatin targets, thereby providing a temporal mechanism that sustains open chromatin for transcriptional responses to homeostatic, environmental, and developmental signals.
The many layers of BOLD. On the contribution of different vascular compartments to laminar fMRI
Authors: Schellekens Wouter , Bhogal Alex A. , Roefs Emiel C.A. , Báez-Yáñez Mario G. , Siero Jeroen C.W. , Petridou Natalia
Published: October 2021

Ultra-high field functional Magnetic Resonance Imaging (fMRI) offers the spatial resolution to measure neural activity at the scale of cortical layers. Most fMRI studies make use of the Blood-Oxygen-Level Dependent (BOLD) signal, arising from a complex interaction of changes in cerebral blood flow (CBF) and volume (CBV), and venous oxygenation. However, along with cyto- and myeloarchitectural changes across cortical depth, laminar fMRI is confronted with additional confounds related to vascularization differences that exist across cortical depth. In the current study, we quantify how the non-uniform distribution of macro- and micro-vascular compartments, as measured with Gradient-Echo (GE) and Spin-Echo (SE) scan sequences, respectively, affect laminar BOLD fMRI responses following evoked hypercapnic and hyperoxic breathing conditions. We find that both macro- and micro-vascular compartments are capable of comparable theoretical maximum signal intensities, as represented by the M-scaling parameter. However, the capacity for vessel dilation, as reflected by the cerebrovascular reactivity (CVR), is approximately three times larger for the macro-compared to the micro-vasculature at superficial layers. Finally, there is roughly a 35% difference in CBV estimates between the macro- and micro-vascular compartments, although this relative difference is approximately uniform across cortical depth.
A multiscale model of the cardiovascular system that regulates arterial pressure via closed loop baroreflex control of chronotropism, cell-level contractility, and vascular tone
Authors: Sharifi Hossein , Mann Charles K. , Wenk Jonathan F. , Campbell Kenneth S.
Published: October 2021

Multiscale models of the cardiovascular system can provide new insights into physiological and pathological processes. PyMyoVent is a computer model that bridges from molecular to organ-level function and which simulates a left ventricle pumping blood through the systemic circulation. Initial work with PyMyoVent focused on the End Systolic Pressure Volume Relationship and ranked potential therapeutic strategies by their impact on contractility. This manuscript extends the PyMyoVent framework by adding closed loop feedback control of arterial pressure. The control algorithm mimics important features of the physiological baroreflex and was developed as part of a long-term program that focuses on growth and biological remodeling. Inspired by the underlying biology, the reflex algorithm uses an afferent signal derived from arterial pressure to drive a kinetic model that mimics the net result of neural processing in the medulla and cell-level responses to autonomic drive. The kinetic model outputs control signals that are constrained between limits that represent maximum parasympathetic and maximum sympathetic drive and which modulate heart rate, intracellular Ca2+ dynamics, the molecular-level function of both the thick and the thin myofilaments, and vascular tone. Simulations show that the algorithm can regulate mean arterial pressure at user-defined set-points as well as maintaining arterial pressure when challenged by changes in blood volume and/or valve resistance. The reflex also regulates arterial pressure when cell-level contractility is modulated to mimic the idealized impact of myotropes. These capabilities will be important for future work that uses computer modeling to investigate clinical conditions and treatments.
Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats
Authors: Oka Kaori , Fujioka Shusuke , Kawamura Yoshimi , Komohara Yoshihiro , Chujo Takeshi , Sekiguchi Koki , Yamamura Yuki , Oiwa Yuki , Omamiuda-Ishikawa Natsuko , Komaki Shohei , Sutoh Yoichi , Sakurai Satoko , Tomizawa Kazuhito , Bono Hidemasa , Shimizu Atsushi , Araki Kimi , Yamamoto Takuya , Yamada Yasuhiro , Oshiumi Hiroyuki , Miura Kyoko
Published: October 2021

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted scientists to study their cancer resistance mechanisms in order to provide clues for human cancer prevention. Although cancer resistance in NMRs has been intensively investigated at the cellular level, it is still unknown how strongly resistant NMR individuals are to carcinogenesis and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration and reduced induction of inflammatory genes. NMRs harbor loss-of-function mutations in receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. A necroptosis-inducing stimulus did not increase death of NMR cells. After carcinogenic insults, leakage of the HMGB1, a marker of necrotic cell death, was not increased in NMR skin. In mice, inhibition or knockout of RIPK3 reduced immune cell infiltration and delayed the onset of chemical carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs. Further in vivo study of the unusual tissue immune system and carcinogenesis resistance of NMRs may lead to the development of new strategies to prevent carcinogenesis in humans.

Significance Statement

In contrast with intensive studies of cancer resistance mechanisms in naked mole-rats (NMRs) at the cellular level, little is known about how NMR individuals respond to carcinogenesis induction, despite the fact that cell-to-cell interactions in tissues regulate carcinogenesis in vivo. Here, we demonstrate that NMRs are remarkably resistant to chemical carcinogenesis induction and characteristically have attenuated tissue inflammatory responses to carcinogenic insults. NMRs have loss-of-function mutations inRIPK3andMLKLgenes and thus cannot activate necroptosis, a type of inflammation-inducing cell death. RIPK3 inhibition in mice reduced immune cell infiltration in response to carcinogenic insults and delayed the onset of chemical-induced carcinogenesis. Our results highlight the importance of studies on dampened tissue inflammatory responses to understand cancer resistance of NMRs.
The epidemiology and genomics of a virulent emerging fungal pathogen in an Australian reptile
Authors: Class B. , Powell D. , Terraube J. , Albery G. , Delmé C. , Bansal S. , Frère C.H.
Published: October 2021

Emerging infectious fungal diseases (EIFDs) represent a major conservation concern worldwide. Here, we provide early insights into the potential threat thatNannizziopsis barbatae(Nb), a novel EIFD, poses to Australian herpetological biodiversity. First known to the reptile pet trade as a primary pathogen causing untreatable severe dermatomycosis, since 2013,Nbhas emerged in a growing number of phylogenetically and ecologically distant free-living reptiles across Australia. Observing its emergence in a long-term study population of wild eastern water dragons (Intellagama lesueurii), we demonstrate the pathogen’s virulence-related genomic features, within-population spatiotemporal spread, and survival costs, all of which imply thatNbcould pose a threat to Australian reptiles in the future. Our findings highlight the need to closely monitor this pathogen in Australian ecosystems.