bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-Effectiveness of HIV Pre-exposure Prophylaxis Among Heterosexual Men in South Africa: A Cost-Utility Modeling Analysis
Authors: Vogelzang Michelle , Terris-Prestholt Fern , Vickerman Peter , Delany-Moretlwe Sinead , Travill Danielle , Quaife Matthew
Published: March 2020

Introduction:

Heterosexual men are not considered a key population in the HIV response and are mostly absent from pre-exposure prophylaxis (PrEP) studies to date. Yet, South African men face considerable HIV risk. We estimate the incremental cost-effectiveness of providing oral PrEP, injectable PrEP, or a combination of both to heterosexual South African men to assess whether providing PrEP would efficiently use resources.

Methods:

Epidemiological and costing models estimated the one-year costs and outcomes associated with PrEP use in 3 scenarios. PrEP uptake was estimated for younger (aged 18–24) and older (aged 25–49) men using a discrete choice experiment. Scenarios were compared with a baseline scenario of male condom use, while a health system perspective was used to estimate discounted lifetime costs averted per HIV infection. PrEP benefit was estimated in disability-adjusted life years (DALYs) averted. Uncertainty around the estimated incremental cost-effectiveness ratios (ICERs) was assessed using deterministic and probabilistic sensitivity analyses.

Results:

No PrEP intervention scenarios were cost-effective for both age groups at a willingness-to-pay threshold of $1175/DALY averted. The lowest ICER ($2873/DALY averted) was for the provision of oral PrEP to older men, although probability of cost-effectiveness was just 0.26%. Results found that ICERs were sensitive to HIV incidence and antiretroviral coverage.

Conclusions:

This study estimates that providing PrEP to heterosexual South African men is not cost-effective at current cost-effectiveness thresholds. Given the ICERs' sensitivity to several variables, alongside the heterogeneity of HIV infection among South African men, PrEP may be cost-effective for older men with high incidence and other subgroups based on locality and race. We recommend further investigation to better identify and target these groups.
Exploring the evidence-practice gap in the use of plain radiography for acute abdominal pain and intestinal obstruction: a systematic review and meta-analysis
Authors: Denham Gary , Smith Tony , James Daphne , McKiernan Sharmaine , Evans Tiffany-Jane
Published: March 2020

Aim:

Previous studies, some dating back several decades, have recommended that the use of plain abdominal radiography should be curbed, particularly with the growth of more accurate imaging modalities. However, evidence from referral data suggests that plain abdominal radiography continues to be a commonly requested examination. The aim of this review was to explore the gap between evidence and practice by re-examining the evidence using a robust methodology, investigating the diagnostic accuracy of plain abdominal radiography.

Methods:

Studies were identified from electronic databases and reference lists. Eligible studies provided data as to the sensitivity and specificity of plain abdominal radiography for either acute abdominal pain (Group A) or suspected intestinal obstruction (Group B). Version 2 of the Quality Assessment of Diagnostic Accuracy Studies was used to assess the quality of studies and hierarchical summary receiver operator characteristic curves and coupled forest plots were generated.

Results:

Four studies evaluated plain abdominal radiography for acute abdominal pain (Group A) and 10 for suspected intestinal obstruction (Group B). Two studies investigated both presentations and were included in both groups. Methodological quality of studies was moderately high, though incorporation bias was a common limitation. Sensitivity for Group A studies ranged from 30 to 46%, with specificity from 75 to 88%. For Group B, the range of sensitivity was 48 to 96% and specificity from 50 to 100%.

Conclusion:

The results suggest that use of plain abdominal radiography could be substantially reduced, particularly for patients with undifferentiated acute abdominal pain. While some guidelines exist, there is sound argument for clinical decision rules for abdominal imaging to inform evidence-based clinical decision-making and radiology referrals.
Rapid molecular testing for Staphylococcus aureus bacteraemia improves clinical management
Authors: McHugh Martin P. , Parcell Benjamin J. , MacKenzie Fiona M. , Templeton Kate E. ,   Scottish Microbiology and Virology Network (SMVN) Molecular Diagnostics Evaluation Group
Published: March 2020

Introduction.

Staphylococcus aureus

bacteraemia (SAB) causes significant morbidity and mortality. Standard diagnostic methods require 24–48 h to provide results, during which time management is guideline-based and may be suboptimal.

Aim. Evaluate the impact of rapid molecular detection of

S. aureus

in positive blood culture bottle fluid on patient management.

Methodology. Samples were tested prospectively at two clinical centres. Positive blood cultures with Gram-positive cocci in clusters on microscopy were tested with the Xpert MRSA/SA blood culture assay (Cepheid), as well as standard culture-based identification and antimicrobial sensitivity tests. Results were passed to clinical microbiologists in real time and used for patient management.

Results. Of 264 blood cultures tested (184 and 80 from each centre),

S. aureus

was grown from 39 (14.8 %) with one identified as methicillin-resistant

S. aureus

; all Xpert results agreed with culture results. Median turnaround time from culture flagging positive to result reporting for Xpert was 1.7 h, compared to 25.7 h for species identification by culture. Xpert results allowed early changes to management in 40 (16.8 %) patients, with Xpert positive patients starting specific therapy for SAB and Xpert negative patients stopping or avoiding empiric antimicrobials for SAB.

Conclusion. Rapid and accurate detection of

S. aureus

with the Xpert MRSA/SA BC assay in positive blood culture bottles allowed earlier targeted patient management. Negative Xpert results are suggestive of coagulase negative staphylococci, allowing de-escalation of antimicrobial therapy if clinically appropriate.
The involvement of HDAC3-mediated inhibition of microRNA cluster 17-92 in hyperoxia-mediated impairment of lung development in neonatal rats
Authors: Wang Di , Hong Hui , Li Xiao-Xia , Li Jing , Zhang Zhi-Qun
Published: March 2020

Background

The incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, has been paradoxically rising despite medical advances. Histone deacetylase 3 (HDAC3) has been reported to be a crucial regulator in alveologenesis. Hence, this study aims to investigate the mechanism of HDAC3 in the pulmonary angiogenesis and alveolarization of BPD.

Methods

A hyperoxia-induced mouse model of BPD was constructed. The mean liner intercept (MLI) and alveolar volume were measured to evaluate the alveolarization in BPD mice. Immunofluorescence assay was performed to detect the microvessel density (MVD) of lung tissues. Next, the expression of HDAC3 and its enrichment in the promoter region of microRNA (miR)-17-92 cluster, as well as the enrichment of p65 in the placental growth factor (Pgf) promoter region were detected by Western blot analysis and chromatin immunoprecipitation (ChIP) assay. The effect of HDAC3 and p65 on the activity of miR-17-92 promoter and Pgf promoter were examined by dual-luciferase reporter gene assay, respectively. Finally, the role of HDAC3 in angiogenesis and alveolarization through miR-17 regulated EZH1-p65-Pgf axis was validated in BPD mouse models.

Results

HDAC3 was involved in the regulation of alveolarization and angiogenesis in BPD. Results demonstrated that the expression of the miR-17-92 cluster in BPD was regulated by HDAC3. miR-17 was related to the regulatory role of HDAC3 in regulating EZH1 expression and in lung fibroblasts of BPD. Besides, results showed that EZH1 could promote Pgf expression by recruiting p65 to regulate BPD. HDAC3 regulated the expression of EZH1 through miR-17 to promote the recruitment of p65 in the Pgf promoter region, thus enhancing the transcription and expression of Pgf. HDAC3 was demonstrated to regulate Pgf through the miR-17-EZH1-p65 axis to mediate angiogenesis and alveolarization of BPD mice.

Conclusion

Altogether, the present study revealed that HDAC3 could regulate the EZH1-p65-Pgf axis through miR-17 in the miR-17-92 cluster in the pulmonary angiogenesis and alveolarization of BPD mice.
Ontogenetic and static allometry of hind femur length in the cricketGryllus bimaculatus(Orthoptera: Gryllidae) with implications for evo-devo of morphological scaling
Authors: Neiro Jakke Sameli
Published: March 2020

The evolution of morphological allometry or scaling is a long-standing enigma in biology. Three types of allometric relationships have been defined: static, ontogenetic and evolutionary allometry. However, the theory of the interrelationship between these three types of allometry have not been tested in Orthopterans and to a lesser extent in hemimetabolous insects. Here, the ontogenetic allometry of hind femur length in the cricketGryllus bimaculatuswas observed to be slightly positive as compared with a negative allometric relationship for Orthopterans in general, while the instar-specific static allometries were highly variable. The findings give support for the size-grain hypothesis in Orthoptera and indicate that ontogenetic allometries may not predict evolutionary allometries. The current model for the developmental basis of allometry derived from holometabolous insects is extended into a phylogenetic context and the potential ofG. bimaculatusand other Orthopterans for further experiments of evo-devo of morphological scaling is discussed.
Physical activity and Retirement: Original analysis of responses to the English Adult Active Lives Survey 2016/17
Authors: Brainard Julii , Cooke Rachel , Lane Kathleen , Salter Charlotte
Published: March 2020

Objectives

Opportunities for older adults to do physical activity may depend on other commitments. To see if reported physical activity was higher or lower among older adults depending on work status: full time, part-time or retired.

Methods

The Active Lives Survey 2016/17 in England was used to see how active people were depending on employment or retirement status. Types of physical activity (PA) considered were: leisure, gardening, active travel and combined total, adjusted for age, sex, BMI, disability, rurality and deprivation in models using hurdle negative binomial regression.

Results

Total PA was significantly greater for retired persons compared to both full- and part-time workers age 55-64, while being retired or working part-time at age 65-74 meant more PA. People did more leisure or gardening with less work, but active travel decreased with fewer work hours, at all ages. Retirement meant more leisure and gardening PA but less active travel.

Conclusions

Demand for opportunities to engage in leisure and gardening PA appears to be high among retired people. Greater promotion of active travel in this cohort may be possible.
High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot
Authors: Keam Simon P , Halse Heloise , Nguyen Thu , Wang Minyu , Van Kooten Losio Nicolas , Mitchell Catherine , Caramia Franco , Byrne David J , Haupt Sue , Ryland Georgina , Darcy Phillip K , Sandhu Shahneen , Blombery Piers , Haupt Ygal , Williams Scott G , Neeson Paul J
Published: March 2020

Prostate cancer (PCa) has a profoundly immunosuppressive microenvironment, we hypothesized that radiation therapy would break this immune suppression. To investigate this, we performed high-throughput immune cell subset analysis, and gene expression profiling of pre-versus post-radiation tissue in a cohort of patients with localized disease that received high dose-rate brachytherapy (HDRBT). We resolved tumor and non-tumor zones in our spatial analysis to explore what drives the immunological response. Nanostring immune profiling revealed numerous immune checkpoint molecules were stimulated in response to HDRBT (e.g. B7-H3, CTLA4, PDL1 and PDL2). A published 16-gene tumor inflammation signature (TIS) gene profiling of immune activation states (high:hot, intermediate and low:cold) showed that most tissues possessed a low TIS pre-HDRBT. Crucially, HDRBT converted 80% of these ‘cold’-phenotype tumors into an ‘intermediate’ or ‘hot’ class. We used digital spatial profiling to show these HDRBT-induced changes in prostate TIS scores were derived from the non-tumor regions. Furthermore, these changes in TIS were also associated with pervasive changes in immune cell density and spatial relationships – in particularly between T cell subsets and antigen presenting cells. We identified increased density of CD4+ FOXP3+ T cells, CD68+ macrophages and CD68+ CD11c+ dendritic cells in response to HDRBT. The only subset change in tumor zones was PDL1+ macrophages. While these immune responses were heterogeneous, HDRBT induced significant changes in immune cell associations, including a gained T cell and HMWCK+ PDL1+ interaction in tumor zones. In conclusion, we showed HDRBT has a clear impact in converting “cold” prostate tumors into more immunologically activated “hot” tissues, with accompanying spatially-organized immune infiltrates and signaling changes. Understanding and potentially harnessing these changes will have widespread implications for the future treatment of localized PCa and the possible use of combination immunotherapies.
Nonsense mediated RNA decay factor UPF1 is critical for post-transcriptional and translational gene regulation in Arabidopsis
Authors: Raxwal Vivek K. , Simpson Craig G. , Gloggnitzer Jiradet , Entinze Juan Carlos , Guo Wenbin , Zhang Runxuan , Brown John W.S. , Riha Karel
Published: March 2020

Nonsense mediated RNA decay (NMD) is an evolutionary conserved RNA control mechanism that has also been implicated in the broader regulation of gene expression. Nevertheless, a role for NMD in genome regulation has not been fully assessed, partially because NMD inactivation is lethal in many organisms. Here, we performed in depth comparative analysis of Arabidopsis mutants lacking key proteins involved in different steps of NMD. We observed that UPF3, UPF1, and SMG7 have different impacts on NMD and the Arabidopsis transcriptome, with UPF1 having the biggest effect. Transcriptome assembly using stringent pipeline in UPF1-null plants revealed genome wide changes in alternative splicing, including switches in mRNA variants, suggesting a role for UPF1 in splicing. We further found that UPF1 inactivation leads to translational repression, manifested by a global shift in mRNAs from polysomes to monosomes and a downregulation of genes involved in translation and ribosome biogenesis. Despite this global change, NMD targets and low-expressed mRNAs with short half-lives were enriched in polysomes, indicating that UPF1 specifically suppresses the translation of aberrant RNAs. Particularly striking was an increase in the translation of TIR domain-containing, nucleotide-binding, leucine-rich repeat (TNL) immune receptors. The regulation of TNLs via UPF1/NMD-mediated mRNA stability and translational de-repression offers a dynamic mechanism for the rapid activation of TNLs in response to pathogen attack.
Assessing the effects of thinning on stem growth allocation of individual Scots pine trees
Authors: Saarinen Ninni , Kankare Ville , Yrttimaa Tuomas , Viljanen Niko , Honkavaara Eija , Holopainen Markus , Hyyppä Juha , Huuskonen Saija , Hynynen Jari , Vastaranta Mikko
Published: March 2020

Forest management alters the growing conditions and thus further development of trees. However, quantitative assessment of forest management on tree growth has been demanding as methodologies for capturing changes comprehensively in space and time have been lacking. Terrestrial laser scanning (TLS) has shown to be capable of providing three-dimensional (3D) tree stem reconstructions required for revealing differences between stem shapes and sizes. In this study, we used 3D reconstructions of tree stems from TLS and an unmanned aerial vehicle (UAV) to investigate how varying thinning treatments and the following growth effects affected stem shape and size of Scots pine (Pinus sylvestrisL.) trees. The results showed that intensive thinning resulted in more stem volume and therefore total biomass allocation and carbon uptake compared to the moderate thinning. Relationship between tree height and diameter at breast height (i.e. slenderness) varied between both thinning intensity and type (i.e. from below and above) indicating differing response to thinning and allocation of stem growth of Scots pine trees. Furthermore, intensive thinning, especially from below, produced less variation in relative stem attributes characterizing stem shape and size. Thus, it can be concluded that thinning intensity, type, and the following growth effects have an impact on post-thinning stem shape and size of Scots pine trees. Our study presented detailed measurements on post-thinning stem growth of Scots pines that have been laborious or impracticable before the emergence of detailed 3D technologies. Moreover, the stem reconstructions from TLS and UAV provided variety of attributes characterizing stem shape and size that have not traditionally been feasible to obtain. The study demonstrated that detailed 3D technologies, such as TLS and UAV, provide information that can be used to generate new knowledge for supporting forest management and silviculture as well as improving ecological understanding of boreal forests.
Optimization of data-independent acquisition using predicted libraries for deep and accurate proteome profiling
Authors: Doellinger Joerg , Blumenscheit Christian , Schneider Andy , Lasch Peter
Published: March 2020

In silicospectral library prediction of all possible peptides from whole organisms has a great potential for improving proteome profiling by data-independent acquisition (DIA) and extending its scope of application. In combination with other recent improvements in the field of mass spectrometry (MS)-based proteomics, including sample preparation, peptide separation and data analysis, we aimed to uncover the full potential of such an advanced DIA strategy by optimization of the data acquisition. The results demonstrate that the combination of high-qualityin silicolibraries, reproducible and high-resolution peptide separation using micro-pillar array columns as well as neural network supported data analysis enables the use of long MS scan cycles without impairing the quantification performance. The study demonstrates that mean coefficient of variations of 4 % were obtained even at only 1.5 data points per peak (full width at half maximum) across different gradient lengths, which in turn improved proteome coverage up to more than 8000 proteins from HeLa cells using empirically-corrected libraries and more than 7000 proteins using a whole humanin silicopredicted library. These data were obtained using a Q Exactive orbitrap mass spectrometer with moderate scanning speed (12 Hz) and perform very well in comparison to recent studies using more advanced MS instruments, which underline the high potential of this optimization strategy for various applications in clinical proteomics, microbiology and molecular biology.
Comprehensive analysis of fungal G1 cyclin docking motif sequences that control CDK regulatory potency in vivo
Authors: Bandyopadhyay Sushobhana , Bhaduri Samyabrata , Örd Mihkel , Davey Norman E. , Loog Mart , Pryciak Peter M.
Published: March 2020

Cyclin-dependent kinases (CDKs) control the ordered series of events during eukaryotic cell division. The stage at which individual CDK substrates are phosphorylated can be dictated by cyclin-specific docking motifs. In budding yeast, substrates with Leu/Pro-rich (LP) docking motifs are recognized by Cln1/2 cyclins in late G1 phase, yet the key sequence features of these motifs and the conservation of this mechanism were unknown. Here we comprehensively analyzed LP motif requirements in vivo by combining a competitive growth assay with mutational scanning and deep sequencing. We quantified the impact of all single-residue replacements in five different LP motifs, using six distinct G1 cyclins from diverse fungi including medical and agricultural pathogens. The results reveal the basis for variations in potency among wild-type motifs, and allow derivation of a quantitative matrix that predicts the potency of other candidate motifs. In one protein, Whi5, we found overlapping LP and phosphorylation motifs with partly redundant effects. In another protein, the CDK inhibitor Sic1, we found that its LP motif is inherently weak due to unfavorable residues at key positions, and this imposes a beneficial delay in its phosphorylation and degradation. The overall results provide a general method for surveying viable docking motif sequences and quantifying their potency in vivo, and they reveal how variations in LP motif potency can tune the strength and timing of CDK regulation.
Quantitative fluxomics of circulating metabolites
Authors: Hui Sheng , Cowan Alexis J. , Zeng Xianfeng , Yang Lifeng , TeSlaa Tara , Li Xiaoxuan , Bartman Caroline , Zhang Zhaoyue , Jang Cholsoon , Wang Lin , Lu Wenyun , Rojas Jennifer , Baur Joseph , Rabinowitz Joshua D.
Published: March 2020

Mammalian organs are nourished by nutrients carried by the blood circulation. These nutrients originate from diet and internal stores, and can undergo various interconversions before their eventual use as tissue fuel. Here we develop isotope tracing, mass spectrometry, and mathematical analysis methods to determine the direct sources of circulating nutrients, their interconversion rates, and eventual tissue-specific contributions to TCA cycle metabolism. Experiments with fifteen nutrient tracers enabled extensive accounting both for circulatory metabolic cycles and tissue TCA inputs, across fed and fasted mice on either high carbohydrate or ketogenic diet. We find that a majority of circulating carbon flux is carried by two major cycles: glucose-lactate and triglyceride-glycerol-fatty acid. Futile cycling through these pathways is prominent when dietary content of the associated nutrients is low, rendering internal metabolic activity robust to food choice. The presented in vivo flux quantification methods are broadly applicable to different physiological and disease states.
Application of combined genomic and transfer analyses to identify factors mediating regional spread of antibiotic resistant bacterial lineages
Authors: Wang Joyce , Foxman Betsy , Pirani Ali , Lapp Zena , Mody Lona , Snitkin Evan
Published: March 2020

Background

Patients entering nursing facilities (NFs) are frequently colonized with antibiotic resistant organisms (AROs). To understand the determinants of ARO colonization on NF admission we applied whole-genome sequencing to track the spread of four ARO species across regional NFs and evaluated patient-level characteristics and transfer acute-care hospitals (ACHs) as risk factors for colonization.

Methods

584 patients from six NFs were surveyed for methicillin-resistantStaphylococcus aureus (MRSA), vancomycin-resistantEnterococcus faecalis/faecium(VREfc/VREfm) and ciprofloxacin-resistantEscherichia coli(CipREc) colonization. Genomic analysis was performed to quantify ARO spread between NFs and compared to patient-transfer networks. The association between admission colonization and patient-level variables and recent ACH exposures was examined using multivariable regression models.

Results

The majority of ARO isolates across study sites belonged to major healthcare-associated lineages: MRSA (ST5;N=89/117); VREfc (ST6;N=68/75); CipREc (ST131; N=58/64), and VREfm (clade A; N=129/129). While the genomic similarity of strains between NF pairs was associated with overlap in their feeder ACHs (Spearman’s rho=0.44-0.75, p<0.05 for MRSA, VREfc and CipREc), limited phylogenetic clustering by either ACH or NF supported regional endemicity. Significant predictors for ARO colonization on NF admission included lower functional status (adjusted odds ratio [aOR]>1 for all four AROs) and recent exposure to glycopeptides (aOR>2 for VREfm, VREfc and MRSA) or 3rd/4th-generation cephalosporins (aOR>2 for MRSA and VREfm). Transfer from specific ACHs was an independent risk factor for only one ARO/ACH pair (VREfm/ACH19, aOR=2.48[1.06-5.83]).

Conclusion

In this region, healthcare-associated ARO lineages are endemic among connected NFs and ACHs, making patient characteristics more informative of NF admission colonization risk than exposure to specific ACHs.

Using a combination of whole-genome sequencing, patient transfer and clinical data, we discerned the dissemination of four high-priority antibiotic-resistant organisms (ARO) in the regional healthcare network, and epidemiolocal drivers underlying the high ARO importation rate into regional nursing facilities.
Reduced arousal during reward anticipation in unmedicated depressed patients
Authors: Schneider Max , Elbau Immanuel G. , Nantawisarakul Taechawidd , Pöhlchen Dorothee , Brückl Tanja ,   BeCOME working group, Czisch Michael , Saemann Philipp G. , Lee Michael D. , Binder Elisabeth B. , Spoormaker Victor I.
Published: March 2020

Depression is a debilitating disorder with high prevalence and socioeconomic cost, but the central processes that are altered during depressive states remain largely elusive. Here, we build on recent findings in macaques that indicate a direct causal relationship between pupil dilation and anterior cingulate cortex mediated arousal during anticipation of reward. Using pupillometry and concurrent fMRI in a sample of unmedicated participants diagnosed with major depression and healthy controls, we observed reduced pupil dilation during reward anticipation in depressed participants with acute symptomatology. We further observed that individual differences in arousal during reward anticipation track the load and impact of depressive symptoms, a correlation that we replicated in a second sample of unmedicated depressed participants. Moreover, these group differences and correlations were mirrored at the neural level. The upregulation and maintenance of arousal during reward anticipation is a translational and well-traceable process that could prove a promising gateway to a physiologically informed patient stratification.
Prediction of New Coronavirus Infection Based on a Modified SEIR Model
Authors: Tang Zhou , Li Xianbin , Li Houqiang
Published: March 2020

BACKGROUND

The outbreak of the new coronavirus infection in Wuhan City, Hubei Province in December 2019, poses a huge threat to China and even global public health security. Respiratory droplets and contact transmission are the main routes of transmission of new coronaviruses. Compared with SARS and Ebola viruses, new coronavirus infections are infectious during the incubation period. Traditional SEIR (susceptibility-exposure-infection-Removal) There are some differences in conditions for the prediction of the epidemic trend of new coronavirus infection. The outbreak of the new coronavirus infection coincided with the Spring Festival before and after the Chinese Spring Festival.It is necessary to make appropriate optimization and amendments to the traditional model to meet the actual evolution of the epidemic situation.

METHODS

The traditional SEIR model assumes that the virus-infected person is not infectious during the incubation period and that the infected person did not take isolation measures during the illness. The transmission of the new coronavirus no longer meets the basic assumptions of the classical kinetic system. Therefore, this article first establishes a modified SEIR model. Predict and analyze the changing trend of the epidemic situation, then estimate the parameters involved in the infection dynamics model, and then use Matlab to simulate the established dynamic equations based on public data and analyze the results. Recommendations for universal prevention and control of infectious diseases.

RESULTS

The first case of new coronavirus infection was confirmed in Wuhan on December 8, 2019. When Wuhan City took no action, assuming the average daily number of contacts per infected person k = 5, the number of infected persons will reach about 2,384,803 people; If wuhan adopts the measures of sealing the city on January 22, 2020, under the premise of k=2, the number of infected people decreases by 19,773 compared with that on January 23, and there is no significant change in the time when the number of infected people reaches the peak. Under the premise of k = 1, the number of infected persons was reduced by 14,330 compared with the closure on January 23, and the time to reach the peak of the number of infected persons was reduced by 2 days. If Wuhan City is closed for one day, the number of infected persons will increase from 106,145 to 130,626 under the premise of k = 2; the number of infected persons will increase from 74,369 to 92,010 under the premise of k = 1.

CONCLUSIONS

Comparing the number of confirmed diagnoses actually notified by the department with the number of infected people obtained from the simulation of the model, it can be seen that the city closure measures adopted by the Wuhan Municipal Government on January 23 and the first-level response measures adopted by the country are effective for the epidemic Prevention and control play a vital role. Wearing a mask when going out and avoiding close contact with people can effectively reduce the infection rate.
Chromosomal-level reference genome of the incense treeAquilaria sinensis
Authors: Nong Wenyan , Law Sean T.S. , Wong Annette Y.P. , Baril Tobias , Swale Thomas , Chu Lee Man , Hayward Alexander , Lau David T.W. , Hui Jerome H.L.
Published: March 2020

Trees in the genusAquilaria(Thymelaeaceae) are known as lign aloes, and are native to the forests of southeast Asia. Lign aloes produce agarwood as an antimicrobial defence. Agarwood has a long history of cultural and medicinal use, and is of considerable commercial value. However, due to habitat destruction and over collection, lign aloes are threatened in the wild. We present a chromosomal-level assembly forAquilaria sinensis, a lign aloe endemic to China known as the incense tree, based on Illumina short-read, 10X Genomics linked-read, and Hi-C sequencing data. Our 783.8MbpA. sinensisgenome assembly is of high physical contiguity, with a scaffold N50 of 87.6Mbp, and high completeness, with a 95.8% BUSCO score for eudicotyledon genes. We include 17 transcriptomes from various plant tissues, providing a total of 35,965 gene models. We reveal the first complete set of genes involved in sesquiterpenoid production, plant defence, and agarwood production for the genusAquilaria, including genes involved in the biosynthesis of sesquiterpenoids via the mevalonic acid (MVA), 1-deoxy-D-xylulose-5-phosphate (DXP), and methylerythritol phosphate (MEP) pathways. We perform a detailed repeat content analysis, revealing that transposable elements account for ∼61% of the genome, with major contributions fromgypsy-like andcopia-like LTR retroelements. We also provide a comparative analysis of repeat content across sequenced species in the order Malvales. Our study reveals the first chromosomal-level genome assembly for a tree in the genusAquilariaand provides an unprecedented opportunity to address a variety of applied, genomic and evolutionary questions in the Thymelaeaceae more widely.
Trends in animal model preference for preclinical drug testing for type-2 diabetes and future directions
Authors: Franco Nuno Henrique , Miranda Sónia Batista , Kovacs Nora , Nagy Attila , Akinsolu Folahanmi Tomiwa , Olsson I Anna S , Varga Orsolya
Published: March 2020

The importance of selecting accurate animal models of disease has become increasingly salient in recent years. This is particularly important for preclinical tests carried out to predict drug efficacy and safety for humans. We mapped past and current trends in animal model selection for type-2 Diabetes Mellitus (T2DM) antidiabetic drug research, and evaluate results in light of their implications for translational research.

From data gathered from published studies on 41 orally administered antidiabetic drug classes from the ‘MEDLINE Evaluator’ web service, we found animal model choice trends within – and across – drug classes to be substantially similar, with outbred rat strains being more prevalently used, since the 1990s. The observed consistency in choice of animal models in T2DM is advantageous for replicability and comparability of experiments, but prevalence of outbred strains raises a few concerns.

In face of current criticism of the translational value of animal tests, predictive validity must be assessed on a case-by-case basis. We address some of the issues pertaining the most popular animal models in antidiabetic drug development and testing, including the lack of information on their predictive validity, and propose a ‘back translation’ approach to estimate it retrospectively.
Ranking Cancer Drivers via Betweenness-based Outlier Detection and Random Walks
Authors: Erten Cesim , Houdjedj Aissa , Kazan Hilal
Published: March 2020

Background

Recent cancer genomic studies have generated detailed molecular data on a large number of cancer patients. A key remaining problem in cancer genomics is the identification of driver genes. Results: We propose BetweenNet, a computational approach that integrates genomic data with a protein-protein interaction network to identify cancer driver genes. BetweenNet utilizes a measure based on betweenness centrality on patient specific networks to identify the so-calledoutlier genesthat correspond to dysregulated genes for each patient. Setting up the relationship between the mutated genes and the outliers through a bipartite graph, it employs a random-walk process on the graph, which provides the final prioritization of the mutated genes. We compare BetweenNet against state-of-the art cancer gene prioritization methods on lung, breast, and pan-cancer datasets. Conclusions: Our evaluations show that BetweenNet is better at recovering known cancer genes based on multiple reference databases. Additionally, we show that the GO terms and the reference pathways enriched in BetweenNet ranked genes and those that are enriched in known cancer genes overlap significantly when compared to the overlaps achieved by the rankings of the alternative methods.
Strategies for identifying dynamic regions in protein complexes: flexibility changes accompany methylation in chemotaxis receptor signaling states
Authors: Malik Nikita , Wahlbeck Katherine A , Thompson Lynmarie K
Published: March 2020

Bacterial chemoreceptors are organized in arrays composed of helical receptors arranged as trimers of dimers, coupled to a histidine kinase CheA and a coupling protein CheW. Ligand binding to the external domain inhibits the kinase activity, leading to a change in the swimming behavior. Adaptation to an ongoing stimulus involves reversible methylation and demethylation of specific glutamate residues. However, the exact mechanism of signal propagation through the helical receptor to the histidine kinase remains elusive. Dynamics of the receptor cytoplasmic domain is thought to play an important role in the signal transduction, and current models propose inverse dynamic changes in different regions of the receptor. We hypothesize that the adaptational modification (methylation) controls the dynamics by stabilizing a partially ordered domain, which in turn modulates the binding of the kinase, CheA. We investigated the difference in dynamics between the methylated and unmethylated states of the chemoreceptor using solid-state NMR. The unmethylated receptor (CF4E) shows increased flexibility relative to the methylation mimic (CF4Q). Methylation helix 1 (MH1) has been shown to be flexible in the methylated receptor. Our analysis indicates that in addition to MH1, methylation helix 2 also becomes flexible in the unmethylated receptor. In addition, we have demonstrated that both states of the receptor have a rigid region and segments with intermediate dynamics. The strategies used in the study for identifying dynamic regions are applicable to a broad class of proteins and protein complexes with intrinsic disorder and dynamics spanning multiple timescales.

Graphical Abstract

Highlights

Receptors exhibit greater ns timescale dynamics in unmethylated vs methylated state

Methylation helix 2 likely involved in increased flexibility of unmethylated state

Dynamics occur on multiple timescales in both states of the receptor
Calcium-induced calcium release and type 3 ryanodine receptors modulate the slow afterhyperpolarising current, sIAHP, and its potentiation in hippocampal pyramidal neurons
Authors: Tedoldi Angelo , Ludwig Petra , Fulgenzi Gianluca , Takeshima Hiroshi , Pedarzani Paola , Stocker Martin
Published: March 2020

The slow afterhyperpolarising current, sIAHP, is a Ca2+-dependent current that plays an important role in the late phase of spike frequency adaptation. sIAHPis activated by voltage-gated Ca2+channels, while the contribution of calcium from ryanodine-sensitive intracellular stores, released by calcium-induced calcium release (CICR), is controversial in hippocampal pyramidal neurons. Three types of ryanodine receptors (RyR1-3) are expressed in the hippocampus, with RyR3 showing a predominant expression in CA1 neurons. We investigated the specific role of CICR, and particularly of its RyR3-mediated component, in the regulation of the sIAHPamplitude and time course, and the activity-dependent potentiation of the sIAHPin rat and mouse CA1 pyramidal neurons.

Here we report that enhancement of CICR by caffeine led to an increase in sIAHPamplitude, while inhibition of CICR by ryanodine caused a small, but significant reduction of sIAHP. Inhibition of ryanodine-sensitive Ca2+stores by ryanodine or depletion by the SERCA pump inhibitor cyclopiazonic acid caused a substantial attenuation in the sIAHPactivity-dependent potentiation in both rat and mouse CA1 pyramidal neurons. Neurons from mice lacking RyR3 receptors exhibited a sIAHPwith features undistinguishable from wild-type neurons, which was similarly reduced by ryanodine. However, the lack of RyR3 receptors led to a faster and reduced activity-dependent potentiation of sIAHP.

We conclude that ryanodine receptor-mediated CICR contributes both to the amplitude of the sIAHPat steady state and its activity-dependent potentiation in rat and mouse hippocampal pyramidal neurons. In particular, we show that RyR3 receptors play an essential and specific role in shaping the activity-dependent potentiation of the sIAHP. The modulation of activity-dependent potentiation of sIAHPby RyR3-mediated CICR contributes to plasticity of intrinsic neuronal excitability and is likely to play a critical role in higher cognitive functions, such as learning and memory.
Consistent behavioral syndrome across seasons in an invasive freshwater fish
Authors: Lukas Juliane , Kalinkat Gregor , Miesen Friedrich Wilhelm , Landgraf Tim , Krause Jens , Bierbach David
Published: March 2020

Understanding the linkage between behavioral types and dispersal tendency has become a pressing issue in light of global change and biological invasions. Here, we explore whether dispersing individuals exhibit behavioral types that differ from those remaining in the source population. We investigated a feral population of guppies (Poecilia reticulata) that undergoes a yearly range shift cycle. Guppies are among the most widespread invasive species in the world, but in temperate regions these tropical fish can only survive in winter-warm freshwaters. Established in a thermally-altered stream in Germany, guppies are confined to a warm-water influx in winter, but can spread to peripheral parts as these become thermally accessible. We sampled fish from the source population and a winter-abandoned site in March, June and August. Fish were tested for boldness, sociability and activity involving open-field tests including interactions with a robotic social partner. Guppies differed consistently among each other in all three traits. Behavioral trait expression in the source population differed across seasons, however, we could not detect differences between source and downstream populations. Instead, all sampled populations exhibited a remarkably stable behavioral syndrome between boldness and activity despite strong seasonal changes in water temperature and associated environmental factors. We conclude that random drift (opposed to personality-biased dispersal) is a more likely dispersal mode for guppies, at least in the investigated stream. In the face of fluctuating environments, guppies seem to be extremely effective in keeping behavioral expressions constant, which could help explain their successful invasion and adaptation to disturbed habitats.
A metabolic shift to glycolysis promotes zebrafish tail regeneration through TGF–β dependent dedifferentiation of notochord cells to form the blastema
Authors: Sinclair Jason W. , Hoying David R. , Bresciani Erica , Nogare Damian Dalle , Needle Carli D. , Wu Weiwei , Bishop Kevin , Elkahloun Abdel G. , Chitnis Ajay , Liu Paul , Burgess Shawn M.
Published: March 2020

Mammals are generally poor at tissue regeneration, in contrast, fish maintain a high capacity for regenerating complex tissues after injury. Using larval zebrafish, we show that tail amputation triggers an metabolic shift to glycolysis in cells surrounding the notochord as they reposition to the amputation site. Blocking glycolysis prevents the fin from regenerating after amputation due to the failure to form a normal, pluripotent blastema. We performed a time series of scRNA-sequencing on regenerating tails under normal conditions or in the absence of glycolysis. Strikingly, we detected a transient cell population in the single cell analysis that represents notochord sheath cells undergoing a TGF–β dependent dedifferentiation and epithelium-to-mesenchyme transition to become pluripotent blastema cells. We further demonstrated that the metabolic switch to glycolysis is required for TGF–β signaling and blocking either glycolysis or TGF–β receptors results in aberrant blastema formation through the suppression of essential EMT mediators such assnai1.
Electroactive biofilms on surface functionalized anodes: the anode respiring behavior of a novel electroactive bacterium,Desulfuromonas acetexigens
Authors: Katuri Krishna P. , Kamireddy Sirisha , Kavanagh Paul , Mohammad Ali , Conghaile Peter Ó , Kumar Amit , Saikaly Pascal E. , Leech Dónal
Published: March 2020

Surface chemistry is known to influence the formation, composition and electroactivity of electron-conducting biofilms with however limited information on the variation of microbial composition and electrochemical response during biofilm development to date. Here we present voltammetric, microscopic and microbial community analysis of biofilms formed under fixed applied potential for modified graphite electrodes during early (90 h) and mature (340 h) growth phases. Electrodes modified to introduce hydrophilic groups (−NH2, −COOH and −OH) enhance early-stage biofilm formation compared to unmodified or electrodes modified with hydrophobic groups (−C2H5). In addition, early-stage films formed on hydrophilic electrodes were dominated by the gram-negative sulfur-reducing bacteriumDesulfuromonas acetexigenswhileGeobactersp. dominated on −C2H5and unmodified electrodes. As biofilms mature, current generation becomes similar, andD. acetexigensdominates in all biofilms irrespective of surface chemistry. Electrochemistry of pure cultureD. acetexigensbiofilms reveal that this microbe is capable of forming electroactive biofilms producing considerable current density of > 9 A/m2in a short period of potential induced growth (~19 h followed by inoculation) using acetate as an electron donor. The inability ofD. acetexigensbiofilms to use H2as a sole source electron donor for current generation shows promise for maximizing H2recovery in single-chambered microbial electrolysis cell systems treating wastewaters.

Highlights

Anode surface chemistry affects the early stage biofilm formation.

Hydrophilic anode surfaces promote rapid start-up of current generation.

Certain functionalized anode surfaces enriched theDesulfuromonas acetexigens.

D. acetexigensis a novel electroactive bacteria.

D. acetexigensbiofilms can produce high current density in a short period of potential induced growth

D. acetexigenshas the ability to maximize the H2recovery in MEC.

Abstract Figure

TOC – Graphical abstract
Cortical and raphe GABAA, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine
Authors: Pham Thu Ha , Defaix Céline , Loan Nguyen Thi Mai , Mendez-David Indira , Tritschler Laurent , David Denis J , Gardier Alain M.
Published: March 2020

At sub-anaesthetic doses, ketamine, a non competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant (AD) efficacy in patients with treatment-resistant depression (TRD). However, its mechanism of action of ketamine is not fully understood. Since comorbid depression and anxiety disorders often occur, GABAergic/inhibitory and glutamatergic/excitatory drug treatments may be co-administered in these patients. Information regarding this combination is critical to establish efficacy or treatment restrictions to maximize translation from animal models to TRD patients, effectiveness and safety. To assess the specific role of excitatory/inhibitory neurotransmission in the medial prefrontal cortex-raphe nuclei (mPFC-DRN) circuit in the sustained antidepressant-like activity (AD) of ketamine (at t24h post dose), AMPA-R antagonist (intra-DRN) and GABAA-R agonist (intra-mPFC) were co-administered with ketamine (intra-mPFC). Twenty-four hours later, responses in the forced swim test (FST) and neurochemical consequences on extracellular mPFC glutamate, GABA and 5-HT levels were measured in BALB/cJ mice. Intra-DRN NBQX prevented the sustained AD-like activity of ketamine evidenced by decreases in FST swimming duration and blunted cortical 5-HTextand Gluext.Intra-mPFC muscimol blocked ketamine AD-like activity and its effects on cortical 5-HText. Moreover, a selective glutamate transporter GLT-1 inhibitor, dihydrokainic acid (DHK) locally perfused into the mPFC produced an AD-like activity at t24h associated with robust increases in mPFC 5-HText, Gluextand GABAext. Thus, the sustained AD-like activity of ketamine is triggered by AMPA-R activation in the DRN and 5-HT - glutamate release in the mPFC, but limited by GABAA-R activation - GABA release in the mPFC. The local blockade of GLT-1 in the mPFC also mimics the rapid responses of ketamine, thus highlighting the role of neuronal-glial adaptation in these effects. These results also suggests the need to test for the concomitant prescription of ketamine and BZD to see whether its sustained antidepressant activity is maintained in TRD patients.