bluuebunny/crossref_metadata_2025 huggingface dataset:
Site-specific amino acid distributions follow a universal shape
Authors: Johnson Mackenzie M. , Wilke Claus O.
Published: August 2020

In many applications of evolutionary inference, a model of protein evolution needs to be fitted to the amino acid variation at individual sites in a multiple sequence alignment. Most existing models fall into one of two extremes: Either they provide a coarse-grained description that lacks biophysical realism (e.g.dN/dSmodels), or they require a large number of parameters to be fitted (e.g. mutation–selection models). Here, we ask whether a middle ground is possible: Can we obtain a realistic description of site-specific amino acid frequencies while severely restricting the number of free parameters in the model? We show that a distribution with a single free parameter can accurately capture the variation in amino acid frequency at most sites in an alignment, as long as we are willing to restrict our analysis to predicting amino acid frequencies by rank rather than by amino acid identity. This result holds equally well both in alignments of empirical protein sequences and of sequences evolved under a biophysically realistic all-atom force field. Our analysis reveals a near universal shape of the frequency distributions of amino acids. This insight has the potential to lead to new models of evolution that have both increased realism and a limited number of free parameters.
Photomap of the polythenic chromosomes ofDrosophila malerkotlianaandin situmapping of the Hsp83locus
Authors: Félix Pierre Teodósio , dos Santos José Ferreira
Published: August 2020

A photomap of the polythenic chromosomes ofD. malerkotlianawas constructed to facilitate the identification of the chromosomal arms and their sections, in order to allow the identification of the breaking points of inversions and the location of the bands marked byin situhybridization. The photomap included the six chromosome arms corresponding to pairs I (chromosome X), II and III, excluding pair IV and Y chromosome, because they were not visualized in the material examined, probably due to their small size. Through thein situhybridization technique with the use of a biotined probe of a fragment of theD. melanogastergene, the Hsp83 locus ofD. malerkotlianawas mapped. The probe hybridized with a frequency of 70% in section 98 of the IIIR chromosome. This is the first mapped gene in the species, and indicates that possibly the IIIR arm ofD. malerkotlianacorresponds to the IIIL arm ofD. melanogaster, where the Hsp83 gene was located.
Spatially Explicit Modeling of Community Occupancy using Markov Random Field Models with Imperfect Observation: Mesocarnivores in Apostle Islands National Lakeshore
Authors: Shen Yunyi , Olsen Erik , Van Deelen Timothy
Published: August 2020

How species organize spatially is one of ecology’s most motivating questions. Multiple theories have been advanced and various models developed to account for the environment, interactions among species, and spatial drivers. However, relative importance comparisons of explanatory phenomena generally are neglected in these analyses. We developed a spatially explicit community occupancy model based on Markov random fields that accounts for spatial auto-correlation and interspecific interactions in occupancy while also accounting for interspecific interaction in detection. Simulations demonstrated that the model can distinguish different mechanisms of environmental sorting, such as competition and spatial-autocorrelation. We applied our model to camera trap data from a fisher (Pekania pennanti)-marten (Martes americana) and coyote (Canis latrans)-fox (Vulpes vulpes) system in Apostle Island National Lakeshore (Wisconsin, USA). Model results indicated that the observed partitioning pattern between marten and fisher distributions could be explained best by a flipped mainland-island source-sink pattern rather than by competition. For the coyote-fox system, we determined that, in addition to a mainland-island source-sink pattern, there was a positive association between fox and coyote that deserved further study. Our model could be readily applied to other landscapes (island and non-island systems), enhancing our understanding of species coexistence patterns.
How Well Do Commonly Used Co-Contraction Indices Approximate Lower Limb Joint Stiffness Trends during Gait?
Authors: Li Geng , Shourijeh Mohammad S. , Ao Di , Patten Carolynn , Fregly Benjamin J.
Published: August 2020

Muscle co-contraction generates joint stiffness to improve stability and accuracy during limb movement but at the expense of higher energetic cost. The quantification of joint stiffness generated from muscle co-contraction is difficult through both experimental and computational means for its benefit and cost to be assessed. Quantification of muscle co-contraction may offer an alternative path for estimating joint stiffness. By choosing the commonly used Co-Contraction Indices (CCIs) to represent muscle co-contraction, this study investigated the feasibility of using CCI to approximate lower limb joint stiffness trends during gait. A calibrated EMG-driven musculoskeletal model of a hemiparetic individual post-stroke from a previous study was used to generate the quantities required for CCI calculation and model-based estimation of joint stiffness. A total of 14 classes of CCIs for various combinations of antagonistic muscle pairs were calculated based on two common CCI formulations, each with 7 types of quantities that included variations of electromyography (EMG) signals and joint moments from the muscles. Correlations between CCIs and model-based estimates of sagittal plane stiffness of the lower extremity joints (hip, knee, ankle) were computed. Although moderate to strong correlation was observed between some CCI formulations and the corresponding joint stiffness, these associations were highly dependent on the methodological choices made for CCI computation. The overall findings of this study were the following: (1) the formulation proposed by Rudolph et al. (2000),CCI1, was more correlated with joint stiffness than that of Falconer and Winter (1985); (2) Moment-basedCCI1from individual antagonistic muscle pairs was more correlated than EMG-basedCCI1; (3) EMG signals with calibrated electromechanical delay and joint moment generated by individual muscle without normalization to a reference value were the most correlated for EMG-basedCCI1and moment-basedCCI1, respectively. The combination of antagonistic muscle pairs for most correlated within each CCI class was also identified. By using CCI to approximate joint stiffness trends, this study may open an alternative path to studying joint stiffness.
Epigenetic Interaction between UTX and DNMT1 Regulates Diet-Induced Myogenic Remodeling in Brown Fat
Authors: Li Fenfen , Jing Jia , Movahed Miranda , Cui Xin , Cao Qiang , Wu Rui , Chen Ziyue , Yu Liqing , Pan Yi , Shi Huidong , Xue Bingzhong , Shi Hang
Published: August 2020

Brown adipocytes share the same developmental origin with skeletal muscle. Here we find that a brown adipocyte-to-myocyte remodeling also exists in mature brown adipocytes, and is induced by prolonged high fat diet (HFD) feeding, leading to brown fat dysfunction. This process is regulated by the interaction of epigenetic pathways involving histone and DNA methylation. In mature brown adipocytes, the histone demethylase UTX maintains persistent demethylation of the repressive mark H3K27me3 atPrdm16promoter, leading to highPrdm16expression. PRDM16 then recruits DNA methyltransferase DNMT1 toMyod1promoter, causingMyod1promoter hypermethylation and suppressing its expression. The interaction between PRDM16 and DNMT1 coordinately serves to maintain brown adipocyte identity while repressing myogenic remodeling in mature brown adipocytes, thus promoting their active brown adipocyte thermogenic function. Suppressing this interaction by HFD feeding induces brown adipocyte-to-myocyte remodeling, which limits brown adipocyte thermogenic capacity and compromises diet-induced thermogenesis, leading to the development of obesity.
Characterization of Israeli COVID-19 Outbreak Drivers and Forecasting Using a Versatile Web App
Authors: Getz Wayne M. , Salter Richard , Horvitz Nir , Vissat Ludovica Luisa
Published: August 2020

Background

No versatile web app exists that allows epidemiologists and managers around the world to fully analyze the impacts of COVID-19 mitigation. TheNMB-DASAweb app presented here fills this gap.

Methods

Our web app uses a model that explicitly identifies a contact class of individuals, symptomatic and asymptomatic classes and a parallel set of response class, subject to lower contact pathogen contact rates. The user inputs a CSV file containing incidence and mortality time series. A default set of parameters is available that can be overwritten through input or online entry, and a subset of these can be fitted to the model using an MLE algorithm. The end of model-fitting and forecasting intervals are specifiable and changes to parameters allows counterfactual and forecasted scenarios to be explored.

Findings

We illustrate the app in the context of the current COVID-19 outbreak in Israel, which can be divided into four distinct phases: an initial outbreak; a social distancing, a social relaxation, and a second wave mitigation phase. Our projections beyond the relaxation phase indicate that an 85% drop in social relaxation rates are needed just to stabilize the current incidence rate and that at least a 95% drop is needed to quell the outbreak.

Interpretation

Our analysis uses only incidence and mortality rates. In the hands of policy makers and health officers, we believe our web app provides an invaluable tool for evaluating the impacts of different outbreak mitigation policies and measures.

Funding

This research was funded by NSF Grant 2032264.
Association of COVID-19-imposed lockdowns and online searches for toothache in Iran
Authors: Sofi-Mahmudi Ahmad , Shamsoddin Erfan , Ghasemi Peyman , Bahar Ali Mehrabi , Azad Mansour Shaban , Sadeghi Ghasem
Published: August 2020

Objective

To assess the association between the lockdowns due to COVID-19 and online searches for toothache in Iran using Google Trends (GT).

Methods

We investigated GT online searches for the search termwithin the past five years. The time frame for data gathering was considered as the initiation and end dates of lockdown in Iran. Relative search volumes (RSVs) for online Google Search queries in 2019 was considered as the control. We performed one-way ANOVA statistical test to identify whether there is a statistical difference for RSV scores between the year 2020 and 2016-2019 for the whole country. Then we investigated the possible association of RSVs in provinces with dentists’ density, prevalence of current daily smokers, Human Development Index (HDI), Internet access, and fluoride concentration in water with linear regression. A p-value<0.05 was considered as statistically significant.

Results

When comparing 2020 with previous four years, there is a statistically significant difference between RSVs of 2020 with all previous years combined and each of these years (P<0.001 for all of them). In the linear model for the year 2020, HDI (B=-3.29, 95% CI: (−5.80, - 0.78), P=0.012), fluoride concentration (B=-0.13, 95% CI: (−0.24, -0.03), P=0.017), and prevalence of daily smokers (B=0.33, 95% CI: (0.13, 0.53), P=0.002) were significantly associated with RSVs. These covariates were not statistically significant for other years, except for Internet access in 2016 (B=-1.13, 95% CI: (−2.26, 0.00), P=0.050).

Conclusion

The RSVs for toothache in 2020 have significantly increased due to COVID-19-imposed lockdowns compared to the same period of the year in the past four years. Knowing that this period mostly overlaps with the national holidays of Nowruz in Iran, reinforces the impacts of lockdowns on people’s CSB about the toothache. In the subnational scale, the RSVs were significantly correlated with HDI, fluoride concentration, and prevalence of daily smokers which emphasises the role of socioeconomic factors in dental health and care-seeking behaviour.
The innate and adaptive immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery
Authors: Syrimi Eleni , Fennell Eanna , Richter Alex , Vrljicak Pavle , Stark Richard , Ott Sascha , Murray Paul G , Al-Abadi Eslam , Chikermane Ashish , Dawson Pamela , Hackett Scott , Jyothish Deepthi , Kanthimathinathan Hari Krishnan , Monaghan Sean , Nagakumar Prasad , Scholefield Barnaby R , Welch Steven , Khan Naeem , Faustini Sian , Kearns Pamela , Taylor Graham S
Published: August 2020

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MIS-C has overlapping clinical features with Kawasaki Disease (KD), a rare childhood vasculitis. MIS-C therapy is largely based on KD treatment protocols but whether these diseases share underpinning immunological perturbations is unknown. We performed deep immune profiling on blood samples from healthy children and patients with MIS-C or KD. Acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells; increased frequencies of B-cell plasmablasts and CD27-IgD-double-negative B-cells; and increased levels of pro-inflammatory (IL6, IL18, IP10, MCP1) but also anti-inflammatory (IL-10, IL1-RA, sTNFR1, sTNFR2) cytokines. Increased neutrophil count correlated with inflammation,cardiac dysfunction and disease severity. Two days after intravenous immunoglobulin (IVIG) treatment, MIS-C patients had increased CD163 expression on monocytes, expansion of a novel population of immature neutrophils, and decreased levels of pro- and anti-inflammatory cytokines in the blood accompanied by a transient increase in arginase in some patients. Our data show MIS-C and KD share substantial immunopathology and identify potential new mechanisms of action for IVIG, a widely used anti-inflammatory drug used to treat MIS-C, KD and other inflammatory diseases.
The effect of a specialist paramedic primary care rotation on appropriate non-conveyance decisions (SPRAINED) study: a controlled interrupted time series analysis
Authors: Pilbery Richard , Young Tracey , Hodge Andrew
Published: August 2020

Introduction

NHS ambulance service conveyance rates in the UK are almost 70%, despite an increase in non-emergency cases. This is increasing the demands on crowded emergency departments (ED) and contributes to increased ambulance turnaround times. Yorkshire Ambulance Service introduced a specialist paramedic (SP) role to try and address this, but non-conveyance rates in this group have not been as high as expected.

Methods

We conducted a controlled interrupted time series analysis using data from incidents between June 2017 and December 2019, to study appropriate non-conveyance rates before and after a GP placement. A costing analysis examined the average cost per appropriate non-conveyance achieved for patients receiving care from intervention group SPs pre- and post-placement was also conducted.

Results

7349 incidents attended by intervention group SPs were eligible for inclusion. Following removal of cases with missing data, 5537/7349 (75.3%) cases remained. Post-placement, the intervention group demonstrated an increase in appropriate non-conveyance rate of 35.0% (95%CI 23.8–46.2%, p<0.001), and a reduction in the trend of appropriate non-conveyance of −1.2% (95%CI −2.8–0.5%, p=0.156), relative to the control group.

Post-placement, the cost per appropriate non-conveyance for intervention group SPs was a mean of £509.38 (95% bootstrapped CI £455.32–£564.59) versus £1258.04 (95% bootstrapped CI £1232.64–£1284.04) for the same group in the pre-placement phase. This represents a mean saving of £748.66 per appropriate non-conveyance (95% bootstrapped CI £719.45–£777.32) and a cost-effectiveness ratio of £2141.15 per percentage increase in appropriate non-conveyance (95% bootstrapped CI £2057.62–£2223.12).

Conclusion

In this single UK NHS ambulance service study, we found a clinically important and statistically significant increase in appropriate non-conveyance rates by specialist paramedics who had completed a 10-week GP placement. This improvement persisted for the 12-month period following the placement and demonstrated cost savings compared to usual care.

What this study adds

What is known about this subject

UK ambulance service conveyance rates are almost 70% despite an increase in the number of non-emergency cases

Health Education England funded a pilot in 2018 to rotate paramedics into a range of health settings to improve patient care and relieve pressures on primary care services.

What this study adds

Clinically important and statistically significant increases in appropriate non-conveyance rates can be achieved by specialist paramedics who complete a 10-week primary care placement.

This improvement is sustained for at least 12-months following the placement cost-effective.
Obtaining prevalence estimates of COVID-19: A model to inform decision-making
Authors: Sahlu Ida , Whittaker Alexander
Published: August 2020

Objectives

The primary aim was to evaluate whether randomly sampling and testing a set number of individuals for active or past COVID-19 while adjusting for misclassification error captures a simulated prevalence. The secondary aim was to quantify the impact of misclassification error bias on publicly reported case data in Maryland.

Methods

Using a stratified random sampling approach, 50,000 individuals were selected from a simulated Maryland population to estimate the prevalence of active and past COVID-19. Data from the 2014-2018 and 2018 American Community Surveys were used. The simulated prevalence was 0.5% and 1.0% for active and past COVID-19, respectively. Bayesian models, informed by published validity estimates, were used to account for misclassification error when estimating the prevalence of active and past COVID-19.

Results

Failure to account for misclassification error overestimated the simulated prevalence for active and past COVID-19. Adjustment for misclassification error decreased the point estimate for active and past COVID-19 prevalence by 55% and 29%, respectively. Adjustment for sampling method and misclassification error only captured the simulated past COVID-19 prevalence. The simulated active COVID-19 prevalence was only captured when set to 0.7% and above. Adjustment for misclassification error for publicly reported Maryland data increased the estimated average daily cases by 8%.

Conclusions

Random sampling and testing of COVID-19 is needed but must be accompanied by adjustment for misclassification error to avoid over- or underestimating the prevalence. This approach bolsters disease control efforts. Implementing random testing for active COVID-19 may be best in a smaller geographic area with highly prevalent cases.
Exometabolomic analysis of decidualizing human endometrial stromal and perivascular cells
Authors: Harden Sarah , Zhou Jieliang , Diniz-da-Costa Maria , Lucas Emma S. , Cui Liang , Murakami Keisuke , Fang Jinling , Chen Qingfeng , Brosens Jan J , Lee Yie Hou
Published: August 2020

Differentiation of endometrial fibroblasts into specialized decidual cells controls embryo implantation and transforms the cycling endometrium into a semi-permanent, immune-protective matrix that accommodates the placenta throughout pregnancy. This process starts during the midluteal phase of the menstrual cycle with decidual transformation of perivascular cells (PVC) surrounding the terminal spiral arterioles and endometrial stromal cells (EnSC) underlying the luminal epithelium. Decidualization involves extensive cellular reprogramming and acquisition of a secretory phenotype, essential for coordinated placental trophoblast invasion. Secreted metabolites are an emerging class of signalling molecules. Here, we used liquid chromatography-mass spectrometry to characterise the dynamic changes in metabolite secretion (exometabolome) of primary PVC and EnSC decidualized over 8 days. We identified 79 annotated metabolites differentially secreted upon decidualization, including prostaglandin, sphingolipid, and hyaluronic acid metabolites. Secreted metabolites encompassed 21 metabolic pathways, most prominently glycerolipid and pyrimidine metabolism. Although temporal exometabolome changes were comparable between decidualizing PVC and EnSC, 32 metabolites were differentially secreted across the decidualization time-course. Further, targeted metabolomics demonstrated a conspicuous difference in xanthine secretion between decidualized PVC and EnSC. Taken together, our findings indicate that the metabolic footprints generated by different decidual subpopulations encode spatiotemporal information that may be important for optimal embryo implantation.
Structure of mycobacterial ATP synthase with the TB drug bedaquiline
Authors: Guo Hui , Courbon Gautier M. , Bueler Stephanie A. , Mai Juntao , Liu Jun , Rubinstein John L.
Published: August 2020

Tuberculosis (TB), the leading cause of death by infectious disease worldwide, is increasingly resistant to first line antibiotics. Developed from a screen againstMycobacterium smegmatis, bedaquiline can sterilize even latentM. tuberculosisinfections that may otherwise persist for decades and has become a cornerstone of treatment for multidrug resistant and extensively-drug resistant TB. Bedaquiline targets mycobacterial ATP synthase, an essential enzyme in the obligate aerobicMycobacteriumgenus. However, how the drug binds the intact enzyme is unknown. We determined the structure ofM. smegmatisATP synthase with and without bedaquiline. The drug-free structure reveals hook-like extensions from the enzyme’s α subunits that inhibit ATP hydrolysis in low-energy conditions, such as during latent infections. Bedaquiline binding induces global conformational changes in ATP synthase, creating tight binding pockets at the interface of subunits a and c. These binding sites explain the drug’s structure-activity relationship and its potency as an antibiotic for TB.
The R1-weighted connectome: complementing brain networks with a myelin-sensitive measure
Authors: Boshkovski Tommy , Kocarev Ljupco , Cohen-Adad Julien , Mišić Bratislav , Lehéricy Stéphane , Stikov Nikola , Mancini Matteo
Published: August 2020

Myelin plays a crucial role in how well information travels between brain regions. Many neurological diseases affect the myelin in the white matter, making myelin-sensitive metrics derived from quantitative MRI of potential interest for early detection and prognosis of those conditions. Complementing the structural connectome, obtained with diffusion MRI tractography, with a myelin sensitive measure could result in a more complete model of structural brain connectivity and give better insight into how the myeloarchitecture relates to brain function. In this work we weight the connectome by the longitudinal relaxation rate (R1) as a measure sensitive to myelin, and then we assess its added value by comparing it with connectomes weighted by the number of streamlines (NOS). Our analysis reveals differences between the two connectomes both in the distribution of their weights and the modular organization. Additionally, the rank-based analysis shows that R1 is able to separate different classes (unimodal and transmodal), following a functional gradient. Overall, the R1-weighted connectome provides a different perspective on structural connectivity taking into account white matter myeloarchitecture.

Author summary

In the present work, we integrate a myelin sensitive MRI metric into the connectome and compare it with a connectome weighted with a standard diffusion-derived metric, number of streamlines (NOS). Our analysis shows that the R1-weighted connectome complements the NOS-weighted connectome. We show that the R1-weighted average distribution does not follow the same trend as the NOS strength distribution, and the two connectomes exhibit different modular organization. We also show that unimodal cortical regions tend to be connected by more streamlines, but the connections exhibit a lower R1-weighted average, while the transmodal regions tend to have a higher R1-weighted average but fewer streamlines. In terms of network communication, this could imply that the unimodal regions require more connections with lower myelination, whereas the transmodal regions take more myelinated, but fewer, connections for a reliable transfer of information.
Site-specific RNA Functionalization via DNA-induced Structure
Authors: Xiao Lu , Habibian Maryam , Kool Eric T.
Published: August 2020

Site-specific RNA functionalization is in high demand, but remains a challenge, particularly for RNAs produced by transcription rather than by total synthesis. Recent studies have described acylimidazole reagents that react in high yields at 2’-OH groups in RNAs. To date, the reactions occur stochastically at non-base-paired regions of RNA, covering much of the RNA in scattered acyl esters. Localized reactions, if possible, could prove useful in many applications, providing functional handles at specific sites and sequences of the biopolymer. Here we describe a DNA-directed strategy forin vitrofunctionalization of RNA at site-localized 2’-OH groups. The method, RNA Acylation at Induced Loops (RAIL), utilizes complementary helper DNA oligonucleotides that expose gaps or loops at selected positions while protecting the remainder in DNA-RNA duplexes. Reaction with acylimidazole reagents is then carried out, providing high yields of 2’-OH conjugation at predetermined sites. Subsequent removal of the DNA provides the RNA functionalized as desired. Experiments reveal optimal helper oligodeoxynucleotide designs and conditions for the reaction, and tests of the approach were carried out to control ribozyme activities and to label RNAs with dual-color fluorescent dyes. The RAIL approach offers a simple new strategy for site-specific labeling and controlling RNAs of any length and origin.
Emerging fungal pathogen on an invasive grass differentially affects native species
Authors: Kendig Amy E. , Svahnstrom Vida J. , Adhikari Ashish , Harmon Philip F. , Flory S. Luke
Published: August 2020

Infectious diseases and invasive species are strong drivers of biological systems that may interact to shift plant community composition. Disease and invasion can each directly suppress native populations, but variation in responses among native species to disease, invasion, and their combined effects are not well characterized. Here, we quantified the responses of three native North American grass species to experimental inoculation with the fungal pathogenBipolaris gigantea, which has recently emerged in populations of the invasive grassMicrostegium vimineum, causing leaf spot disease. In a greenhouse experiment, we examined the direct effects of disease on the native species and the indirect effects of disease on the native species through altered competition withM. vimineum, which was planted at a range of densities. Pathogen inoculation directly affected each of the three native species in unique ways, by increasing, decreasing, or not changing their biomass relative to mock inoculation. HigherM. vimineumdensities, however, reduced the biomass of all three native species, regardless of inoculation treatment, suggesting that disease had no indirect effects through altered competition. In addition, competition withM. vimineumsuppressed native plant biomass to a greater extent than disease. The differential impacts ofB. giganteaand the consistent impacts ofM. vimineumon native species biomass suggest that disease may modify native plant community composition while plant invasion may suppress multiple native plant species in systems where these drivers co-occur.
Genomic Signature of Sexual Reproduction in the Bdelloid RotiferMacrotrachella quadricornifera
Authors: Laine Veronika N. , Sackton Timothy , Meselson Matthew
Published: August 2020

Bdelloid rotifers, common freshwater invertebrates of ancient origin and worldwide distribution have long been thought to be entirely asexual, being the principal exception to the view that in eukaryotes the loss of sex leads to early extinction. That bdelloids are facultatively sexual is shown by a study of allele sharing within a group of closely related bdelloids of the speciesMacrotrachella quadricornifera, making it likely that sexual reproduction is essential for long-term success in all eukaryotes.
Identifying reliable fitness proxies for growing animals responding to anthropogenic changes
Authors: Higginson Andrew D.
Published: August 2020

Anthropogenic influences on habitats often affect predation on species by introducing novel predators, supporting additional predators, or reducing animals’ ability to detect or avoid predators. Other changes may reduce the ability of animals to feed, or alter their energy use. An increase in predation risk is assumed to reduce prey populations by increasing mortality, reducing foraging and growth. Often animals don’t appear to have been adversely affected, or may even increase growth rate. However, theoretical predictions that may have been overlooked suggest that optimal foraging rate, mortality rate and growth rate may change in counter-intuitive ways, depending on exactly how predation risk or costs have been increased. Increasing predator density may increase mortality rate when foraging, reduce the safety of refuges, or alter the relationship between vigilance and attack likelihood. Increasing temperature may increase metabolic costs in ectotherms and reduce thermogenesis costs in endotherms, which affects the costs of active foraging and inactivity differently. Here, I review the theory on how predation risk and metabolic costs should affect foraging behaviour, mortality and growth in order to explain the great variation in behavioural responses. I show that in some situations animals may not respond behaviourally even though a change severely affects survival, and the mortality may be a poor metric of the impact of a change on population viability. In other situations a fitness proxy may change dramatically whilst fitness is unaffected due to compensatory changes in behaviour or life history. Other measures may change in a positive way whilst fitness declines. I describe how to identify the situations in the field and thereby make reliable measure of fitness in particular study systems. Overall, this work shows how behavioural theory can help understand the impacts of environmental change and highlights promising directions to better understand and mitigate their effects on ecosystems.
When does parasitism maintain sex in the absence of Red Queen Dynamics?
Authors: Ashby Ben
Published: August 2020

Abstract

Parasites can select for sexual reproduction in host populations, preventing replacement by faster growing asexual lineages. This is usually attributed to so-called “Red Queen Dynamics” (RQD), where antagonistic coevolution causes fluctuating selection in allele frequencies, which provides sex with an advantage over asex. However, parasitism may also maintain sex in the absence of RQD when sexual populations are more genetically diverse – and hence more resistant, on average – than clonal populations, allowing sex and asex to stably coexist. While the maintenance of sex due to RQD has been studied extensively, the conditions that allow sex and asex to stably coexist have yet to be explored in detail. In particular, we lack an understanding of how host demography and parasite epidemiology affect the maintenance of sex in the absence of RQD. Here, I use an eco-evolutionary model to show that both population density and the type and strength of virulence are important for maintaining sex, which can be understood in terms of their effects on disease prevalence and severity. In addition, I show that even in the absence of heterozygote advantage, asexual heterozygosity affects coexistence with sex due to variation in niche overlap. These results reveal which host and parasite characteristics are most important for the maintenance of sex in the absence of RQD, and provide empirically testable predictions for how demography and epidemiology mediate competition between sex and asex.
Change in social rank and brain dopamine levels: findings from a novel pig model
Authors: Cheng Hui G. , Mohammed Abiy M. , Pease Anthony P. , Gehrke Joshua , Bohart George , Burnett Robert , Nader Michael A. , Anthony James C.
Published: August 2020

Dopamine (DA) signaling is central in hypothesized causal paths linking the influence of social and environmental variables with cognition, behavior and affective states, including vulnerability to drug dependence. Here, we study whetherchange in one’s social rankinduces DA and norepinephrine (NE) changes using a novel pig model with a social-ranking-and-re-ranking protocol to investigate social context influences on catecholamine concentrations in cerebrospinal fluid (CSF) and blood. For two weeks, 16 recently weaned male piglets were socially housed in four groups, with video-recordings for social rank assessments (α, β, γ, and δ); CSF and blood were obtained from these stable social groups. Next, all four α were housed together, as were all four β, etc., again with video recording for blinded social ranking. CSF and blood samples were collected at three time points: prior to initial social housing, following social housing and following re-organization. Regression analyses disclosed a positive relationship between changes in social rank and post-rank change in CSF levels of DA; one unit increase of social rank predicted a 17.4 pg/ml increase in CSF dopamine concentrations (95% CI= 1.2, 33.7). Compared to piglets with downward shifts in ranks (i.e., high-to-low), piglets with upward shifts (i.e., low-to-high) had a statistically significant greater increase in CSF DA levels. No relationship was observed for CSF NE or blood concentrations of DA or NE at any phase of this experiment. This work, using a novel pig model, adds new evidence on alteration of the brain dopaminergic system induced by social rank change.
Exploration of Chemical Space with Partial Labeled Noisy Student Self-Training for Improving Deep Learning Performance: Application to Drug Metabolism
Authors: Liu Yang , Lim Hansaim , Xie Lei
Published: August 2020

Motivation

Drug discovery is time-consuming and costly. Machine learning, especially deep learning, shows a great potential in accelerating the drug discovery process and reducing its cost. A big challenge in developing robust and generalizable deep learning models for drug design is the lack of a large amount of data with high quality and balanced labels. To address this challenge, we developed a self-training method PLANS that exploits millions of unlabeled chemical compounds as well as partially labeled pharmacological data to improve the performance of neural network models.

Result

We evaluated the self-training with PLANS for Cytochrome P450 binding activity prediction task, and proved that our method could significantly improve the performance of the neural network model with a large margin. Compared with the baseline deep neural network model, the PLANS-trained neural network model improved accuracy, precision, recall, and F1 score by 13.4%, 12.5%, 8.3%, and 10.3%, respectively. The self-training with PLANS is model agnostic, and can be applied to any deep learning architectures. Thus, PLANS provides a general solution to utilize unlabeled and partially labeled data to improve the predictive modeling for drug discovery.

Availability

The code that implements PLANS is available athttps://github.com/XieResearchGroup/PLANS
Manganese depletion leads to multisystem changes in the transcriptome of the opportunistic pathogenStreptococcus sanguinis
Authors: Puccio Tanya , Kunka Karina S. , Zhu Bin , Xu Ping , Kitten Todd
Published: August 2020

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Streptococcus sanguinisis a primary tooth colonizer and is typically considered beneficial due to its antagonistic relationship with the cariogenic pathogenStreptococcus mutans. However,S. sanguiniscan also act as an opportunistic pathogen should it enter the bloodstream and colonize a damaged heart valve, leading to infective endocarditis. Studies have implicated manganese acquisition as an important virulence determinant in streptococcal endocarditis. A knockout mutant lacking the primary manganese import system inS. sanguinis, SsaACB, is severely attenuated for virulence in anin vivorabbit model. Manganese is a known cofactor for several important enzymes inS. sanguinis, including superoxide dismutase, SodA, and the aerobic ribonucleotide reductase, NrdEF. To determine the effect of manganese depletion onS. sanguinis, we performed transcriptomic analysis on a ΔssaACBmutant grown in aerobic fermentor conditions after the addition of the metal chelator EDTA. Despite the broad specificity of EDTA, analysis of cellular metal content revealed a decrease in manganese, but not in other metals, that coincided with a drop in growth rate. Subsequent supplementation with manganese, but not iron, zinc, or magnesium, restored growth in the fermentor post-EDTA. Reduced activity of Mn-dependent SodA and NrdEF likely contributed to the decreased growth rate post-EDTA, but did not appear entirely responsible. With the exception of the Dps-like peroxide resistance gene,dpr, manganese depletion did not induce stress response systems. By comparing the transcriptome of ΔssaACBcells pre- and post-EDTA, we determined that manganese deprivation led to altered expression of diverse systems, including ethanolamine utilization, CRISPR/Cas, and a type IV pilus. Manganese depletion also led to an apparent induction of carbon catabolite repression in a glucose-independent manner. The combined results suggest that manganese limitation produces effects inS. sanguinisthat are diverse and complex, with no single protein or system appearing entirely responsible for the observed growth rate decrease. This study provides further evidence for the importance of this trace element in streptococcal biology. Future studies will focus on determining mechanisms for regulation, as the multitude of changes observed in this study indicate that multiple regulators may respond to manganese levels.
The human Origin Recognition Complex is essential for pre-RC assembly, mitosis and maintenance of nuclear structure
Authors: Chou Hsiang-Chen , Bhalla Kuhulika , Demerdesh Osama El , Klingbeil Olaf , Hanington Kaarina , Aganezov Sergey , Andrews Peter , Alsudani Habeeb , Chang Kenneth , Vakoc Christopher R. , Schatz Michael C. , McCombie W. Richard , Stillman Bruce
Published: August 2020

The Origin Recognition Complex (ORC) cooperates with CDC6, MCM2-7, and CDT1 to form pre- RC complexes at origins of DNA replication. Here we report tiling-sgRNA CRISPR screens that show that each subunit of ORC and CDC6 are essential in human cells. Using an auxin-inducible degradation system, stable cell lines were created that ablate ORC2 rapidly, revealing multiple cell division cycle phenotypes. The primary defect in the absence of ORC2 was cells encountering difficulty in initiating DNA replication or progressing through the cell division cycle due to reduced MCM2-7 loading onto chromatin in G1 phase. The nuclei of ORC2 deficient cells were also large, with decompacted heterochromatin. Some ORC2 deficient cells that completed DNA replication entered into, but never exited mitosis. ORC1 knockout cells also demonstrated extremely slow cell proliferation and abnormal cell and nuclear morphology. Thus, ORC proteins and CDC6 are indispensable for normal cellular proliferation and contribute to nuclear organization.
Consensus transcriptional states describe human mononuclear phagocyte diversity in the lung across health and disease
Authors: Peters Joshua M. , Blainey Paul C. , Bryson Bryan D.
Published: August 2020

Monocytes, dendritic cells, and macrophages, commonly referred to as mononuclear phagocytes (MNPs), are innate immune cells capable of adopting diverse homeostatic and pathogenic phenotypes. Recent single-cell RNA-sequencing studies across many diseases in the lung have profiled this diversity transcriptionally, defining new cellular states and their association with disease. Despite these massive cellular profiling efforts, many studies have focused on defining myeloid dysfunction in specific diseases without identifying common pan-disease trends in the mononuclear phagocyte compartment within the lung. To address these gaps in our knowledge, we collate, process, and analyze 561,390 cellular transcriptomes from 12 studies of the human lung across multiple human diseases. We develop a computational framework to identify and compare dominant gene markers and gene expression programs and characterize MNP diversity in the lung, proposing a conserved dictionary of gene sets. Utilizing this reference, we efficiently identify disease-associated and rare MNP populations across multiple diseases and cohorts. Furthermore, we demonstrate the utility of this dictionary in characterizing a recently published dataset of bronchoalveolar lavage cells from COVID-19 patients and healthy controls which further reveal novel transcriptional shifts directly relatable to other diseases in the lung. These results underline conserved MNP transcriptional programs in lung disease, provide an immediate reference for characterizing the landscape of lung MNPs and establish a roadmap to dissecting MNP transcriptional complexity across tissues.
STAG2 loss-of-function affects short-range genomic contacts and modulates urothelial differentiation in bladder cancer cells
Authors: Richart Laia , Lapi Eleonora , Pancaldi Vera , Cuenca Mirabai , Carrillo-de-Santa Pau Enrique , Madrid-Mencía Miguel , Neyret-Kahn Hélène , Radvanyi François , Rodríguez Juan A. , Cuartero Yasmina , Serra François , Le Dily François , Valencia Alfonso , Marti-Renom Marc A. , Real Francisco X.
Published: August 2020

Cohesin exists in two variants, containing either STAG1 or STAG2.STAG2is one of the most commonly mutated genes in human cancer, and a major bladder cancer tumor suppressor. Little is known about how its inactivation contributes to tumor development. Here, we analyze the genomic distribution of STAG1 and STAG2 and perform STAG2 loss-of-function experiments using RT112 bladder cancer cells; we then analyze the resulting genomic effects by integrating gene expression and chromatin interaction data. Cohesin-STAG2 is required for DNA contacts within topological domains, but not for compartment maintenance of domain boundary integrity. Cohesin-STAG2-mediated interactions are short-ranged and engage promoters and gene bodies with higher frequency than those mediated by cohesin-STAG1. STAG2 knockdown resulted in a modest but consistent down-regulation of the luminal urothelial differentiation signature, mirroring differences between STAG2-high and STAG2-low bladder tumors. Both lost and gained contacts were enriched among STAG1/STAG2 common sites as well as STAG2-enriched sites. Contacts lost upon depletion of STAG2 were significantly assortative, indicating their proximity at the 3D level, and were associated with changes in gene expression. Overall, our findings indicate that, in urothelial cells, STAG2 is required for the establishment and/or maintenance of DNA looping that, in turn, sustains the luminal differentiation program. This mechanism may contribute to the tumor suppressor function of STAG2 in bladder cancer.
Bioactivity of Aqueous Extract of Pulp ofCrysophyllum albidium(G. Don-Holl.) on Isoproterenol Treated Albino Rats
Authors: Morakinyo Adetoun , Akinlusi Ifeoluwani , Timileyin Ogundana , Adepoju Ayodeji , Akinpelu Bolajoko , Oyedepo Temitope , Oyedapo Oluboade
Published: August 2020

Cardiovascular disorder is one of the causes of death globally. Quite a number of medicinal plants have been demonstrated to possess and exhibit beneficial effects on cardiovascular system throuhg their antioxidant properties. The study investigated thein vivoantioxidant properties of aqueousC. albidiumpulp extract on isoproterenol-induced cardiotoxicity in albino rats. Cardiotoxicity was induced in rats by subcutaneous injection of ISO (85 mg/kg bwt) into adult albino rats and treated with the extract (100 and 200 mg/kg bwt). The levels of nitrite, lipid peroxidation, reduced glutathione total protein and activities of glutathione peroxidase, catalase and superoxide dismutase were evaluated using standard methods. The concentration of total protein was also determined. Administration of ISO (85 mg/kg body weight) caused significant (p< 0.05) reduction in the antioxidant status of animals. The enzymatic and non-enzymatic antioxidants perturbed by the administration of ISO were restored in theC. albidiumtreated rats. The study concludes that the aqueous extract ofC. albidumpulp protected against Isoproterenol-induced cardiotoxicity in adult male Albino rats.
Identification of the keystone species in non-alcoholic fatty liver disease by causal inference and dynamic intervention modeling
Authors: Wu Dingfeng , Jiao Na , Zhu Ruixin , Zhang Yida , Gao Wenxing , Fang Sa , Li Yichen , Cheng Sijing , Tian Chuan , Lan Ping , Loomba Rohit , Zhu Lixin
Published: August 2020

Objective

Keystone species are required for the integrity and stability of an ecological community, and therefore, are potential intervention targets for microbiome related diseases.

Design

Here we describe an algorithm for the identification of keystone species from cross-sectional microbiome data of non-alcoholic fatty liver disease (NAFLD) based on causal inference theories and dynamic intervention modeling (DIM).

Results

Eight keystone species in the gut of NAFLD, represented byP. loveana,A. indistinctusandD. pneumosintes, were identified by our algorithm, which could efficiently restore the microbial composition of the NAFLD toward a normal gut microbiome with 92.3% recovery. These keystone species regulate intestinal amino acids metabolism and acid-base environment to promote the growth of the butyrate-producing Lachnospiraceae and Ruminococcaceae species.

Conclusion

Our method may benefit microbiome studies in the broad fields of medicine, environmental science and microbiology.

What is already known about this subject?

Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disease whose pathogenesis remains unclear.

Dysbiosis in the gut microbiota affects the initiation and development of NAFLD, but the mechanisms is yet to be established.

Keystone species represent excellent candidate targets for gut microbiome-based interventions, as they are defined as the species required for the integrity and stability of the ecological system.

What are the new findings?

NAFLD showed significant dysbiosis in butyrate-producing Lachnospiraceae and Ruminococcaceae species.

Microbial interaction networks were constructed by the novel algorithm with causal inference.

Keystone species were identified form microbial interaction networks through dynamic intervention modeling based on generalized Lotka-Volterra model.

Eight keystone species of NAFLD with the highest potential for restoring the microbial composition were identified.

How might it impact on clinical practice in the foreseeable future?

An algorithm for the identification of keystone species from cross-sectional microbiome data based on causal inference theories and dynamic intervention modeling.

Eight keystone species in the gut of NAFLD, represented byP. loveana,A. indistinctusandD. pneumosintes, which could efficiently restore the microbial composition of the NAFLD toward a normal gut microbiome.

Our method may benefit microbiome studies in the broad fields of medicine, environmental science and microbiology.