bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrogen sulfide exposure reduces thermal set point in zebrafish
Authors: Skandalis Dimitri A. , Dobell Cheryl D. , Shaw Joshua C. , Tattersall Glenn J.
Published: November 2020

Behavioural flexibility allows ectotherms to exploit the environment to govern their metabolic physiology, including in response to environmental stress. Hydrogen sulfide (H
2
S) is a widespread environmental toxin that can lethally inhibit metabolism. However, H
2
S can also alter behaviour and physiology, including a hypothesized induction of hibernation-like states characterized by downward shifts of the innate thermal set point (anapyrexia). Support for this hypothesis has proved controversial because it is difficult to isolate active and passive components of thermoregulation, especially in animals with high resting metabolic heat production. Here, we directly test this hypothesis by leveraging the natural behavioural thermoregulatory drive of fish to move between environments of different temperatures in accordance with their current physiological state and thermal preference. We observed a decrease in adult zebrafish (
Danio rerio
) preferred body temperature with exposure to 0.02% H
2
S, which we interpret as a shift in the thermal set point. Individuals exhibited consistent differences in shuttling behaviour and preferred temperatures, which were reduced by a constant temperature magnitude during H
2
S exposure. Seeking lower temperatures alleviated H
2
S-induced metabolic stress, as measured by reduced rates of aquatic surface respiration. Our findings highlight the interactions between individual variation and sublethal impacts of environmental toxins on behaviour.
Efficiency of mobile eye camps for providing combined eye and vision care in underserved areas in Uttarakhand
Authors: Wahl Siegfried , Leube Alexander , Dhasmana Renu , Moodbidri Premjeeth , Kumar Vasuki Krishna , Sisodia Nitin , Kuss Joachim
Published: November 2020

To report eye examinations findings and cost-efficiency of mobile eye and vision care screening in underserved areas in north India. The Aloka Vision Program combines optometrical and ophthalmological screening as mobile eye camps with organized referrals to local eye hospitals. 402 people from urban (N = 191) and rural (N = 211) areas in the district of Uttarakhand, India, were screened for refractive error (RE), visual acuity (VA) and eye health. Statistical analysis was performed using ANOVA model and odd ratios. Costs were estimated based on the expenses of the camps. 44 % of the participants were male and 56 % were female and the age ranged from 7 to 72 years (urban) and 7 to 80 years (rural). Lack of accessibility of eye care was mentioned by 10% of the urban and 47% of the rural participants, why not attending regular vision test. Mild and severe visual impairment VA < 0.5 logMAR affected every fifth person, independent from the living environment. RE showed a myopic trend for the urban environment (Δ M = 0.67 D, p = 0.11). The risk for blindness was three times higher in rural compared to the urban area, mainly caused by cataract. The major costs are given by the treatments (58 %), followed by mobilization and organization (∼30 %), whereas personal costs are low (∼11%). Combined eye and vision care models reduce costs for separated screening’s organization and thus can increase the effectiveness of eye screening programs significantly.
miR-21 blocks obesity in mice: a potential therapy for humans
Authors: Lhamyani Said , Gentile Adriana-Mariel , Giráldez-Pérez Rosa M. , Feijóo-Cuaresma Mónica , Romero-Zerbo Silvana Yanina , Clemente-Postigo Mercedes , Zayed Hatem , Olivera Wilfredo Oliva , Bermúdez-Silva Francisco Javier , Salas Julián , López Gómez Carlos , Hajji Nabil , Fuster Gabriel Olveira , Tinahones Francisco J. , Bekay Rajaa El
Published: November 2020

microRNAs are promising drug targets in obesity and metabolic disorders. miR-21 expression is upregulated in obese white adipose tissue (WAT); however, its physiological role in WAT has not been fully explored. We aimed to dissect the underlying molecular mechanisms of miR-21 in treating obesity, diabetes, and insulin resistance. We demonstrated, in human and mice, that elevated miR-21 expression is associated with metabolically healthy obesity. miR-21 mimic affected the expression of genes associated with adipogenesis, thermogenesis, and browning in 3T3-L1 adipocytes. In addition, it blocked high fat diet-induced weight gain in obese mice, without modifying food intake or physical activity. This was associated with metabolic enhancements, WAT browning and thermogenic programming, and brown AT induction through VEGF-A, p53, and TGFβ1 signaling pathways. Our findings add a novel role of miR-21 in the regulation of obesity and a potential therapy for both obesity and T2D without altering caloric intake and physical activities.
Genetic Underpinnings of Regional Adiposity Distribution in African Americans: Assessments from the Jackson Heart Study
Authors: Anwar Mohammad Y. , Raffield Laura M. , Lange Leslie A. , Correa Adolfo , Taylor Kira C.
Published: November 2020

Background

African ancestry individuals with comparable overall anthropometric measures to Europeans have lower abdominal adiposity. To explore genetic underpinning of different adiposity patterns, we investigated if genetic risk scores for well-studied adiposity phenotypes also predict other adiposity measures in 2420 African American individuals from the Jackson Heart Study.

Methods

Polygenic risk scores (PRS) for BMI, WHR adjusted for BMI (WHRBMIadj), WCBMIadj, and body fat percentage (BF%) were calculated using GWAS significant variants from mostly European ancestry studies. Associations between each PRS and adiposity measures were examined using multivariable linear regression.

Results

The BMI-PRS was found to be a positive predictor of BF% (β=0.005 per allele, 95% CI: 0.002, 0.008) and subcutaneous adiposity (β=0.004, CI: 0.002, 0.008). The BF%-PRS was associated with subcutaneous (β=0.022, CI: 0.010, 0.032) but not visceral adiposity; neither BMI nor BF%-PRS were predictors of central obesity measures. Other PRS were not associated with BF%.

Conclusion

These analyses suggest: (a) genetically driven increases in BF% strongly associate with subcutaneous but not visceral adiposity; (b) BF% is strongly associated with BMI but not central adiposity associated genetic variants. How these variants may contribute to observed differences in adiposity patterns between African and European ancestry individuals requires further study.
Repeatability and reproducibility of in-vivo brain temperature measurements
Authors: Sharma Ayushe A. , Nenert Rodolphe , Mueller Christina , Maudsley Andrew , Younger Jarred , Szaflarski Jerzy P.
Published: November 2020

Background

Magnetic resonance spectroscopic imaging (MRSI) is a neuroimaging technique that can be used to noninvasively map brain temperature (i.e., thermometry) over a large brain volume. To date, intra-subject reproducibility of MRSI-based brain temperature (MRSI-t) has not been investigated. The objective of this repeated measures MRSI-t study was to establish intra-subject reproducibility and repeatability of brain temperature, as well as typical brain temperature range.

Methods

Healthy participants aged 23-46 years (N=18; 7 females) were scanned at two time points, ∼12-weeks apart. Volumetric MRSI data were processed by reconstructing metabolite and water images using parametric spectral analysis. Brain temperature was derived using the frequency difference between water and creatine (TCRE) for 47 regions of interest (ROIs) delineated by the modified Automated Anatomical Labeling (AAL) atlas. Reproducibility was measured using the coefficient of variation for repeated measures (COVrep), and repeatability was determined using the standard error of measurement (SEM). For each region, the upper and lower bounds of Minimal Detectable Change (MDC) were established to characterize the typical range of TCRE values.

Results

The mean global brain temperature over all subjects was 37.2°C, with spatial variations across ROIs. There was a significant main effect for time (F(1, 1591)=37.0, p < 0.0001) and for brain region (F(46, 1591)=2.66, p<0.0001). The time*brain region interaction was not significant (F(46, 1591)=0.80, p=0.83)). Participants’ TCRE was stable for each ROI across both time points, with ROIs’ COVrep ranging from 0.81 – 3.08% (mean COVrep = 1.92%); 30 ROIs had a COVrep < 2.0%.

Conclusions

Brain temperature demonstrated subtle regional variations that were highly consistent between both time points, indicating high reproducibility and repeatability of MRSI-t. MRSI-t may be a promising diagnostic, prognostic, and therapeutic tool for non-invasively monitoring pathological brain temperature changes when other modalities are unrevealing. However, further studies of healthy participants with larger sample size(s) and numerous repeated acquisitions are imperative for establishing a reference range of typical brain TCRE, as well as the threshold above which TCRE is likely pathological.
From 5Vs to 6Cs: Operationalizing Epidemic Data Management with COVID-19 Surveillance
Authors: Peddireddy Akhil Sai , Xie Dawen , Patil Pramod , Wilson Mandy L. , Machi Dustin , Venkatramanan Srinivasan , Klahn Brian , Porebski Przemyslaw , Bhattacharya Parantapa , Dumbre Shirish , Raymond Erin , Marathe Madhav
Published: November 2020

The COVID-19 pandemic brought to the forefront an unprecedented need for experts, as well as citizens, to visualize spatio-temporal disease surveillance data. Web application dashboards were quickly developed to fill this gap, including those built by JHU, WHO, and CDC, but all of these dashboards supported a particular niche view of the pandemic (ie, current status or specific regions). In this paper1, we describe our work developing our own COVID-19 Surveillance Dashboard, available at https://nssac.bii.virginia.edu/covid-19/dashboard/, which offers a universal view of the pandemic while also allowing users to focus on the details that interest them. From the beginning, our goal was to provide a simple visual way to compare, organize, and track near-real-time surveillance data as the pandemic progresses. Our dashboard includes a number of advanced features for zooming, filtering, categorizing and visualizing multiple time series on a single canvas. In developing this dashboard, we have also identified 6 key metrics we call the 6Cs standard which we propose as a standard for the design and evaluation of real-time epidemic science dashboards. Our dashboard was one of the first released to the public, and remains one of the most visited and highly used. Our group uses it to support federal, state and local public health authorities, and it is used by people worldwide to track the pandemic evolution, build their own dashboards, and support their organizations as they plan their responses to the pandemic. We illustrate the utility of our dashboard by describing how it can be used to support data story-telling – an important emerging area in data science.
Estimates of the Value of Life Lost from COVID-19 in Ohio
Authors: Mallow Peter J.
Published: November 2020

The economic burden of mortality due to the novel coronavirus (COVID-19) was estimated for the State of Ohio. Data from the Ohio Department of Public Health and Social Security Administration was used to estimate the years of potential life lost, 56,518, and economic value of those lost lives, $13.60 billion. These estimates may be used to assess the risk-trade off of COVID-19 mitigation strategies in Ohio.
Impact of environmental factors in predicting daily severity scores of atopic dermatitis
Authors: Hurault Guillem , Delorieux Valentin , Kim Young-Min , Ahn Kangmo , Williams Hywel C. , Tanaka Reiko J.
Published: November 2020

Background

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 20% of children worldwide. Although environmental factors including weather and air pollutants have been shown to be associated with AD symptoms, the time-dependent nature of such a relationship has not been adequately investigated.

Objective

This paper aims to assess the short-term impact of weather and air pollutants on AD severity scores.

Methods

Using longitudinal data from a published panel study of 177 paediatric patients followed up for 17 months, we developed statistical machine learning models to predict daily AD severity scores for individual study participants. Exposures consisted of daily meteorological variables and concentrations of air pollutants and outcomes were daily recordings of scores for six AD signs. We developed a mixed effect autoregressive ordinal logistic regression model, validated it in a forward-chaining setting, and evaluated the effects of the environmental factors on the predictive performance.

Results

Our model outperformed benchmark models for daily prediction of the AD severity scores. The predictive performance of AD severity scores was not improved by the addition of measured environmental factors. Any potential short-term influence of environmental exposures on AD severity scores was outweighed by the underlying persistence of preceding scores.

Conclusions

Our data does not offer enough evidence to support a claim that AD symptoms are associated with weather or air pollutants on a short-term basis. Inferences about the magnitude of the effect of environmental factors require consideration of the time-dependence of the AD severity scores.
Features of creatine-kinase in COVID-19 patients with different ages, clinical types and outcomes: A cohort study
Authors: Wan Shanshan , Qu Gaojing , Yu Hui , Zhu Haoming , Huang Guoxin , Chen Lei , Zhang Meiling , Liu Jiangtao , Pei Bin
Published: November 2020

Objectives

To study the features of creatine-kinase (CK) in COVID-19 patients with different ages, clinical types and outcomes and quantify the relationship between CK value and clinical type.

Methods

All laboratory confirmed COVID-19 patients hospitalized in Xiangyang No.1 People’s Hospital were included. Patients’ general information, clinical type, all CK values and outcome were collected.

Results

The peak median value of CK in cases aged ≥ 71 years old (appeared at T2) was higher than that in cases aged ≤ 70 years old. There was statistical difference between the two groups (P=0.001). Similarly, the peak in critical cases (appeared at T2) was higher than moderate and severe types, and significant difference were existed among moderate, severe, and critical types (P=0.000). Moreover, the peak value in death group (appeared at T2) was higher than those in survival group. Significant difference was also found between them (P=0.000). According to the optimal scale regression model, the CK value (P=0.000) and age (P=0.000) were associated with the clinical type.

Conclusions

Difference of the CK in different ages, clinical types, and outcomes were significant. The results of the optimal scale regression model are helpful to judge the clinical type of COVID-19 patients.
Features of α-Hydroxybutyrate Dehydrogenase during various specific periods in COVID-19 patients within Xiangyang, China: a cohort study
Authors: Zhu Haoming , Qu Gaojing , Yu Hui , Huang Guoxin , Chen Lei , Zhang Meiling , Wan Shanshan , Pei Bin
Published: November 2020

Background

Coronavirus disease-2019 (COVID-19) has spread all over the world and brought extremely huge losses. There is no study to systematically analyse the features of hydroxybutyrate dehydrogenase (α-HBDH) in COVID-19 patients during the periods before and after illness progression, before death and course from exposure onset.

Methods

We collected all included patients’ general information, clinical type, α-HBDH value and outcome, and analyzed α-HBDH values within different initial time and different periods.

Results

In the first 30 days after symptom onset, the α-HBDH median value was 156.33 U/L. The first test of α-HBDH since exposure onset appeared on the 8th day, it increased from the 8th day to 18th day and decreased after the 18th day. α-HBDH median value showed a slight change until it started to increase 1 day before transforming to severe type, while it continued to increase during 4 days before and after transforming to critical type. The α-HBDH median value ranged from 191.11 U/L to 455.11U/L before death.

Conclusions

α-HBDH value increases in some COVID-19 patients, obviously in severe type, critical type and death patients, and mainly in 18 days after exposure onset and 10 days after symptom onset. α-HBDH increases 1 day before transforming to severe type, continues to increase in critical type and death patients, increases rapidly 5 days before death. The increase of α-HBDH suggests that COVID-19 patients have tissues and organs damage, mainly in heart. In brief, α-HBDH is an important indicator to judge the severity and prognosis of COVID-19.
Forecasting new daily confirmed cases infected by COVID-19 in Italy from April 9th to May 18th 2020
Authors: Jamshidi Babak , Talaei-Khoei Amir , Zargaran Shahriar Jamshidi , Rezaei Mansour
Published: November 2020

We aim at forecasting the outbreak of COVID-19 in Italy by using a two-part time series to model the daily relative increments. Our model is based on the data observed from 22 February to 8 April 2020 and its objective is forecasting 40 days from 9 April to 18 May 2020. All the calculations, simulations, and results in the present paper have been done in MatLab R2015b. The average curve and 80% upper and lower bounds are calculated based on 100 simulations of the fitted models. According to our model, it is expected that by May 18th, 2020, the relative increment (RI) falls to the interval of 0.31% to 1.24% (average equal to 0.78%). During the last three days of the studied period, the RI belonged to the interval 2.5% to 3%. Accordingly, It is expected that the new daily confirmed cases face a decreasing to around 1900 on average. Finally, our prediction establishes that the cumulative number of confirmed cases reaches 237635 (with 80% confidence interval equal to [226340 248417] by May 18th, 2020.
Infant Inhibited Temperament in Primates Predicts Adult Behavior, is Heritable, and is Associated with Anxiety-Relevant Genetic Variation
Authors: Fox AS , Harris RA , Del Rosso L , Raveendran M , Kamboj S , Kinnally EL , Capitanio JP , Rogers J
Published: November 2020

An anxious or inhibited temperament (IT) early in life is a major risk factor for the later development of stress-related psychopathology. Starting in infancy, nonhuman primates, like humans, begin to reveal their temperament when exposed to novel situations. Here, in Study 1 we demonstrate this infant IT predicts adult behavior. Specifically, in over 600 monkeys, we found that individuals scored as inhibited during infancy were more likely to refuse treats offered by potentially-threatening human experimenters as adults. In Study 2, using a sample of over 4000 monkeys from a large multi-generational family pedigree, we demonstrate that infant IT is partially heritable. The data revealed infant IT to reflect a co-inherited substrate that manifests across multiple latent variables. Finally, in Study 3 we performed whole-genome sequencing in 106 monkeys to identify IT-associated single-nucleotide variations (SNVs). Results demonstrated a genome-wide significant SNV nearCTNNA2, suggesting a molecular target worthy of additional investigation. Moreover, we observed lower p-values in genes implicated in human association studies of neuroticism and depression. Together, these data demonstrate the utility of our model of infant inhibited temperament in the rhesus monkey to facilitate discovery of genes that are relevant to the long-term inherited risk to develop anxiety and depressive disorders.
Phenology and Robustness in plant-pollinator networks
Authors: Guzman Laura Melissa , Chamberlain Scott A. , Elle Elizabeth
Published: November 2020

Many metrics that describe the structure of mutualistic plant-pollinator networks have been found to be important for network stability and robustness. These metrics are impacted by a suite of variables, including species traits, species abundances, their spatial configuration, and their phylogenetic history. Here, we consider a specific trait, phenology, or the timing of life history events. We expect that timing and duration of activity of pollinators, or of flowering in plants, could greatly affect the structure of the networks in which they are embedded. Using plant-pollinator networks from 33 sites in southern British Columbia, Canada, we asked a) how phenological species traits, specifically timing of first appearance in the network and duration of activity in a network, were related to network structure, and b) how those traits affected network robustness to phenologically biased species loss. We found that long duration of activity increased connection within modules for both pollinators and plants and among modules for plants. We also found that date of first appearance was positively related to interaction strength asymmetry in plants but negatively related in pollinators. Networks were generally more robust to the loss of pollinators than plants, but robustness declined with loss of early-flying or long-duration pollinators. These pollinators tended to be among-module connectors. Our results show that changes in phenology have the potential to impact plant-pollinator networks, which may have conservation relevance in a time of changing climate.
Transcriptomic signature and metabolic programming of bovine classical and nonclassical monocytes indicate distinct functional specializations
Authors: Talker Stephanie C. , Barut G. Tuba , Rufener Reto , von Münchow Lilly , Summerfield Artur
Published: November 2020

Similar to human monocytes, bovine monocytes can be split into CD14+CD16−classical and CD14−CD16+nonclassical monocytes (cM and ncM, respectively). Here, we present an in-depth analysis of their steady-state transcriptomes, highlighting pronounced functional specializations. Gene transcription indicates that pro-inflammatory and antibacterial processes are associated with cM, while ncM appear to be specialized in regulatory/anti-inflammatory functions and tissue repair, as well as antiviral responses and T-cell immunomodulation. In support of these functional differences, we found that oxidative phosphorylation prevails in ncM, whereas cM are clearly biased towards aerobic glycolysis. Furthermore, bovine monocyte subsets differed in their responsiveness to TLR ligands, supporting an antiviral role of ncM. Taken together, these data clearly indicate a variety of subset-specific functions in cM and ncM that are likely to be transferable to monocyte subsets of other species, including humans.
Mating and starvation modulate feeding and host-seeking responses in female bed bugs,Cimex lectularius
Authors: Saveer Ahmed M. , DeVries Zachary C. , Santangelo Richard , Schal Coby
Published: November 2020

Adaptive insect behavior is subject to modulation by internal physiological states and external social contexts to enhance reproductive fitness and survival. The common bed bug,Cimex lectulariusis an obligate hematophagous ectoparasite that requires host blood for growth, development, and reproduction. We investigated how mating, starvation and social factors such as harassment by males affect host-seeking, blood feeding, oviposition, and survival of female bed bugs. The percentage of females that fed and the amount of blood they ingested were greater in mated females (90–100%) than in unmated females (48–60%). Mating state also modulated the female’s orientation towards human skin odor in an olfactometer; more mated (69%) than unmated (23%) females responded to human odors. The response rate of unmated females (60%) to human odor increased with longer starvation period, while the opposite pattern was observed in mated females (20%). Although fecundity after a single blood meal was unaffected by long or short residence with males, females subjected to frequent copulations had lower survivorship and lifespan than females subjected to males for only 24 h. Taken together, these results indicate that behaviors are adaptively expressed based on the internal physiological state to maximize survival and reproductive fitness.
Paper-based Sensing of Fucosylated Biological Compounds
Authors: Enam Fatima , Kramer Emily , Robinson Frederick , Alvarez-Acosta Andrea , Cademartiri Rebecca , Mansell Thomas J.
Published: November 2020

Advances in sensing technology have enabled rapid analysis of various biomolecules including complex carbohydrates. However, glycan analysis is limited by the throughput and complexity of assays for quantifying them. We describe a simple, low-cost enzymatic assay for the rapid analysis of fucosylation, down to linkage specificity, and its application to high-throughput screening of biologically relevant fucosylated compounds, to facilitate simple and straightforward analytical techniques. Paper-based devices integrate biosensor platforms and other diagnostic assays by fusing them with wax printing technology, making their fabrication even more inexpensive and simple. The specificity of the assay is established by linkage-specific glycosidic enzymes and the colorimetric output is visible to the naked eye, with costs that are lower than fluorescence/luminescence-based assays ($0.02/reaction). This platform was further improved by enhancing storage stability to retain analytical performance over time using desiccation and freeze-drying techniques. The assay platform allows analysis of hundreds of samples in minutes and we anticipate that this rapid and simple analytical method will be extended towards developing a universal glyco-barcoding platform for high throughput screening of glycosylation.
Leapfrog dynamics in phage-bacteria coevolution revealed by joint analysis of cross-infection phenotypes and whole genome sequencing
Authors: Gupta Animesh , Peng Shengyun , Leung Chung Yin , Borin Joshua M. , Medina Sarah J. , Weitz Joshua S. , Meyer Justin R.
Published: November 2020

Viruses and their hosts can undergo coevolutionary arms races where hosts evolve increased resistance and viruses evolve counter-resistance. Given these arms race dynamics (ARD), viruses and hosts are each predicted to evolve along a single trajectory as more recently evolved genotypes replace their predecessors. Here, by coupling phenotypic and genomic analyses of coevolving populations of bacteriophage λ andEscherichia coli, we find conflicting evidence for ARD. Virus-host infection phenotypes fit the ARD model, yet whole genome analyses did not. Rather than coevolution unfolding along a single trajectory, cryptic genetic variation emerges during initial virus-host coevolution. This variation is maintained across generations and eventually supplants dominant lineages. These observations constitute what we term ‘leapfrog’ coevolutionary dynamics, revealing weaknesses in the predictive power of standard coevolutionary models. The findings shed light on the mechanisms that structure coevolving ecological networks and reveal the limits of using phenotypic assays alone in characterizing coevolutionary dynamics.
Soaring styles of extinct giant birds and pterosaurs
Authors: Goto Yusuke , Yoda Ken , Weimerskirch Henri , Sato Katsufumi
Published: November 2020

The largest extinct volant birds (Pelagornis sandersiandArgentavis magnificens) and pterosaurs (PteranodonandQuetzalcoatlus) are thought to have used wind-dependent soaring flight, similar to modern large birds. There are two types of soaring: thermal soaring, used by condors and frigatebirds, which involves the use of updrafts to ascend and then glide horizontally over the land or the sea; and dynamic soaring, used by albatrosses, which involves the use of wind speed differences with height above the sea surface. Previous studies have suggested thatPelagornis sandersiused dynamic soaring, whileArgenthavis magnificens, Pteranodon, andQuetzalcoatlusused thermal soaring. However, the performance and wind speed requirements of dynamic and thermal soaring for these species have not yet been quantified comprehensively. We quantified these values using aerodynamic models and compared them with that of extant birds. For dynamic soaring, we quantified maximum flight speeds and maximum upwind flight speeds. For thermal soaring, we quantified the animal’s sinking speed circling at a given radius and how far it could glide losing a given height. Our results confirmed those from previous studies thatPteranodonandArgentavis magnificensused thermal soaring. Conversely, the results forPelagornis sandersiandQuetzalcoatluswere contrary to those from previous studies.Pelagornis sandersiused thermal soaring, andQuetzalcoatlushad a poor ability both in dynamic and thermal soaring. Our results demonstrate the need for comprehensive assessments of performance and required wind conditions when estimating soaring styles of extinct flying species.
Programmable downsizing of CRISPR-Cas9 activity for precise and safe genome editing
Authors: Kawamata Masaki , Suzuki Hiroshi I. , Kimura Ryota , Suzuki Atsushi
Published: November 2020

CRSIPR-Cas9 system has opened up the avenue to efficient genome editing1–4. However, together with known off-target effects, several concerns of current CRISPR-Cas9 platform, including severe DNA damage, cytotoxicity, and large genomic alteration, have emerged in recent reports5–7and establish a formidable obstacle to precisely model allele dosage effects of disease mutations and risk variants, especially mono-allelic effects, and correct them. Here, by developing an allele-specific indel monitor system (AIMS), we demonstrate that small and simple modification of conventional single-guide RNAs (sgRNAs) enable programmable tuning of CRISPR-Cas9 activities and alleviate such adverse effects. AIMS, which visualizes various indel events in two alleles separately in living cells, is convenient and accurate to determine thein vitroediting efficiency and revealed frequent mosaicism during genome editing. Using AIMS, we show that adding cytosine stretches to the 5’ end of conventional sgRNA efficiently reduced Cas9 activity in a length dependent manner. By combining systematic experiments and computational modeling, we established the quantitative relationships between the length of cytosine extension and multiple aspects of CRISPR-Cas9 system. In general, short cytosine extension dramatically relieves p53-dependent cytotoxicity and suppression of homology-directed repair (HDR) while relatively maintaining on-target activity. Long cytosine extension further decreases on-target activity, thereby maximizing mono-allelic editing, while conventional system typically induces bi-allelic editing. Furthermore, such downregulation of on-target activity contributes to downregulation of relative off-target activity and protection of HDR-allele from second off-target editing. Therefore, cytosine extension method finally enables both single-step generation of heterozygous single-nucleotide disease mutations from homozygous states in mouse ES cells and correction of heterozygous disease mutations in human iPS cells. Taken together, our study proposes updates of standard CRISPR-Cas9 platform in mammalian cells toward precise and safe genome editing in diverse applications.
Photosynthetic activity triggers pH and NAD redox signatures across different plant cell compartments
Authors: Elsässer Marlene , Feitosa-Araujo Elias , Lichtenauer Sophie , Wagner Stephan , Fuchs Philippe , Giese Jonas , Kotnik Florian , Hippler Michael , Meyer Andreas J. , Maurino Veronica G. , Finkemeier Iris , Schallenberg-Rüdinger Mareike , Schwarzländer Markus
Published: November 2020

A characteristic feature of most plants is their ability to perform photosynthesis, which ultimately provides energy and organic substrates to most life. Photosynthesis dominates chloroplast physiology but represents only a fraction of the tightly interconnected metabolic network that spans the entire cell. Here, we explore how photosynthetic activity affects the energy physiological status in cell compartments beyond the chloroplast. We develop precision live monitoring of subcellular energy physiology under illumination to investigate pH, MgATP2−and NADH/NAD+dynamics at dark-light transitions by confocal imaging of genetically encoded fluorescent protein biosensors in Arabidopsis leaf mesophyll. We resolve thein vivosignature of stromal alkalinisation resulting from photosynthetic proton pumping and observe a similar pH signature also in the cytosol and the mitochondria suggesting that photosynthesis triggers an ‘alkalinisation wave’ that affects the pH landscape of large parts of the cell. MgATP2−increases in the stroma at illumination, but no major effects on MgATP2−concentrations in the cytosol were resolved. Photosynthetic activity triggers a signature of substantial NAD reduction in the cytosol that is driven by photosynthesis-derived electron export. Strikingly, cytosolic NAD redox status was deregulated in mutants of chloroplastic NADP- and mitochondrial NAD-dependent malate dehydrogenases even at darkness, pinpointing the participation of the chloroplasts and mitochondria in shaping cytosolic redox metabolismin vivowith a dominant function of malate metabolism. Our data illustrate how profoundly and rapidly changes in photosynthetic activity affect the physiological and metabolic landscape throughout green plant cells.

One-sentence summary:

Dark-light transitions trigger profound re-orchestration of subcellular pH and NAD redox physiology not only in the chloroplast but also beyond, in the cytosol and the mitochondria, as revealed by precision live-monitoring using fluorescent protein biosensors.
Study on H3K9 acetylation modification and TLR9 immune regulation mechanism in patients with anti-HBV treatment using thymosin a1 combined with entecavir
Authors: Zhu Hai-Peng , Wang Ke , Du Wei , Cao Huan-Huan , Zhong Qing-Yang , Yin Si-Chun , Zhong Jian-Bo , Li Fa-Wu
Published: November 2020

For hepatitis B antiviral treatment, there has been no comprehensive method yet. Interferon has poor antiviral efficacy, while nucleoside drugs have long course of treatment and high relapse rate. To improve the anti-HBV curative effect, treatment methods such as thymosin combined with entecavir have become a focus of clinical investigation. To explore potential mechanism of the combination therapy, based on previous studies, this paper explores the relationship between TLR9 expression in PBMCs, secretion of corresponding downstream inflammatory factors and HBV load in anti-HBV treatment with Thymosin a1 (Ta1) combined with entecavir. Chromatin immunoprecipitation combined with PCR method was adopted to detect H3K9 acetylation modification in patients. The relationship between TLR9 expression was explored using RT-QPCR, the relationship between secretion of inflammatory factors, efficacy and TLR9 mRNA expression was determined using Luminex technology. The results showed that during anti-HBV treatment with Ta1 combined with entecavir, histone acetylation increased in patients’ PBMCs, acetylated protein H3K9Ac had significant binding with promoter region of the TRL9 gene, thereby increasing the expression of TRL9 mRNA, activating the immune pathway under TRL9 regulation, promoting secretion of inflammation factors IL-6, IL-12, IFN-γ, and TNF-α, boosting the progress of antiviral therapy. H3K9 acetylation modification of TLR9 exists and plays an important role in patients with chronic hepatitis B. During the combination therapy with entecavir and Ta1, histone acetylation modification of TLR9 was significantly improved, which increased the expression of TLR9 at the mRNA and protein levels, and further regulated IL-6, IL-12 and other cytokines.
CovidSIMVL – Agent-Based Modeling of Localized Transmission within a Heterogeneous Array of Locations – Motivation, Configuration and Calibration
Authors: Moselle Kenneth A. , Chang Ernie
Published: November 2020

CovidSIMVL is an agent-based infectious disease modeling tool that is designed specifically to simulate localized spread of infectious disease. It is intended to support tactical decision-making around localized/staged re-institution of pre-pandemic levels and patterns of social/economic/health service delivery activity, following an initial stage of pan-societal closures of social/economic institutions and broad-based reductions in services.

By design, CovidSIMVL supports the generation of dynamic models that reflect heterogeneity within and between a network of interacting localized contexts. This heterogeneity is embodied in a hierarchically organized set of rules. Primary rules reflect the pathophysiology of transmission. Secondary rules (“HazardRadius” and “Mingle Factor” in CovidSIMVL) relate transmission to proximity and movement within physically demarcated and relatively contained spaces (“Universes”). Tertiary rules (“Schedules”) relate probabilities of transmission to movement of people between a network of localized contexts (a CovidSIMVL “Multiverse”).

This report focuses mainly on calibration of secondary rules. To calibrate the HazardRadius and MingleFactor parameters, growth curves were generated with CovidSIMVL by setting different configurations of values on those two proximal determinants of viral transmission. These were compared to the characteristic shapes of curves generated by equation-based compartmental models (e.g., SEIR models) that fit different real-world datasets embodying different reproduction numbers (R0).

By operating with parameter values in CovidSIMVL that generate “real-world” growth curves, the tool can be used to produce plausible simulations of localized chains of transmission. These include transmission among different groups of persons (e.g., staff, patients) who are co-located within a single setting such as a long-term care facility. The Multiverse version of CovidSIMVL can be used to simulate localized cross-over transmission among arrays consisting of both unaffected and impacted contexts and associated sub-populations, via agents who interact within and across arrays of contexts such as schools, multigenerational families, recreational facilities, places of work, emergency shelters for homeless persons, or other settings in which people are in close physical proximity.
Photoacoustic 3D imaging detects potential microvascular injuries
Authors: Ishida Yoshihiro , Matsumoto Yoshiaki , Asao Yasufumi , Yoshikawa Aya , Kataoka Masako , Yagi Takayuki , Kabashima Kenji , Toi Masakazu
Published: November 2020

The photoacoustic imaging (PAI) system is an emerging imaging modality that can be useful in clinical diagnostic testing. Previous studies have shown utility of PAI in diagnosing breast cancer, visualizing vascular change in ageing, and planning flap reconstruction surgeries. In this study, we show that PAI can be used to non-invasively visualize microvascular injuries in smokers, and in a vasculitis patient.

We used two prototype PAI systems, PAI-03, and PAI-04 in this study. These systems were equipped with hemisphere-detector arrays, and used lasers at wavelengths of 795 nm (PAI-03), 756 and 797nm (PAI-04). Healthy volunteers and a patient diagnosed with vasculitis were enrolled upon obtaining written informed consent. The whole hand of the volunteers was scanned.

We noted there were unique circular structures that we coined “minute signals”. There were higher number of minute signals in smokers than in non-smokers. Enhanced minute signals were noted in the patient with vasculitis. In this patient, minute signals were suggested to have lower oxygenated hemoglobin content, likely suggesting blood clots or hemorrhage. Our study shows PAI systems can visualize unappreciated abnormalities in fine vasculatures non-invasively. Use of PAI can extend to other clinical entities with suspected vascular involvement.
Predicting progression to septic shock in the emergency department using an externally generalizable machine learning algorithm
Authors: Wardi Gabriel , Carlile Morgan , Holder Andre , Shashikumar Supreeth , Hayden Stephen R , Nemati Shamim
Published: November 2020

Objective

Machine-learning (ML) algorithms allow for improved prediction of sepsis syndromes in the ED using data from electronic medical records. Transfer learning, a new subfield of ML, allows for generalizability of an algorithm across clinical sites. We aimed to validate the Artificial Intelligence Sepsis Expert (AISE) for the prediction of delayed septic shock in a cohort of patients treated in the ED and demonstrate the feasibility of transfer learning to improve external validity at a second site.

Methods

Observational cohort study utilizing data from over 180,000 patients from two academic medical centers between 2014 and 2019 using multiple definitions of sepsis. The AISE algorithm was trained using 40 input variables at the development site to predict delayed septic shock (occurring greater than 4 hours after ED triage) at varying prediction windows. We then validated the AISE algorithm at a second site using transfer learning to demonstrate generalizability of the algorithm.

Results

We identified 9354 patients with severe sepsis of which 723 developed septic shock at least 4 hours after triage. The AISE algorithm demonstrated excellent area under the receiver operating curve (>0.8) at 8 and 12 hours for the prediction of delayed septic shock. Transfer learning significantly improved the test characteristics of the AISE algorithm and yielded comparable performance at the validation site.

Conclusions

The AISE algorithm accurately predicted the development of delayed septic shock. The use of transfer learning allowed for significantly improved external validity and generalizability at a second site. Future prospective studies are indicated to evaluate the clinical utility of this model.
SARS-CoV-2 transmission during team-sport: Do players develop COVID-19 after participating in rugby league matches with SARS-CoV-2 positive players?
Authors: Jones Ben , Phillips Gemma , Kemp Simon PT , Payne Brendan , Hart Brian , Cross Matt , Stokes Keith A
Published: November 2020

Objectives

Evaluate the interactions between SARS-CoV-2 positive players and other players during rugby league matches, to determine the risk of in-game SARS-CoV-2 transmission.

Design

Observational.

Setting

Super League rugby league during four matches in which SARS-CoV-2 positive players were retrospectively found to have participated (2nd August and 4th October 2020).

Participants

136 male elite rugby league players: eight SARS-CoV-2 positive participants, 28 identified close contacts and 100 other players who participated in any of the four matches.

Main Outcome measures

Close contacts were defined by analysis of video footage for player interactions and microtechnology (GPS) data for proximity analysis. Close contacts and other players involved in the matches becoming positive for SARS-CoV-2 by RT-PCR within 14 days of the match were reported.

Results

The eight SARS-CoV-2 positive players were involved in up to 14 tackles with other individual players. SARS-CoV-2 positive players were within a 2 m proximity of other players for up to 316 secs, from 60 interactions. One identified contact returned a positive SARS-CoV-2 result within 14 days of the match (subsequently linked to an outbreak within their club environment, rather than in-match transmission), whereas the other 27 identified contacts returned negative SARS-CoV-2 follow up tests and no one developed COVID-19 symptoms. Ninety-five players returned negative and five players returned positive SARS-CoV-2 RT-PCR routine tests within 14 days of the match. Sources of transmission in the five cases were linked to internal club COVID-19 outbreaks and wider-community transmission.

Conclusion

Despite a high number of tackle involvements and close proximity interactions between SARS-CoV-2 positive players and players on the same and opposition teams during a rugby league match, these data suggest that in-game SARS-CoV-2 transmission is limited during these types of team sport activities played outdoors.
The National Defense Education Act, the American Association of University Professors and the dilemma of academic freedom in the mid-twentieth century
Authors: Wang Huimin
Published: November 2020

Purpose

This study asks how American institutions of higher education defended the principles of academic freedom (or intellectual autonomy) during the 1950s, even as they became increasingly dependent on the federal government's financial support, their eligibility for which required an oath of political loyalty under the terms of the National Defense Education Act of 1958. Universities whose students or professors resisted the oath faced a dilemma of institutional governance as well as intellectual integrity during the early years of the Cold War.

Design/methodology/approach

The study draws on documentary and archival sources, including the Congressional Record, the AAUP Bulletin, student pamphlets, newspapers and other publications of the US federal government, and on secondary sources.

Findings

The author finds that the US federal government began to invest heavily in higher education during the 1950s, but financial support was often accompanied by political oversight. Higher education institutions and their professors struggled to reconcile a sense of responsibility for national service with a desire for academic freedom. The findings show how the federal government treated institutions of higher education and dealt with the issue of academic freedom during the Cold War.

Originality/value

This study draws on a large pool of primary sources and previous research to offer new insights into an enduring ideological tension between academic freedom, public service and financial patronage.
Supply chain structures for distributing surplus food
Authors: Sundgren Caroline
Published: November 2020

Purpose

New actors have emerged in the food supply chain in response to the increased awareness of food waste and the need to distribute surplus food. The purpose of this study is to analyse the different supply chain structures that have emerged to make surplus food available to consumers.

Design/methodology/approach

This study adopts a qualitative multiple-case study of three new surplus food actors: a surplus food platform, an online retailer and a surplus food terminal. Data sources included interviews, documentary evidence and participatory observations.

Findings

Three different types of actor constellations in surplus food distribution have been identified: a triad, a tetrad and a chain. Both centralised (for ambient products) and decentralised supply chain structures (for chilled products) have emerged. The analysis identified weak links amongst new actors and surplus food suppliers. The new actors have adopted the roles of connector, service provider and logistics service provider and the sub-roles of mediator, auditor and consultant.

Originality/value

This paper contributes to research on closed-loop or circular supply chains for the reuse of products in the context of surplus food distribution.