bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiological, Clinical Characteristics and Outcome of Medical Staff Infected with COVID-19 in Wuhan, China: A Retrospective Case Series Analysis
Authors: Liu Jie , Ouyang Liu , Guo Pi , Wu Haisheng , Fu Peng , Chen Yuliang , Yang Dan , Han Xiaoyu , Cao Yukun , Alwalid Osamah , Tao Juan , Peng Shuyi , Shi Heshui , Yang Fan , Zheng Chuansheng
Published: March 2020

Backgrounds

Since December 2019, a novel coronavirus epidemic has emerged in Wuhan city, China and then rapidly spread to other areas. As of 20 Feb 2020, a total of 2,055 medical staff confirmed with coronavirus disease 2019 (COVID-19) caused by SARS-Cov-2 in China had been reported. We sought to explore the epidemiological, clinical characteristics and prognosis of novel coronavirus-infected medical staff.

Methods

In this retrospective study, 64 confirmed cases of novel coronavirus-infected medical staff admitted to Union Hospital, Wuhan between 16 Jan, 2020 to 15 Feb, 2020 were included. Two groups concerned were extracted from the subjects based on duration of symptoms: group 1 (≤10 days) and group 2 (>10 days). Epidemiological and clinical data were analyzed and compared across groups. The Kaplan-Meier plot was used to inspect the change in hospital discharge rate. The Cox regression model was utilized to identify factors associated with hospital discharge.

Findings

The median age of medical staff included was 35 years old. 64% were female and 67% were nurses. None had an exposure to Huanan seafood wholesale market or wildlife. A small proportion of the cohort had contact with specimens (5%) as well as patients in fever clinics (8%) and isolation wards (5%). Fever (67%) was the most common symptom, followed by cough (47%) and fatigue (34%). The median time interval between symptoms onset and admission was 8.5 days. On admission, 80% of medical staff showed abnormal IL-6 levels and 34% had lymphocytopenia. Chest CT mainly manifested as bilateral (61%), septal/subpleural (80%) and ground-glass (52%) opacities. During the study period, no patients was transferred to intensive care unit or died, and 34 (53%) had been discharged. Higher body mass index (BMI) (≥ 24 kg/m2) (HR 0.14; 95% CI 0.03-0.73), fever (HR 0.24; 95% CI 0.09-0.60) and higher levels of IL-6 on admission (HR 0.31; 95% CI 0.11-0.87) were unfavorable factors for discharge.

Interpretation

In this study, medical staff infected with COVID-19 have relatively milder symptoms and favorable clinical course, which may be partly due to their medical expertise, younger age and less underlying diseases. Smaller BMI, absence of fever symptoms and normal IL-6 levels on admission are favorable for discharge for medical staff. Further studies should be devoted to identifying the exact patterns of SARS-CoV-2 infection among medical staff.
Effect of Erufosine on Membrane Lipid Order in Breast Cancer Cell Models
Authors: Tzoneva R. , Stoyanova T. , Petrich A. , Popova D. , Uzunova V. , Momchilova A. , Chiantia S.
Published: March 2020

Alkylphospholipids are a novel class of antineoplastic drugs showing remarkable therapeutic potential. Among them, Erufosine (EPC3) is a promising drug for the treatment of several types of tumors. While EPC3 is supposed to exert its function by interacting with lipid membranes, the exact molecular mechanisms involved are not known yet. In this work, we applied a combination of several fluorescence microscopy and analytical chemistry approaches (i.e., scanning fluorescence correlation spectroscopy, line-scan fluorescence correlation spectroscopy, generalized polarization imaging, as well as thin layer and gas chromatography) to quantify the effect of EPC3 in biophysical models of the plasma membrane, as well as in cancer cell lines. Our results indicate that EPC3 affects lipid-lipid interactions in cellular membranes by decreasing lipid packing and increasing membrane disorder and fluidity. As a consequence of these alterations in the lateral organization of lipid bilayers, the diffusive dynamics of membrane proteins are also significantly increased. Taken together, these findings suggest that the mechanism of action of EPC3 might be linked to its effects on fundamental biophysical properties of lipid membranes, as well as lipid metabolism in cancer cells.
Selection into shift work is influenced by educational attainment and body mass index: A Mendelian randomization study
Authors: Daghlas Iyas , Richmond Rebecca C. , Lane Jacqueline M. , Dashti Hassan S. , Ollila Hanna M. , Schernhammer Eva S. , Smith George Davey , Rutter Martin K. , Saxena Richa , Vetter Céline
Published: March 2020

Background

Shift work is associated with increased cardiometabolic disease risk, but whether this association is influenced by cardiometabolic risk factors driving selection into shift work is currently unclear. We addressed this question using Mendelian randomization (MR) in the UK Biobank.

Methods

We created genetic risk scores (GRS) associating with nine cardiometabolic risk factors (including education, body mass index [BMI], smoking, and alcohol consumption), and tested associations of each GRS with self-reported current frequency of shift work and night shift work amongst employed UKB participants of European ancestry (n=190,573). We used summary-level MR sensitivity analyses and multivariable MR to probe robustness of the identified effects, and tested whether effects were mediated through sleep timing preference.

Results

Genetically instrumented lower educational attainment and higher body mass index increased odds of reporting frequent shift work (odds ratio [OR] per 3.6 years [1-SD] decrease in educational attainment=2.40, 95% confidence interval [CI]=2.22-2.59, p=4.84 × 10−20; OR per 4.7kg/m2 [1-SD] increase in BMI=1.30, 95%CI=1.14-1.47, p=5.85 × 10−05). Results were unchanged in sensitivity analyses allowing for different assumptions regarding horizontal pleiotropy, and the effects of education and BMI were independent in multivariable MR. No causal effects were evident for the remaining factors, nor for any exposures on selection out of shift work. Sleep timing preference did not mediate any causal effects.

Conclusions

Educational attainment and BMI may influence selection into shift work, which may have implications for epidemiologic associations of shift work with cardiometabolic disease.

Key messages

Although it has been hypothesized that cardiometabolic risk factors and diseases may influence selection into shift work, little evidence for such an effect is currently available.

Using Mendelian randomization, we assessed whether cardiometabolic risk factors and diseases influenced selection into or out of shift work in the UK Biobank.

Our results were consistent with a causal effect of both higher BMI and lower educational attainment on selection into current shift work, with stronger effects seen for shift work that is more frequent and includes more night shifts.

Using multivariable Mendelian randomization, we found that effects of higher BMI and lower education were independent. Sleep timing preference had a null effect on shift work selection and therefore did not mediate these effects.

Selection through education and BMI may bias the relationship of shift work with cardiometabolic disease. Social mechanisms underlying these effects warrant further investigation.
Patient-level micro-simulation model for evaluating the future potential cost–effectiveness of pharmacy-based interventions in the control and management of diabetes-related complications in Canada
Authors: Yaghoubi Mohsen , Mansell Kerry , Vatanparast Hassanali , Zeng Wu , Javanbakht Mehdi , Farag Marwa
Published: March 2020

Background

The increased risk of complications among diabetes patients poses a serious threat to population health. Pharmacy-based interventions can decrease the burden of diabetes and its related complications. This study evaluates the cost-effectiveness of pharmacy-based interventions and offers insights on the practicality of their adoption by health practitioners.

Methods

We developed population-based micro-simulation model using 2,931 patients with diabetes in Canada. We used the risk equations on the UK Prospective Diabetes Study (UKPDS) to estimate the incidence and mortality of four of the most common diabetes-related complications (heart failure, stroke, amputation, and blindness). We extrapolated the potential effects of pharmacy interventions on reducing time-varying risk factors for diabetes complications. Cost was quantified as the annual cost of complications; and, the cost associated with pharmacy-based interventions. The final outcomes were the incremental costs per quality-adjusted life years (QALY) gained. Both deterministic and probabilistic sensitivity analysis were conducted to examine the robustness of the ratio.

Result

Pharmacy-based interventions could prevent 155 preventable deaths, 159 strokes, 29 cases of blindness, 24 amputations, and 19 heart failures across the lifetime of 2,931 patients. In addition, an estimated 953 QALYs (0.32 per patient) would be gained among the intervention group. Per QALY, the incremental discounted cost is $3,928, suggesting that pharmacy-based interventions are likely cost-effective compared to usual care. At an ICER threshold of $50,000, over 92% of the simulation remains cost-effective.

Conclusion

Pharmacist-based interventions targeted at addressing the development of diabetes-related complications among Canadian patients have the potential to offer a cost-effective strategy.
Prediction of the COVID-19 outbreak based on a realistic stochastic model
Authors: Zhang Yuan , You Chong , Cai Zhenghao , Sun Jiarui , Hu Wenjie , Zhou Xiao-Hua
Published: March 2020

The current outbreak of coronavirus disease 2019 (COVID-19) has become a global crisis due to its quick and wide spread over the world. A good understanding of the dynamic of the disease would greatly enhance the control and prevention of COVID-19. However, to the best of our knowledge, the unique features of the outbreak have limited the applications of all existing models. In this paper, a novel stochastic model is proposed which aims to account for the unique transmission dynamics of COVID-19 and capture the effects of intervention measures implemented in Mainland China. We find that, (1) instead of aberration, there is a remarkable amount of asymptomatic individuals, (2) an individual with symptoms is approximately twice more likely to pass the disease to others than that of an asymptomatic patient, (3) the transmission rate has reduced significantly since the implementation of control measures in Mainland China, (4) it is expected that the epidemic outbreak would be contained by early March in the the selected provinces and cities.
A practical technique for clinicians to approximate platelet function after fifteen-minutes using thromboelastography
Authors: Sharp Elliott , Fludder Vanessa
Published: March 2020

Background

Point-of-care platelet function tests are used by anaesthetists and surgeons to create risk management plans for patients who have recently taken antiplatelet medication. Thromboelastography (TEG), one method of determining platelet function, sometimes takes >60 minutes to produce results. Previous studies have shown a novel parameter, area under the curve at 15 minutes (AUC15), correlates with clinical outcomes but used privately-owned, custom-made software to calculate AUC15. This study aimed to create a formula that clinicians can use to approximate AUC15 which correlates to the most widely used measure of platelet function, percentage of platelet aggregation.

Methods

Platelet function after 15 minutes can be approximated by the equation: AUC15 = 225(tan(θ)) where θ = α(MAADP/MAThrombin). A retrospective database review was performed on eligible platelet function tests that assessed ADP receptor inhibition on a TEG 6s Hemostasis Analyzer (Haemonetics®) across 15 months. Results were analysed using a bivariate scatter plot with linear regression line and a two-tailed Pearson correlation coefficient was calculated.

Results

Forty-seven tests were retrieved, of which, forty-five were eligible for analysis. Pearson two-tailed correlation coefficient showed that AUC15 correlated significantly with percentage of platelet aggregation (R = 0.748, 95% CI [0.582, 0.854], p < 0.001).

Conclusion

This study creates the first practical method for clinicians to approximate platelet function on TEG analysers after 15 minutes, instead of >60 minutes, using routinely generated outputs and a calculator. Clinicians who use this method will afford themselves more time to create risk management plans for patients which may improve patient outcomes.
Point Process Temporal Structure Characterizes Electrodermal Activity
Authors: Subramanian Sandya , Barbieri Riccardo , Brown Emery N.
Published: March 2020

Electrodermal activity (EDA) is a read-out of the body’s sympathetic nervous system measured as sweat-induced changes in the electrical conductance properties of the skin. There is growing interest in using EDA to track physiological conditions such as stress levels, sleep quality and emotional states. Standardized EDA data analysis methods are readily available. However, none considers two established physiological features of EDA: 1) sympathetically mediated pulsatile changes in skin sweat measured as EDA resemble an integrate-and-fire process; 2) inter-pulse interval times vary depending upon the local physiological state of the skin. Based on the anatomy and physiology that underlie feature 1, we postulate that inverse Gaussian probability models would accurately describe EDA inter-pulse intervals. Given feature 2, we postulate that under fluctuating local physiological states, the inter-pulse intervals would follow mixtures of inverse Gaussian models, that can be represented as lognormal models if the conditions favor longer intervals (heavy tails) or by gamma models if the conditions favor shorter intervals (light tails). To assess the validity of these probability models we recorded and analyzed EDA measurements in 11 healthy volunteers during 1 to 2 hours of quiet wakefulness. We assess the tail behavior of the probability models by computing their settling rates. All data series were accurately described by one or more of the models: two by inverse Gaussian models; five by lognormal models and three by gamma models. These probability models suggest a highly succinct point process framework for real-time tracking of sympathetically-mediated changes in physiological state.
A long intergenic non-coding RNA regulates nuclear localisation of DNA methyl transferase-1
Authors: Jones Rhian , Wijesinghe Susanne , Halsall John , Kanhere Aditi
Published: March 2020

DNA methyl-transferase-1 or DNMT1 maintains DNA methylation in the genome and is important for regulating gene expression in cells. Aberrant changes in DNMT1 activity are observed in many diseases. Therefore, understanding the mechanisms behind alteration of DNMT1 activity is important. Here, we show thatCCDC26, a nuclear long non-coding RNA frequently mutated in myeloid leukaemia, directly interacts with DNMT1. In the absence ofCCDC26RNA, DNMT1 is mis-located in the cytoplasm. As a result, genomic DNA is significantly hypomethylated, which is accompanied by a slower cell growth rate and increased cell death. These results point to a previously unrecognised mechanism of long non-coding RNA mediated subcellular localisation of DNMT1 and regulation of DNA methylation. These observations are significant given the importance of DNMT1 in cancer and number of other diseases.
Ultra-high-order ICA: fine overlapping functional parcellations and spatiotemporal reconfiguration
Authors: Iraji Armin , Fu Zening , DeRamus Thomas , Qi Shile , Rachakonda Srinivas , Du Yuhui , Calhoun Vince
Published: March 2020

Our recent findings show that functional organizations evolve spatially over time, highlighting the importance of considering within-subject spatial variations and dynamic functional parcellations in brain functional analyses. Meanwhile, a considerable level of multi-functionality suggests the need for overlapping brain parcellations. In this work, we used ultra-high-order ICA to identify fine overlapping functional dynamic parcellations of the brain. The preliminary result of this work was presented at the organization for human brain mapping workshop (OHBM 2019)1.
Axillary Microbiota Compositions from Men and Women in a Tertiary Institution-South East Nigeria: Effects of Deodorants/Antiperspirants on Bacterial Communities
Authors: Anukam Kingsley C , Nmewurum Victoria , Agbakoba Nneka R
Published: March 2020

The axillary skin microbiota compositions of African populations that live in warm climate is not well studied with modern next-generation sequencing methods. To assess the microbiota compositions of the axillary region of healthy male and female students, we used 16S rRNA metagenomics method and clustered the microbial communities between those students that reported regular use of deodorants/antiperspirants and those that do not. Axillary skin swab was self-collected by 38 male and 35 females following uBiome sample collection instructions. Amplification of the V4 region of the 16S rRNA genes was performed and sequencing done in a pair-end set-up on the Illumina NextSeq 500 platform rendering 2 × 150 base pair. Microbial taxonomy to species level was generated using the Illumina Greengenes database. 26 phyla were identified in males withActinobacteriaas the most abundant (60%), followed byFirmicutes(31.53%),Proteobacteria(5.03%),Bacteroidetes(2.86%) and others. Similarly, 25 phyla were identified in females andActinobacteriawas the most abundant (59.28%), followed byFirmicutes(34.28%),Proteobacteria(5.91%),Bacteroidetes(0.45%) and others. A total of 747 genera were identified, out of which 556 (74.4%) were common to both males and females and 163 (21.8%) were exclusive to males while 28 (3.8%) were exclusive to females.Corynebacterium(53.89% vs 50.17%) was the most relative abundant genera in both male and female subjects, followed byStaphylococcus(19.66% vs 20.90%),Anaerococcus(4.91% vs 7.51%),Propionibacterium(1.21% vs 1.84%). There was a significant difference (P=0.0075) between those males that reported regular use of antiperspirant/deodorants and those that reported non-use of antiperspirants/deodorants in the relative abundance ofCorynebacterium(68.06% vs 42.40%). Higher proportion ofCorynebacteriumwas observed in male subjects than females, while more relative abundance ofStaphylococcuswas found in females than males. This study detectedLactobacilliin the axilla of over 82% of female and over 81% of male subjects, though in low relative abundance which suggests thatLactobacillustaxa might be considered as part of the normal axillary bacterial community. The study also revealed that the relative abundance ofCorynebacterium(68.06% vs 42.40%) was higher in those that reported regular use of deodorants/antiperspirants.
LSTrAP-Cloud: A User-friendly Cloud Computing Pipeline to Infer Co-functional and Regulatory Networks
Authors: Tan Qiao Wen , Goh William , Mutwil Marek
Published: March 2020

As genomes become more and more available, gene function prediction presents itself as one of the major hurdles in our quest to extract meaningful information on the biological processes genes participate in. In order to facilitate gene function prediction, we show how our user-friendly pipeline, Large-Scale Transcriptomic Analysis Pipeline in Cloud (LSTrAP-Cloud), can be useful in helping biologists make a shortlist of genes that they might be interested in. LSTrAP-Cloud is based on Google Colaboratory and provides user-friendly tools that process and quality-control RNA sequencing data streamed from the European Sequencing Archive. LSTRAP-Cloud outputs a gene co-expression network that can be used to identify functionally related genes for any organism with a sequenced genome and publicly available RNA sequencing data. Here, we used the biosynthesis pathway ofNicotiana tabacumas a case study to demonstrate how enzymes, transporters and transcription factors involved in the synthesis, transport and regulation of nicotine can be identified using our pipeline.
Atypical chemoreceptor arrays accommodate high membrane curvature
Authors: Muok Alise R. , Ortega Davi R. , Kurniyati Kurni , Yang Wen , Mabrouk Adam Sidi , Li Chunhao , Crane Brian R. , Briegel Ariane
Published: March 2020

Abstract/Summary

The prokaryotic chemotaxis system is arguably the best-understood signaling pathway in biology, but most insights have been obtained from only a few model organisms and many studies have relied on artificial systems that alter membrane curvature1–3. In all previously described species, chemoreceptors organize with the histidine kinase (CheA) and coupling protein (CheW) into a hexagonal (P6 symmetry) extended array that is considered universal among archaea and bacteria4,5. Here, for the first time, we report an alternative symmetry (P2) of the chemotaxis apparatus that emerges from a strict linear organization of CheA inTreponema denticolacells, which possesses arrays with the highest native curvature investigated thus far. Using cryo-ET, we reveal that theTdchemoreceptor arrays assume a truly unusual arrangement of the supra-molecular protein assembly that has likely evolved to accommodate the high membrane curvature. The arrays have several additional atypical features, such as an extended dimerization domain of CheA and a variant CheW-CheR-like fusion protein that is critical for maintaining an ordered chemosensory apparatus in an extremely curved cell. Furthermore, the previously characterizedTdoxygen sensor ODP influences array integrity and its loss substantially orders CheA. These results suggest a greater diversity of the chemotaxis signaling system than previously thought and demonstrate the importance of examining transmembrane systemsin vivoto retain native membrane curvature.
How to use random walks for modeling the movement of wild animals
Authors: Berthelot Geoffroy , Saïd Sonia , Bansaye Vincent
Published: March 2020

Animal movement has been identified as a key feature in understanding animal behavior, distribution and habitat use and foraging strategies among others. At the same time, technological improvements now allow for generating large datasets of high sampled GPS data over a long period of time. However, such datasets often remain unused or used only in part due to the lack of practical models that can directly infer the desired features from raw GPS locations and the complexity of existing approaches. Some of them being disputed for their lack of rational or biological justifications in their design. We propose a simple model of individual movement with explicit parameters based on essential features of animal behavior. The main thrust was to stick to empirical observations, rather than using black-box models that could possibly perform very well while providing little insight from an ecological perspective. We used a simple model, based on a two-dimensional biased and correlated random walk with three forces related to advection, attraction and immobility of the animal. These forces can be directly estimated using individual raw GPS data. The performance of the model is assessed through 5 statistics that describe the spatial features of animal movement. We demonstrate the approach by using GPS data of 5 roe deer with high frequency sampling. We show that combining the three forces significantly improves the model performance. We also found that the model’s parameters are not affected by the sampling rate of the GPS, suggesting that our model could also be used with low frequency sampling GPS devices. Additionally, the practical design of the model was verified for detecting spatial feature abnormalities (such as voids) and for providing estimates of density and abundance of wild animals. Our results show that a simple and practicable random walk template can account for the spatial complexity of wild animals. Integrating even more additional features of animal movement, such as individuals’ interactions or environmental repellents, could help to better understand the spatial behavior of wild animals.
NormiRazor – Tool Applying GPU-accelerated Computing for Determination of Internal References in MicroRNA Transcription Studies
Authors: Grabia Szymon , Smyczynska Ula , Pagacz Konrad , Fendler Wojciech
Published: March 2020

Motivation

Multi-gene expression assays are an attractive tool in revealing complex regulatory mechanisms in living organisms. Normalization is an indispensable step of data analysis in all those studies, since it removes unwanted, non-biological variability from data. In targeted qPCR assays the normalization is typically performed with respect to prespecified reference genes, but the lack of robust strategy of their selection is reported in literature, especially in studies concerning circulating microRNAs (miRNA).

Results

Previous studies concluded that averaged expressions of multi-miRNA combinations are more stable references than single genes. However, due to the number of such combinations the computational load is considerable and may be hindering for objective reference selection in large datasets. Existing implementations of normalization algorithms (geNorm, NormFinder and BestKeeper) have poor performance as every combination is evaluated sequentially. Thus, we designed an integrative tool which implemented those methods in a parallel manner on a graphics processing unit (GPU) using CUDA platform. We tested our approach on publicly available microRNA expression datasets. As a result the times of executions decreased 19-, 105- and 77-fold respectively for geNorm, BestKeeper and NormFinder.

Availability

NormiRazor is available as web application at norm.btm.umed.pl.

Contact

Wojciech Fendler,wojciech_fendler@dfci.harvard.edu.
Long-read transcriptome data of bee fungal parasite,Nosema ceranae
Authors: Chen Huazhi , Du Yu , Fan Yuanchan , Jiang Haibin , Xiong Cuiling , Zheng Yanzhen , Chen Dafu , Guo Rui
Published: March 2020

Nosema ceranae, a widespread fungal parasite that infects honeybee and many other bee species, can seriously affect bee health and colony productivity. In this article,N. ceranaespores were purified followed by third-generation sequencing using Nanopore PromethION platform. Totally, 6988795 raw reads were yielded from purified spores, with a length distribution among 1 kb~10 kb and a quality (Q) score distribution among Q6~Q12. A total of 6953469 clean reads were obtained, and among them 73.98% were identified as being full-length. The length of redundant reads-removed full-length transcripts was ranged from 1 kb to 5 kb, with the most abundant length of 1 kb. These data will improve transcriptome quality ofN. ceranaesignificantly.
Early-life microbial intervention reduces colitis risk promoted by antibiotic-induced gut dysbiosis
Authors: Miyoshi Jun , Miyoshi Sawako , Delmont Tom O. , Cham Candace , Lee Sonny T.M. , Sakatani Aki , Yang Karen , Shan Yue , Kiefl Evan , Yousef Mahmoud , Crosson Sean , Sogin Mitchell , Antonopoulos Dionysios A. , Eren A. Murat , Leone Vanessa , Chang Eugene B.
Published: March 2020

Perturbations in the early life gut microbiome are associated with increased risk to complex immune disorder like inflammatory bowel diseases. We previously showed maternal antibiotic-induced gut dysbiosis vertically passed to offspring increases experimental colitis risk in IL-10 gene deficient (IL-10−/−) mice. While this could arise from emergence of pathobionts or loss/lack of essential microbes needed for appropriate immunological education, our findings suggest the latter. A dominantBacteroidesstrain absent following antibiotic-induced perturbation was cultivated from murine fecal samples. Addition of this strain into mice with antibiotic-induced dysbiosis significantly promoted immune tolerance and reduced incidence of colitis in IL-10−/−mice, but only if engrafted early in life, and not during adulthood. Thus, key members of the gut microbiome are essential for development of immune tolerance to commensal microbes in early life and their addition in presence of gut dysbiosis during this period can reduce colitis risk in genetically prone hosts.

Highlights

Specific gut microbes promote early life immune tolerance to key commensal microbes

Loss of early life keystone microbes increases colitis risk in genetically prone hosts

Emergence of absent commensal microbes late in life worsened colitis outcome

Early life exposure to a missing keystone Bacteroides strain reduced colitis risk
Perceived ambiguity of social interactions increases coupling between frontal and temporal nodes of the social brain
Authors: Ainsworth Matthew , Sallet Jérôme , Joly Olivier , Kyriazis Diana , Kriegeskorte Nikolaus , Duncan John , Schüffelgen Urs , Rushworth Matthew FS , Bell Andrew H
Published: March 2020

Social behaviour is coordinated by a network of brain regions, including those involved in the perception of social stimuli and those involved in complex functions like inferring perceptual and mental states and controlling social interactions. The properties and function of many of these regions in isolation is relatively well understood but little is known about how these regions interact whilst processing dynamic social interactions. To investigate whether social network connectivity is modulated by social context we collected fMRI data from monkeys viewing “affiliative”, “aggressive”, or “ambiguous” social interactions. We show activation relating to the perception of social interactions along both banks of the superior temporal sulcus, parietal, medial and lateral PFC and caudate nucleus. Within this network we demonstrate that fronto-temporal connectivity are significantly modulated by social context. Crucially, we link the observation of specific behaviours to changes in connectivity within our network. Viewing aggressive or affiliative behaviour was associated with a limited increase in temporo-temporal and premotor-temporal connectivity respectively. By contrast, viewing ambiguous interactions was associated with a pronounced increase in cingulate-cingulate, temporo-temporal, and cingulate-temporal connectivity. We hypothesise that this widespread network synchronisation occurs when cingulate and temporal areas coordinate their activity when more difficult social inferences are made.
Testing the two-step model of plant root microbiome acquisition under multiple plant species and soil sources
Authors: Barajas Hugo R. , Martínez-Sánchez Shamayim , Romero Miguel F. , Hernández-Álvarez Cristóbal , Servín-González Luis , Peimbert Mariana , Cruz-Ortega Rocío , García-Oliva Felipe , Alcaraz Luis D.
Published: March 2020

The two-step model for plant root microbiomes considers soil as the primary microbial source. Active selection of the plant’s bacterial inhabitants results in a biodiversity decrease towards roots. We collectedin situruderal plant roots and their soils and used these soils as the main microbial input for single genotype tomatoes grown in a greenhouse. We massively sequenced the 16S rRNA and shotgun metagenomes of the soils,in situplants, and tomato roots. Tomato roots did follow the two-step model, while ruderal plants did not. Ruderal plants and their soils are closer than tomato and its soil, based on protein comparisons. We calculated a metagenomic tomato root core of 51 bacterial genera and 2,762 proteins, which could be the basis for microbiome-oriented plant breeding programs. The tomato and ruderal metagenomic differences are probably due to plant domestication trade-offs, impacting plant-microbe interactions.
Immune Digital Twin Blueprint: A Comprehensive Mechanistic Model of the Human Immune System
Authors: Amin Rada , Aghamiri Sara Sadat , Puniya Bhanwar Lal , Mayo Lauren , Startsev Dennis , Poore Kashish , Helikar Resa , Helikar Tomáš
Published: March 2020

The immune system is a complex and dynamic network, crucial for combating infections and maintaining health. Developing a comprehensive digital twin of the immune system requires incorporating essential cellular components and their interactions. This study presents the first blueprint for an immune system digital twin, consisting of a comprehensive and simulatable mechanistic model. It integrates 51 innate and adaptive immune cells, 37 secretory factors, and 11 disease conditions, providing the foundation for developing a multi-scale model. The cellular-level model demonstrates its potential in characterizing immune responses to various single and combinatorial disease conditions. By making the model available in easy-to-use formats directly in the Cell Collective platform, the community can easily and further expand it. This blueprint represents a significant step towards developing general-purpose immune digital twins, with far-reaching implications for the future of digital twin technology in life sciences and healthcare, advancing patient care, and accelerating precision medicine.
Activation of Macrophages by CpG DNA and LPS: an FTIR Spectroscopic Study
Authors: Spahiu Emrulla , Dogan Senol , Schnauß Jörg , Gursel Mayda , Severcan Feride
Published: March 2020

The innate immune response triggered by CpG DNA can improve host survival following pathogen challenge. Whether CpG ODN-mediated immune activation leads to global molecular changes in cells that are detectable by FTIR spectroscopy is currently unknown. Here, we used Attenuated Total Reflectance (ATR) Fourier Transform Infrared (FTIR) spectroscopy to monitor the molecular changes in murine macrophage RAW 264.7 cells upon activation with CpG DNA and lipopolysaccharide (LPS). By PCA analysis, we identified the sources of variation to follow with detailed spectral analysis. CpG DNA and LPS treatment increase the total nucleic acid concentration from the early periods post-activation, and DNA synthesis follows RNA synthesis. RNA-specific peak shows the activation state of macrophages in early periods post-treatment. CpG DNA and LPS result in an initial rapid increase in the total protein concentration, leveling off two hours post-activation. Both activated groups increase the concentration of fatty acids, triglycerides, and cholesterol, pointing out to a shared synthesis pathway andde novolipogenesis. This study, for the first time, demonstrates the use of FTIR spectroscopy as an independent modality to monitor the activation dynamics of murine macrophages upon activation with CpG DNA and LPS.
The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor
Authors: Ansell T. Bertie , Song Wanling , Sansom Mark S. P.
Published: March 2020

The extracellular domain (ECD) of Class B1 G-protein coupled receptors (GPCRs) plays a central role in signal transduction and is uniquely positioned to sense both the extracellular and membrane environments. Whilst recent studies suggest a role for membrane lipids in the modulation of Class A and Class F GPCR signalling properties, little is known about the effect of lipids on Class B1 receptors. In this study, we employed multiscale molecular dynamics (MD) simulations to access the dynamics of the glucagon receptor (GCGR) ECD in the presence of native-like membrane bilayers. Simulations showed that the ECD could move about a hinge region formed by residues Q122-E126 to adopt both closed and open conformations relative to the TMD. ECD movements were modulated by binding of the glycosphingolipid GM3. These large-scale fluctuations in ECD conformation that may affect the ligand binding and receptor activation properties. We also identify a unique PIP2interaction profile near ICL2/TM3 at the G-protein coupling interface, suggesting a mechanism of engaging G-proteins which may have a distinct dependence on PIP2compared to Class A GPCRs. Given the structural conservation of Class B1 GPCRs, the modulatory effects of GM3 and PIP2on GCGR may be conserved across these receptors, offering new insights into potential therapeutic targeting.

Statement of Significance

The role of lipids in regulation of Class B GPCRs remains elusive, despite recent structural advances. In this study, multi-scale molecular dynamics simulations are used to evaluate lipid interactions with the glucagon receptor, a Class B1 GPCR. We find that the glycosphingolipid GM3 binds to the glucagon receptor extracellular domain (ECD), modulating the dynamics of the ECD and promoting movement away from the transmembrane domain. We also identify a unique PIP2interaction fingerprint in a region known to be important for bridging G-protein coupling in Class A GPCRs. Thus, this study provides molecular insight into the behaviour of the glucagon receptor in a complex lipid bilayer environment which may aid understanding of glucagon receptor signalling properties.
Poly(ADP-ribose) glycohydrolase promotes formation and homology-directed repair of meiotic DNA double-strand breaks independent of its catalytic activity
Authors: Janisiw Eva , Raices Marilina , Balmir Fabiola , Paz Luis Paulin , Baudrimont Antoine , von Haeseler Arndt , Yanowitz Judith L. , Jantsch Verena , Silva Nicola
Published: March 2020

Poly(ADP-ribosyl)ation is a reversible post-translational modification synthetized by ADP-ribose transferases and removed by poly(ADP-ribose) glycohydrolase (PARG), which plays important roles in DNA damage repair. While well-studied in somatic tissues, much less is known about poly(ADP-ribosyl)ation in the germline, where DNA double-strand breaks are introduced by a regulated program and repaired by crossover recombination to establish a tether between homologous chromosomes. The interaction between the parental chromosomes is facilitated by meiotic specific adaptation of the chromosome axes and cohesins, and reinforced by the synaptonemal complex. Here, we uncover an unexpected role for PARG in promoting the induction of meiotic DNA breaks and their homologous recombination-mediated repair inCaenorhabditis elegans. PARG-1/PARG interacts with both axial and central elements of the synaptonemal complex, REC-8/Rec8 and the MRN/X complex. PARG-1 shapes the recombination landscape and reinforces the tightly regulated control of crossover numbers without requiring its catalytic activity. We unravel roles in regulating meiosis, beyond its enzymatic activity in poly(ADP-ribose) catabolism.
Hippocampal inputs engage CCK+ interneurons to mediate endocannabinoid-modulated feed-forward inhibition in the prefrontal cortex
Authors: Liu Xingchen , Dimidschstein Jordane , Fishell Gordon , Carter Adam G.
Published: March 2020

Connections from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) regulate cognition, emotion and memory. These functions are also tightly regulated by inhibitory networks in the PFC, whose disruption is thought to contribute to mental health disorders. However, relatively little is known about how the vHPC engages different populations of interneurons in the PFC. Here we use slice physiology and optogenetics to study vHPC-evoked feed-forward inhibition in the mouse PFC. We first show that cholecystokinin (CCK+), parvalbumin (PV+), and somatostatin (SOM+) interneurons are prominent in layer 5 (L5) of infralimbic PFC. We then show that vHPC inputs primarily activate CCK+ and PV+ interneurons, with weaker connections onto SOM+ interneurons. CCK+ interneurons make stronger synapses onto pyramidal tract (PT) cells over nearby intratelencephalic (IT) cells. However, CCK+ inputs undergo depolarization-induced suppression of inhibition (DSI) and CB1 receptor modulation only at IT cells. Moreover, vHPC-evoked feed-forward inhibition undergoes DSI only at IT cells, confirming a central role for CCK+ interneurons. Together, our findings show how vHPC directly engages multiple populations of inhibitory cells in deep layers of the infralimbic PFC, highlighting unexpected roles for both CCK+ interneurons and endocannabinoid modulation in hippocampal-prefrontal communication.
The relationship between effective molarity and affinity governs rate enhancements in tethered kinase-substrate reactions
Authors: Speltz Elizabeth B. , Zalatan Jesse G.
Published: March 2020

Scaffold proteins are thought to accelerate protein phosphorylation reactions by tethering kinases and substrates together, but there is little quantitative data on their functional effects. To assess the contribution of tethering to kinase reactivity, we compared intramolecular and intermolecular kinase reactions in a minimal model system. We find that tethering can enhance reaction rates in a flexible tethered kinase system, and the magnitude of the effect is sensitive to the structure of the tether. The largest effective molarity we obtained was ∼0.08 µM, which is much lower than the effects observed in small molecule model systems and tethered protein-ligand interactions. We further demonstrate that the tethered, intramolecular reaction only makes a significant contribution to observed rates when the scaffolded complex assembles at concentrations below the effective molarity. These findings provide a quantitative framework that can be applied to understand endogenous protein scaffolds and to engineer synthetic networks.
Rho1 activation recapitulates early gastrulation events in the ventral, but not dorsal, epithelium ofDrosophilaembryos
Authors: Rich Ashley , Fehon Richard G. , Glotzer Michael
Published: March 2020

Ventral furrow formation, the first step inDrosophilagastrulation, is a well-studied example of tissue morphogenesis. Rho1 is highly active in a subset of ventral cells and is required for this morphogenetic event. However, it is unclear whether spatially patterned Rho1 activity alone is sufficient to recapitulate all aspects of this morphogenetic event, including anisotropic apical constriction and coordinated cell movements. Here, using an optogenetic probe that rapidly and robustly activates Rho1 inDrosophilatissues, we show that Rho1 activity induces ectopic deformations in the dorsal and ventral epithelia ofDrosophilaembryos. These perturbations reveal substantial differences in how ventral and dorsal cells, both within and outside the zone of Rho1 activation, respond to spatially and temporally identical patterns of Rho1 activation. Our results demonstrate that an asymmetric zone of Rho1 activity is not sufficient to recapitulate ventral furrow formation and indicate that additional, ventral-specific factors contribute to the cell- and tissue-level behaviors that emerge during ventral furrow formation.
IMRPS: Inserted and Modified Residues in Protein Structures. A database
Authors: Santhosh R. , Bankoti Namrata , Gurudarshan M. , Jeyakanthan J. , Sekar K.
Published: March 2020

Modified residues present in proteins are the result of post-translational modifications (PTMs). These PTMs increase the functional diversity of the proteome and influence various biological processes and diseased conditions. Therefore, identification and understanding of PTMs in various protein structures is of great significance. In view of this, an online database, Inserted and Modified Residues in Protein Structures (IMRPS), has been developed. IMRPS is a derived database that furnishes information on the residues modified and inserted in the protein structures available in the Protein Data Bank (PDB). The database is equipped with a graphical user interface and has an option to view the data for non-redundant protein structures (25 and 90%) as well. A quality criteria cutoff has been incorporated to assist in displaying the specific set of PDB codes. The entire protein structure along with the inserted or modified residues can be visualized in JSmol. This database will be updated regularly (presently, every three months) and can be accessed through the URL http://cluster.physics.iisc.ac.in/imrps/.
Different packing motifs in the crystal structures of three molecular salts containing the 2-amino-5-carboxyanilinium cation: C7H9N2O2
+·Cl−, C7H9N2O2
+·Br− and C7H9N2O2
+·NO3
−·H2O
Authors: Mukombiwa Edson T. , Harrison William T A
Published: March 2020

The syntheses and crystal structures of three molecular salts of protonated 3,4-diaminobenzoic acid, viz. 2-amino-5-carboxyanilinium chloride, C7H9N2O2
+·Cl−, (I), 2-amino-5-carboxyanilinium bromide, C7H9N2O2
+·Br−, (II), and 2-amino-5-carboxyanilinium nitrate monohydrate, C7H9N2O2
+·NO3
−·H2O, (III), are described. The cation is protonated at the meta-N atom (with respect to the carboxy group) in each case. In the crystal of (I), carboxylic acid inversion dimers linked by pairwise O—H...O hydrogen bonds are seen and each N—H group forms a hydrogen bond to a chloride ion to result in (100) undulating layers of chloride ions bridged by the inversion dimers into a three-dimensional network. The extended structure of (II) features O—H...Br, N—H...Br and N—H...O hydrogen bonds: the last of these generates C(7) chains of cations. Overall, the packing in (II) features undulating (100) sheets of bromide ions alternating with the organic cations. Intermolecular interactions in the crystal of (III) include O—H...O, O—H...(O,O), N—H...O, N—H...N and O—H...N links. The cations are linked into (001) sheets, and the nitrate ions and water molecules form undulating chains. Taken together, alternating (001) slabs of organic cations plus anions/water molecules result. Hirshfeld surfaces and fingerprint plots were generated to give further insight into the intermolecular interactions in these structures. The crystal used for the data collection of (II) was twinned by rotation about [100] in reciprocal space in a 0.4896 (15):0.5104 (15) ratio.
Home buyouts: a tool for mitigation or recovery?
Authors: Binder Sherri Brokopp , Greer Alex , Zavar Elyse
Published: March 2020

Purpose

Home buyout programs are typically funded by the federal government and implemented by local agencies. How these agencies design and implement buyouts has considerable impacts on participating households and communities, making understanding the internal processes of implementing agencies a critical component of buyout research. This study addresses this issue by exploring the early design and implementation phases of a buyout program in Harris County, Texas, following Hurricane Harvey.

Design/methodology/approach

Data were collected via semi-structured interviews with buyout staff and government stakeholders. Data were analyzed in two phases using grounded theory methodology and holistic coding.

Findings

There was considerable tension regarding the role of buyouts in mitigation and recovery. Participants conceptualized buyouts as mitigation programs, but recognized that residents, in contrast, viewed buyouts as a tool for household recovery.

Research limitations/implications

This study adds to questions raised in the literature about the efficacy of buyouts and other relocation efforts implemented in response to disasters and global climate change. Future research should work to build systematic knowledge regarding design, implementation, and impacts of buyouts on affected households and communities.

Practical implications

Tension in the purpose of buyouts may be the cause of consistent shortcomings in buyout implementation including attrition, checkerboarding, and transfer of risk. Funding, timing, and the scale of buyouts do not align with household recovery needs and priorities, limiting the mitigation potential of buyouts.

Originality/value

This study identifies a fundamental tension in the purpose of buyout programs that has yet to be discussed in the literature.