bluuebunny/crossref_metadata_2025 huggingface dataset:
EXPERIMENTAL EXAMINATION OF RADIATION DOSES OF DUAL- AND SINGLE-ENERGY COMPUTED TOMOGRAPHY IN CHEST AND UPPER ABDOMEN IN A PHANTOM STUDY
Authors: Bos Denise , König Britta , Blex Sebastian , Zensen Sebastian , Opitz Marcel , Maier Sandra , Forsting Michael , Zylka Waldemar , Kühl Hilmar , Wetter Axel , Guberina Nika
Published: March 2021

The aim of this phantom study is to examine radiation doses of dual- and single-energy computed tomography (DECT and SECT) in the chest and upper abdomen for three different multi-slice CT scanners. A total of 34 CT protocols were examined with the phantom N1 LUNGMAN. Four different CT examination types of different anatomic regions were performed both in single- and dual-energy technique: chest, aorta, pulmonary arteries for suspected pulmonary embolism and liver. Radiation doses were examined for the CT dose index CTDIvol and dose-length product (DLP). Radiation doses of DECT were significantly higher than doses for SECT. In terms of CTDIvol, radiation doses were 1.1–3.2 times higher, and in terms of DLP, these were 1.1–3.8 times higher for DECT compared with SECT. The third-generation dual-source CT applied the lowest dose in 7 of 15 different examination types of different anatomic regions.
Seismic running safety of trains and a new type of seismic-isolation railway structure
Authors: Luo Xiu
Published: March 2021

Until now, seismic-isolation structures have not yet been applied in the railway field. The reason is that though a seismic-isolation structure can reduce the inertial force to the structure, the energy absorption causes big response displacement on the structure, which adversely effects the running safety of the trains supported by the structure. In this paper, a methodology for seismic running safety assessment is introduced, and a new type of seismic-isolation foundation is proposed, which can convert the seismic response displacement in the lateral direction of track to the longitudinal direction that has a less adverse effect on the running safety of the train. The isolation foundation is composed of FPS (Friction Pendulum System) slider, concave plate and guide ditch. Moreover, through model experiments and 3D numerical simulation, it is verified that the proposed foundation can keep both the effects of the seismic isolation and the running safety of the train during an earthquake.
Evolutionary history of cotranscriptional editing in the paramyxoviral phosphoprotein gene
Authors: Douglas Jordan , Drummond Alexei J , Kingston Richard L
Published: March 2021

The phosphoprotein gene of the paramyxoviruses encodes multiple protein products. The P, V, and W proteins are generated by transcriptional slippage. This process results in the insertion of non-templated guanosine nucleosides into the mRNA at a conserved edit site. The P protein is an essential component of the viral RNA polymerase and is encoded by a faithful copy of the gene in the majority of paramyxoviruses. However, in some cases, the non-essential V protein is encoded by default and guanosines must be inserted into the mRNA in order to encode P. The number of guanosines inserted into the P gene can be described by a probability distribution, which varies between viruses. In this article, we review the nature of these distributions, which can be inferred from mRNA sequencing data, and reconstruct the evolutionary history of cotranscriptional editing in the paramyxovirus family. Our model suggests that, throughout known history of the family, the system has switched from a P default to a V default mode four times; complete loss of the editing system has occurred twice, the canonical zinc finger domain of the V protein has been deleted or heavily mutated a further two times, and the W protein has independently evolved a novel function three times. Finally, we review the physical mechanisms of cotranscriptional editing via slippage of the viral RNA polymerase.
Developing a Greenhouse Protocol for Evaluating Resistance to Corynespora cassiicola in Cotton (Gossypium hirsutum)
Authors: Moore C. , Sharma N. , Bowen K. L. , Koebernick J.
Published: March 2021

Target spot, caused by Corynespora cassiicola, has reemerged as a disease of economic importance in cotton (Gossypium hirsutum L.) in the southeastern United States. Although this pathogen affects other economically important crops, relatively little is known about C. cassiicola on cotton, especially with regard to conditions conducive for disease development and sources of genetic resistance. Therefore, to more efficiently screen cotton genotypes for resistance, a greenhouse protocol is needed. Optimum temperature and conducive leaf wetness duration were determined in growth chamber trials. Temperature range for disease onset and greatest lesion counts occurred between 20 and 28°C. Generally, with ≥24 h of leaf wetness at these temperatures, disease onset was noted as rapidly as 1 day after inoculation on a cultivar that was previously determined to be susceptible to target spot. A mist irrigation system was used to maintain prolonged periods of leaf wetness in the greenhouse. In greenhouse trials, inoculation of cotyledons with 4 × 104 conidia/ml allowed differentiation of five selected genotypes with disease reactions that reflected their field rankings. The current protocol will be useful for evaluating cotton breeding lines for resistance to target spot.
Detection of Four New Tomato Viruses in Serbia Using Post Hoc High-Throughput Sequencing Analysis of Samples From a Large-Scale Field Survey
Authors: Vučurović Ana , Kutnjak Denis , Mehle Nataša , Stanković Ivana , Pecman Anja , Bulajić Aleksandra , Krstić Branka , Ravnikar Maja
Published: March 2021

Tomato production worldwide is affected by numerous plant virus species. The early and accurate detection of viruses is a critical step for disease control. However, the simultaneous detection of the most known tomato viruses can be difficult because of the high number and diversity of tomato-infecting viruses. Here, we have identified four new viruses in Serbia by applying target-independent small RNA high-throughput sequencing (HTS). HTS was applied on pools of samples and separate samples, in total comprising 30 tomato samples that exhibited (severe) virus-like symptoms and were collected in Serbia during three annual surveys (2011 to 2013). These samples had previously tested negative for the presence of 16 tomato viruses using targeted detection methods. Three divergent complete genome sequences of Physostegia chlorotic mottled virus were obtained from different localities, indicating for the first time that this virus is widespread in Serbia and might represent an emergent viral pathogen of tomato. The tomato torrado virus was detected at one locality with devastating yield losses. The southern tomato virus was detected at two localities, and the spinach latent virus was detected at one locality. In addition, we detected the presence of one already-known virus in Serbia, the tomato spotted wilt orthotospovirus. All the HTS results were subsequently confirmed by targeted detection methods. In this study, the successful application of post hoc HTS testing of a limited number of pooled samples resulted in the discovery of new viruses. Thus, our results encourage the use of HTS in research and diagnostic laboratories, including laboratories that have limited resources to resolve disease etiology.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Surgical Prevention of Weight Regain and Type 2 Diabetes Recurrence in 3 Different Bariatric Operations and Their Differential Long-Term Outcome
Authors: Steffen Rudolf , Horber Fritz F.
Published: March 2021

Introduction:

Comparative data on long-term outcomes of mechanistically different bariatric operations are scarce.

Methods:

In this prospective, observational study, consecutive patients with severe obesity were studied using a predefined reoperation algorithm to determine long-term health outcomes after bariatric surgery (BS): adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD). All patients were assessed for mortality, postoperative weight loss, rate of reoperation, comorbidities, and quality of life (QoL) 8 years after surgery.

Results:

Between 1996 and 2008, 2364 Swiss patients, with a mean body mass index of 43 ± 7 kg/m2 (mean ± SD) underwent AGB (n = 1404), RYGB (n = 790), or BPD (n = 170). Two thousand two hundred twenty-eight (94%) were followed for 8 years after BS. Eight-year mortality of the whole study group was 34.3 per 104 person-years. Percent excessive weight loss at 8 years was 56.7 ± 1.4% (95% confidence interval) in AGB, 62.5 ± 2.4% in RYGB and 64.8+-3.0% in BPD. The rate of major reoperation was highest in AGB and significantly lower in RYGB and BPD (63.4 vs 54.3 vs 47.2 per 103 person-years, P < 0.001). Remission of comorbidities was observed across all 3 groups, with key improvement (P < 0.01) in esophagitis in the RYGB group, and type 2 diabetes (T2D) (>60%) in procedures involving duodenal exclusion. Total improvement in QoL was similar between the 3 types of operations but was strongly correlated with weight loss preservation (P < 0.001).

Conclusions:

BS, at the expense of a high reoperation rate but low procedural mortality, considerably improves the QoL and results in sustained remission of comorbidities, especially T2D using a predefined reoperation algorithm developed to prevent weight regain and operation-specific complications.
Harnessing the Microbiome to Optimize Surgical Outcomes in the COVID-19 Era
Authors: Toni Tiffany , Alverdy John
Published: March 2021

In this era of testing uncertainties, changing guidelines, and incomplete knowledge, “clearing” patients for surgery in the time of SARS-COVID-19 has been met with various challenges. Efforts to increase patient fitness have long been at the forefront of surgical practicing guidelines, but the current climate requires a renewed sense of focus on these measures. It is essential to understand how dietary history, previous antibiotic exposure, and baseline microbiota can inform and optimize preoperative and postoperative management of the surgical patient in the time of COVID-19. This piece focuses on the clinical, molecular, and physiologic dynamics that occur in preparing patients for surgery during COVID-19, considering the physiologic stress inherent in the procedure itself and the importance of specialized perioperative management approaches. COVID-19 has created a renewed sense of urgency to maintain our discipline in implementing those practices that have long been confirmed to be beneficial to patient outcome. This practice, along with a renewed interest in understanding how the gut microbiome is affected by the confinement, social distancing, etc., due to the COVID pandemic, is ever more important. Therefore, here we discuss the microbiome’s role as a defense against viral infection and its potential for reactivation during the process of surgery as the next frontier for surgical advancement.
Forehead and Hairline Surgery for Gender Affirmation
Authors: Pansritum Kamol
Published: March 2021

Background:

With the improvement of the results of surgical treatment for facial transformation globally, many female transgender individuals seek surgical management for their faces, especially the forehead and hairline. These are critical aspects in the surgical management of the frontonasal-orbital area because the anatomy of the frontal sinuses is complicated and shows a high variation.

Methods:

The author presents a grid method to measure the boundary of the frontal sinus in the female transgender forehead contouring and reconstruction. The surgical technique of forehead set back and simultaneous hairline advancement is described.

Results:

Between January 2015 and December 2017, there were 23 cases of forehead and hairline feminization procedures by the author. Patient age was between 20 and 74 years (mean 32.56). There were 11 Asians and 12 White patients. Eleven patients underwent supraorbital ridge contouring, and 12 underwent forehead reconstruction. Hairline advancement was simultaneously performed in 9 patients, and 3 underwent forehead augmentation at the supraorbital ridge. The postoperative follow-up time ranged from 3 weeks to 18 months.

Conclusions:

The key to the success of forehead contouring surgery in female transgender patients is the precise measurement of the boundary of the frontal sinus. This technique offers a practical way to estimate the frontal sinus sizes and shapes to avoid intraoperative complications and reduces the possibility of surface irregularity.
Effects of Slowness, Frailty, Insufficient Intake, and Delirium in Patients Following Cardiac Surgery
Authors: Teng Chiao-Hsin , Hsu Ron-Bin , Chi Nai-Hsin , Wang Shoei-Shen , Chen Yih-Sharng , Chen Ssu-Yuan , Chen Cheryl Chia-Hui
Published: March 2021

Background

Slow gait, frailty, insufficient postoperative caloric intake, and delirium, although seemingly distinct, can appear simultaneously in patients who underwent cardiac surgery.

Objectives

The aim of this study was to evaluate how these 4 factors overlap and how they individually and cumulatively affect cardiac surgery outcomes.

Methods

The effects of slowness (gait speed <0.83 m/s), frailty (≥3/5 Fried criteria), insufficient postoperative intake (<800 kcal/d), and delirium (defined by the Confusion Assessment Method) on hospital length of stay (LOS) and 3-month mortality were analyzed in 308 adult patients.

Results

Slowness, frailty, insufficient intake, and delirium affected 27.5%, 29.5%, 31.5%, and 13.3% of participants, respectively; only 42.2% (130/308) were free from these risks. Risk overlap was prevalent, as 26.3% (n = 81) had 2 or more risk factors. The most obvious overlap was in delirium (80% of delirious participants had other risks), suggesting that delirium cannot be managed in isolation. Individually, whereas slowness was associated only with longer LOS, frailty, insufficient intake, and delirium all led to longer LOS and higher mortality. When equally weighting each risk factor to analyze their cumulative effects, LOS increased by 4.4 days (95% confidence interval, 3.0–5.7) and 3-month mortality increased by 2.6-fold (95% confidence interval, 1.4–4.6), with each risk factor added, independent of participants' educational level, body mass index, and risk for cardiac surgery (EuroSCORE II ≥6).

Conclusions

Because a clinical overlap of slowness, frailty, insufficient postoperative intake, and delirium was evident in patients who underwent cardiac surgery, and risk of death and longer hospital stay increased with each factor added, care should be revised to consider these overlapping factors to maximize patient outcomes.
A Case of Self-Cannibalism
Authors: Aras Neriman
Published: March 2021

Self-mutilation is a behavior often associated with various psychiatric diseases, and it has various risk factors. Self-cannibalism, an extremely rare form of self-mutilation, can also be observed in the absence of psychosis and substance abuse. This study reports a case of self-cannibalism with multiple risk factors including history of substance use, previous self-mutilation actions, suicidal attempts, antisocial personality disorder, imprisonment, and active symptoms associated with untreated schizophrenia.
Physician, Protect Thyself
Authors: MacIntyre Michael R. , Appel Jacob M.
Published: March 2021

Modern psychiatric practice requires the use of the Internet, and the current pandemic has accelerated the adoption of technology in clinics. Psychiatrists receive significant education on protecting patient privacy and medical information when using these tools. However, they receive little training regarding protecting their own personal privacy in the Internet era. Private information, often without one's knowledge, is frequently available online and accessible by patients. The work of physicians and psychiatrists creates additional unique vulnerabilities to privacy. Given the essential nature of the Internet in modern clinical practice, physicians should understand how to monitor and protect personal privacy and safety online. We provide advice to minimize vulnerability to a privacy breach, with a focus on areas unique to psychiatrists and psychiatric practice. We review the literature on physician safety online and offer guidance to get started.
A Systematic Review of the Efficacy of DASH Diet in Lowering Blood Pressure Among Hypertensive Adults
Authors: Balasubramaniam Janani , Hewlings Susan J.
Published: March 2021

Despite interventions such as the Dietary Approaches to Stop Hypertension (DASH), hypertension remains prevalent. This systematic review assesses the efficacy of the DASH diet in lowering blood pressure among hypertensive adults. PubMed and Google Scholar were searched for original research trials on the DASH diet published between 2014 and 2019. Randomized trials and secondary analyses of adult subjects 18 years and older with prehypertension and hypertension but with no associated medical illnesses and not following any specific diet or exercise were included. Eight studies were eligible and had a low risk of bias. The DASH diet has the potential to lower blood pressure with enhanced effect when combined with reduced sodium, weight loss, and exercise. Although the DASH diet is an efficacious strategy for managing hypertension, further studies should address poor adherence.
Effect of Food Odors on Subjective Degree of Appetite Among Patients Undergoing Convalescent Rehabilitation
Authors: Nunokawa Kihou , Tokairin Nagisa , Homma Kasumi , Nagai Toru
Published: March 2021

The goal of this study was to evaluate the effect of food odors on subjective degree of appetite in patients on a convalescent rehabilitation ward. The degree of subjective appetite for sauce and curry odor samples was significantly stronger than that for the odorless sample. But the evoked intensity of subjective appetite did not differ between the 2 groups, and none of the samples affected the degree of perceived favorability. These results suggested that sauce and curry odors can enhance the appetite and food consumption of patients in convalescent rehabilitation wards.
Describing Critical Thinking Dispositions and Skills Among Registered Dietitian Nutritionists
Authors: Serna Theresa A. , Zheng Grace Q. , Hand Rosa K.
Published: March 2021

Critical thinking is essential for registered dietitian nutritionists (RDNs) to obtain and interpret data within the Nutrition Care Process Model, but critical thinking dispositions and skills have not been quantified previously in RDNs. This cross-sectional study used validated tools to describe critical thinking dispositions and skills of 78 RDNs. Results suggest that RDNs have relatively strong critical thinking skills but the study did not reach adequate power to make planned comparisons of critical thinking based on participant personal or professional characteristics. This study raises awareness of critical thinking definition and measurement to encourage additional participation in future research on this topic.
Regional spread of blaNDM-1-containing Klebsiella pneumoniae Sequence Type 147 in post-acute care facilities
Authors: Lapp Zena , Crawford Ryan , Miles-Jay Arianna , Pirani Ali , Trick William E. , Weinstein Robert A. , Hayden Mary K. , Snitkin Evan S. , Lin Michael Y.
Published: March 2021

Background

Carbapenem-resistant Enterobacterales (CRE) harboring blaKPC have been endemic in Chicago-area healthcare networks for more than a decade. During 2016-2019, a series of regional point prevalence surveys identified increasing prevalence of blaNDM-containing CRE in multiple long-term acute care hospitals (LTACHs) and ventilator-capable skilled nursing facilities (vSNFs). We performed a genomic epidemiology investigation of blaNDM-producing CRE to understand their regional emergence and spread.

Methods

We performed whole-genome sequencing on NDM+ CRE isolates from four point-prevalence surveys across 35 facilities (LTACHs, vSNFs, and acute care hospital medical intensive care units) in the Chicago area and investigated the genomic relatedness and transmission dynamics of these isolates over time.

Results

Genomic analyses revealed that the rise of NDM+ CRE was due to the clonal dissemination of an ST147 Klebsiella pneumoniae strain harboring blaNDM-1 on an IncF plasmid. Dated phylogenetic reconstructions indicated that ST147 was introduced into the region around 2013 and likely acquired NDM around 2015. Analyzing genomic data in the context of patient transfer networks supported initial increases in prevalence due to intra-facility transmission in certain vSNFs, with evidence of subsequent inter-facility spread to connected LTACHs and vSNFs via patient transfer.

Conclusions

We identified a regional outbreak of blaNDM-1 ST147 that began in and disseminated across Chicago area post-acute care facilities. Our findings highlight the importance of performing genomic surveillance at post-acute care facilities to identify emerging threats.
An automated Dashboard to improve laboratory COVID-19 diagnostics management
Authors: Maury Emma , Boldi Marc-Olivier , Greub Gilbert , Chavez Valérie , Jaton Katia , Opota Onya
Published: March 2021

Background

In response to the CoVID-19 pandemic, our microbial diagnostic laboratory located in a university hospital has implemented several distinct SARS-CoV-2 RT-PCR systems in a very short time. Thanks to our automated molecular diagnostic platform, more than 140’000 SARS-CoV-2 RT-PCR tests were achieved over 12 months, with peaks higher than 1’500 daily tests. A dashboard was developed to give access to Key Performance Indicators (KPIs) to improve laboratory operational management.

Methods

RT-PCR data extraction of four respiratory viruses – SARS-CoV-2, influenza A and B and RSV – from our laboratory information system (LIS), was automated. Important KPIs were identified and the visualization was achieved using an in-house dashboard based on the open-source language R (Shiny). Information is updated every 4 hours.

Results

The dashboard is organized into three main parts. The “Filter” page presents all the KPIs, divided into five sections: i) general and gender-related indicators, ii) number of tests and positivity rate, iii) cycle threshold and viral load, iv) test durations, and v) not valid results. Filtering allows to select a given period, a dedicated instrument, a given specimen, or a requester for instance. The “Comparison” page allows a custom charting of all the available variables, which represents more than 182 combinations. The “Data” page gives the user access to the raw data in table format, with the possibility of filtering, allowing for a deeper analysis and data download in Excel format.

Conclusions

The dashboard, that gives a rapid access to a huge number of up-to-date information, represents a reliable and user-friendly tool improving the decision-making process, resource planning and quality management. The dashboard represent an added value for diagnosric laboratories during a pandemic, where rapid and efficient adaptation is mandatory.
Derivation of stationary distributions of biochemical reaction networks via structure transformation
Authors: Hong Hyukpyo , Kim Jinsu , Al-Radhawi M Ali , Sontag Eduardo D. , Kyoung Kim Jae
Published: March 2021

Long-term behaviors of biochemical reaction networks (BRNs) are described by steady states in deterministic models and stationary distributions in stochastic models. Unlike deterministic steady states, stationary distributions capturing inherent fluctuations of reactions are extremely difficult to derive analytically due to the curse of dimensionality. Here, we develop a method to derive analytic stationary distributions from deterministic steady states by transforming BRNs to have a special dynamic property, called complex balancing. Specifically, we merge nodes and edges of BRNs to match in- and out-flows of each node. This allows us to derive the stationary distributions of a large class of BRNs, including autophosphorylation networks of EGFR, PAK1, and Aurora B kinase and a genetic toggle switch. This reveals the unique properties of their stochastic dynamics such as robustness, sensitivity and multi-modality. Importantly, we provide a user-friendly computational package, CASTANET, that automatically derives symbolic expressions of the stationary distributions of BRNs to understand their long-term stochasticity.
Cell-type-specific meQTL extends melanoma GWAS annotation beyond eQTL and informs melanocyte gene regulatory mechanisms
Authors: Zhang Tongwu , Choi Jiyeon , Dilshat Ramile , Einarsdóttir Berglind Ósk , Kovacs Michael A , Xu Mai , Malasky Michael , Chowdhury Salma , Jones Kristine , Bishop D Timothy , Goldstein Alisa M , Iles Mark M , Landi Maria Teresa , Law Matthew H , Shi Jianxin , Steingrímsson Eiríkur , Brown Kevin M
Published: March 2021

While expression quantitative trait loci (eQTL) have been powerful in identifying susceptibility genes from genome-wide association studies (GWAS) findings, most trait-associated loci are not explained by eQTL alone. Alternative QTLs including DNA methylation QTL (meQTL) are emerging, but cell-type-specific meQTL using cells of disease origin has been lacking. Here we established an meQTL dataset using primary melanocytes from 106 individuals and identified 1,497,502 significantcis-meQTLs. Multi-QTL colocalization using meQTL, eQTL, and mRNA splice-junction QTL from the same individuals together with imputed methylome-wide and transcriptome-wide association studies identified susceptibility genes at 63% of melanoma GWAS loci. Among three molecular QTLs, meQTLs were the single largest contributor. To compare melanocyte meQTLs with those from malignant melanomas, we performed meQTL analysis on skin cutaneous melanomas from The Cancer Genome Atlas (n = 444). A substantial proportion of meQTL probes (45.9%) in primary melanocytes are preserved in melanomas, while a smaller fraction of eQTL genes is preserved (12.7%). Integration of melanocyte multi-QTL and melanoma meQTL identified candidate susceptibility genes at 72% of melanoma GWAS loci. Beyond GWAS annotation, meQTL-eQTL colocalization in melanocytes suggested that 841 unique genes potentially share a causal variant with a nearby methylation probe in melanocytes. Finally, melanocytetrans-meQTL identified a hotspot for rs12203592, acis-eQTL of a transcription factor, IRF4, with 131 candidate target CpGs. Motif enrichment and IRF4 ChIPseq analysis demonstrated that these target CpGs are enriched in IRF4 binding sites, suggesting an IRF4-mediated regulatory network. Our study highlights the utility of cell-type-specific meQTL.
ExploringLeishmania-Host Interaction with Reactome, a Database of Biological Pathways and Processes
Authors: Murillo Julieth , Jassal Bijay , Gómez Maria Adelaida , Hermjakob Henning
Published: March 2021

Leishmaniasis is a parasitic disease with a wide range of clinical manifestations. Multiple aspects of theLeishmania-host interaction, such as genetic factors and modulation of microbicidal functions in host cells, influence pathogenesis, disease severity and treatment outcome. How do scientists contend with this complexity? Here, we work towards representing detailed, contextual knowledge onLeishmania-host interactions in the Reactome pathway database to facilitate the extraction of novel mechanistic insights from existing datasets. The Reactome database uses a hierarchy of abstractions that allows for the incorporation of detailed contextual knowledge on biological processes matched to differentially expressed genes. It also includes tools for enhanced over-representation analysis that exploits this extra information. We conducted a systematic curation of published studies documenting different aspects of theLeishmania-host interaction. The “Leishmaniainfection pathway” included four sub-pathways: phagocytosis, killing mechanisms, cell recruitment, andLeishmaniaparasite growth and survival. As proof-of-principle of the usefulness of the released pathway, we used it to analyze two previously released transcriptomic datasets of human and murine macrophages infected withLeishmania. Our results provide insights on the participation of ADORA2B signaling pathway in the modulation of IL10 and IL6 in infected macrophages. This work opens the way for other researchers to contribute to, and make use of, the Reactome database.

Importance

Leishmaniasis is a neglected disease infectious disease which affects more than 1.5 million people annually. Many researchers in the field apply -omic technologies to dissect the basis of clinical and therapeutic outcomes and access drug targetable features in the host-parasite interaction, among others. However, getting mechanistic insights from -omics data to such end is not an easy task. The most common approach is to use the -omics data to inquire pathways databases. The retrieved list of pathways often contains vague names that lack the biological context. In this study, we worked to create theLeishmaniainfection pathway in the Reactome database. With two practical examples from transcriptomics and microarray data, we demonstrated how this pathway facilitates the analysis of such data. In both datasets, we found a common mechanism of IL10 and IL6 production that the authors did not advert in their previous analysis, providing proof-of-principle of the tool’s enhanced potential for knowledge extraction.Leishmaniainfection pathway is in its first version, and must be expanded to cover the current knowledge base of theLeishmania-host interaction. We strongly encourage contributions from domain experts for the completion ofLeishmaniainfection pathways.
Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer
Authors: El-Kenawi Asmaa , Dominguez-Viqueira William , Liu Min , Awasthi Shivanshu , Keske Aysenur , Steiner KayLee K. , Noel Leenil , Dhillon Jasreman , Gillies Robert J. , Yamoah Kosj , Yu Xiaoqing , Koomen John , Gatenby Robert A. , Ruffell Brian
Published: March 2021

Tumor-associated macrophages are key immune cells associated with cancer progression. Here we sought to determine the role of macrophages in castration-resistant prostate cancer (CRPC) using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of CRPC tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. Since cholesterol is the precursor of the five major classes of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localizationin vitroandin vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cellsin vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC.
Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer
Authors: Becker Winston R. , Nevins Stephanie A. , Chen Derek C. , Chiu Roxanne , Horning Aaron , Laquindanum Rozelle , Mills Meredith , Chaib Hassan , Ladabaum Uri , Longacre Teri , Shen Jeanne , Esplin Edward D. , Kundaje Anshul , Ford James M. , Curtis Christina , Snyder Michael P. , Greenleaf William J.
Published: March 2021

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated 451,886 single-cell chromatin accessibility profiles and 208,557 single-cell transcriptomes from 48 polyps, 27 normal tissues, and 6 CRCs collected from patients with and without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from normal to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T-cells, and a subtype of FOX-regulated pre-cancer associated fibroblasts. In the cancerous state, we observe T-cell exhaustion, RUNX1-regulated cancer associated fibroblasts, and increasing accessibility associated with HNF4A motifs in epithelia. Methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.
A stochastic oscillator model simulates the entrainment of vertebrate cellular clocks by light
Authors: Kumpošt Vojtěch , Vallone Daniela , Gondi Srinivas Babu , Foulkes Nicholas S. , Mikut Ralf , Hilbert Lennart
Published: March 2021

The circadian clock is a cellular mechanism that synchronizes various biological processes with respect to the time of the day. While much progress has been made characterizing the molecular mechanisms underlying this clock, it is less clear how external light cues influence the dynamics of the core clock mechanism and thereby entrain it with the light-dark cycle. Zebrafish-derived cell cultures possess clocks that are directly light-entrainable, thus providing an attractive laboratory model for circadian entrainment. Here, we have developed a stochastic oscillator model of the zebrafish circadian clock, which accounts for the core clock negative feedback loop, light input, and the proliferation of single-cell oscillator noise into population-level luminescence recordings. The model accurately predicts the entrainment dynamics observed in bioluminescent clock reporter assays upon exposure to a wide range of lighting conditions. Furthermore, we have applied the model to obtain refitted parameter sets for cell cultures exposed to a variety of pharmacological treatments and predict changes in single-cell oscillator parameters. Our work paves the way for model-based, large-scale screens for genetic or pharmacologically-induced modifications to the entrainment of circadian clock function.

Author summary

The circadian clock is a key, cell-autonomous timing mechanism that is encountered in most organisms. It is entrained by environmental lighting conditions and in turn temporally coordinates most aspects of physiology according to the time of day. Cell lines derived from zebrafish are attractive experimental models for studying how clocks are entrained by light since they possess clocks that respond directly to light stimuli. Here we describe a mathematical model for the behavior of the circadian clock in zebrafish cell lines during exposure to a range of lighting conditions. Using this model, we can determine how different pharmacological treatments may affect the entrainment dynamics of the clock and the degree of synchronization of individual cells’ circadian clocks in bioluminescent clock reporter assays. Our current model is mathematically simple and thus easy to apply and extend in future studies.
A computational probe into the behavioral and neural markers of atypical facial emotion processing in autism
Authors: Kar Kohitij
Published: March 2021

Despite ample behavioral evidence of atypical facial emotion processing in individuals with autism (IwA), the neural underpinnings of such behavioral heterogeneities remain unclear. Here, I have used brain-tissue mapped artificial neural network (ANN) models of primate vision to probe candidate neural and behavior markers of atypical facial emotion recognition in IwA at an image-by-image level. Interestingly, the ANNs’ image-level behavioral patterns better matched the neurotypical subjects’ behavior than those measured in IwA. This behavioral mismatch was most remarkable when the ANN behavior was decoded from units that correspond to the primate inferior temporal (IT) cortex. ANN-IT responses also explained a significant fraction of the image-level behavioral predictivity associated with neural activity in the human amygdala — strongly suggesting that the previously reported facial emotion intensity encodes in the human amygdala could be primarily driven by projections from the IT cortex. Furthermore, in silico experiments revealed how learning under noisy sensory representations could lead to atypical facial emotion processing that better matches the image-level behavior observed in IwA. In sum, these results identify primate IT activity as a candidate neural marker and demonstrate how ANN models of vision can be used to generate neural circuit-level hypotheses and guide future human and non-human primate studies in autism.
Fuzzy-Discernibility Matrix-based Efficient Feature Selection Techniques for Improved Motor-Imagery EEG Signal Classification
Authors: Chatterjee Rajdeep , Sanyal Debarshi Kumar , Chatterjee Ankita
Published: March 2021

Brain activities, calledbrain rhythms, are the micro-level electrical signals (that is, Electroencephalogram or EEG) generated in our brain while we are performing a task. Even when we imagine a limb movement, it generates the same EEG signals called motor-imagery. Motor-imagery based Brain-computer Interface (BCI) provides a non-muscular means to connect the human brain with limbs through computer-based interpretations. The main aim of this paper is to find a suitable feature-set and a classifier to efficiently classify EEG signals into distinct motor-imagery brain-states. We propose to use sliding temporal window-based approaches for feature extraction from EEG and a mix-bagging classifier which is essentially a bagging-based ensemble of multiple types of learners for motor imagery EEG classification. We observe that mix-bagging with overlapping sliding window-based feature extraction achieves an accuracy of 91.43% on the BCI Competition II Dataset III. To reduce the feature size further, we use a fuzzy discernibility matrix that selects the most discriminative features instead of all the features. This additional feature selection strategy improves the classification accuracy to 92.14% and sets a new state-of-the art result on this dataset.
An open-source and wearable system for measuring 3D human motion in real-time
Authors: Slade Patrick , Habib Ayman , Hicks Jennifer L. , Delp Scott L.
Published: March 2021

Analyzing human motion is essential for diagnosing movement disorders and guiding rehabilitation interventions for conditions such as osteoarthritis, stroke, and Parkinson’s disease. Optical motion capture systems are the current standard for estimating kinematics but require expensive equipment located in a predefined space. While wearable sensor systems can estimate kinematics in any environment, existing systems are generally less accurate than optical motion capture. Further, many wearable sensor systems require a computer in close proximity and rely on proprietary software, making it difficult for researchers to reproduce experimental findings. Here, we present OpenSenseRT, an open-source and wearable system that estimates upper and lower extremity kinematics in real time by using inertial measurement units and a portable microcontroller. We compared the OpenSenseRT system to optical motion capture and found an average RMSE of 4.4 degrees across 5 lower-limb joint angles during three minutes of walking (n= 5) and an average RMSE of 5.6 degrees across 8 upper extremity joint angles during a Fugl-Meyer task (n= 5). The open-source software and hardware are scalable, tracking between 1 and 14 body segments, with one sensor per segment. Kinematics are estimated in real-time using a musculoskeletal model and inverse kinematics solver. The computation frequency, depends on the number of tracked segments, but is sufficient for real-time measurement for many tasks of interest; for example, the system can track up to 7 segments at 30 Hz in real-time. The system uses off-the-shelf parts costing approximately $100 USD plus $20 for each tracked segment. The OpenSenseRT system is accurate, low-cost, and simple to replicate, enabling movement analysis in labs, clinics, homes, and free-living settings.
Transthyretin promotes axon growth via regulation of microtubule dynamics and tubulin acetylation
Authors: Eira Jessica , Magalhães Joana , Macedo Nídia , Pero Maria Elena , Misgeld Thomas , Sousa Mónica M , Bartolini Francesca , Liz Márcia A
Published: March 2021

Transthyretin (TTR), a plasma and cerebrospinal fluid protein, increases axon growth and organelle transport in sensory neurons. These TTR functions were suggested to underlie its activity in promoting nerve regeneration. While neurons extend their axons, the microtubule (MT) cytoskeleton is crucial for the segregation of functional compartments and axonal outgrowth. Herein, we investigated the hypothesis that TTR promotes axon elongation and regeneration by modulating MT dynamics. Indeed, we found that TTR KO mice have an intrinsic increase in dynamic MTs and reduced levels of acetylated α-tubulin in uninjured peripheral axons, and fail to modulate microtubule dynamics in response to sciatic nerve injury. Importantly, restoring acetylated α-tubulin levels of TTR KO DRG neurons using an HDAC6 inhibitor was sufficient to completely revert defective MT dynamics and neurite outgrowth. In summary, our results revealed a new role for TTR in the modulation of MT dynamics by regulating α-tubulin acetylation and support that this activity underlies TTR neuritogenic function.
Analysing and simulating energy-based models in biology using BondGraphTools
Authors: Cudmore Peter , Pan Michael , Gawthrop Peter J. , Crampin Edmund J.
Published: March 2021

Like all physical systems, biological systems are constrained by the laws of physics. However, mathematical models of biochemistry frequently neglect the conservation of energy, leading to unrealistic behaviour. Energy-based models that are consistent with conservation of mass, charge and energy have the potential to aid the understanding of complex interactions between biological components, and are becoming easier to develop with recent advances in experimental measurements and databases. In this paper, we motivate the use of bond graphs (a modelling tool from engineering) for energy-based modelling and introduce,BondGraphTools, a Python library for constructing and analysing bond graph models. We use examples from biochemistry to illustrate howBondGraphToolscan be used to automate model construction in systems biology while maintaining consistency with the laws of physics.
Modular Dynamic Biomolecular Modelling with Bond Graphs: The Unification of Stoichiometry, Thermodynamics, Kinetics and Data
Authors: Gawthrop Peter J. , Pan Michael , Crampin Edmund J.
Published: March 2021

Renewed interest in dynamic simulation models of biomolecular systems has arisen from advances in genome-wide measurement and applications of such models in biotechnology and synthetic biology. In particular, genome-scale models of cellular metabolism beyond the steady state are required in order to represent transient and dynamic regulatory properties of the system. Development of such whole-cell models requires new modelling approaches. Here we propose the energy-based bond graph methodology, which integrates stoichiometric models with thermo-dynamic principles and kinetic modelling. We demonstrate how the bond graph approach intrinsically enforces thermodynamic constraints, provides a modular approach to modelling, and gives a basis for estimation of model parameters leading to dynamic models of biomolecular systems. The approach is illustrated using a well-established stoichiometric model ofEscherichia coli(E. coli) and published experimental data.
Directed differentiation of hPSCs through lateral plate mesoderm for generation of articular cartilage progenitors
Authors: Smith Christopher A , Humphreys Paul A , Naven Mark A , Mancini Fabrizio E , Kimber Susan J
Published: March 2021

Developmentally the articular joints are derived from lateral plate (LP) mesoderm. However, no study has produced LP derived prechondrocytes or preosteoblasts from human pluripotent stem cells (hPSC) in a chemically defined manner. Differentiation of hPSCs through the authentic route, via an LP-osteochondral progenitor (OCP), may aid understanding of human cartilage development and the generation of effective cell therapies for osteoarthritis. We refined our existing chondrogenic protocol, incorporating knowledge from development and other studies to produce a LP-OCP from which prechondrocytes- and preosteoblast-like cells can be produced. Results show the formation of an OCP, which can be further driven to prechondrocytes and preosteoblasts. Prechondrocytes cultured in pellets produced cartilage like matrix with lacunae and superficial flattened cells expressing lubricin. Additionally, preosteoblasts were able to generate a mineralised structure. This protocol can therefore be used to further investigate cartilage development and in the development of joint cartilage for potential treatments.
The Arabidopsis F-box protein FBW2 degrades AGO1 to avoid spurious loading of illegitimate small RNA
Authors: Hacquard Thibaut , Clavel Marion , Baldrich Patricia , Lechner Esther , Pérez-Salamó Imma , Schepetilnikov Mikhail , Derrien Benoît , Dubois Marieke , Hammann Philippe , Kuhn Lauriane , Brun Danaé , Bouteiller Nathalie , Vaucheret Hervé , Meyers Blake C. , Genschik Pascal
Published: March 2021

RNA silencing is a conserved mechanism in eukaryotes and is involved in development, heterochromatin maintenance and defense against viruses. In plants, ARGONAUTE1 (AGO1) protein plays a central role in both microRNA (miRNA) and small interfering RNA (siRNA)-directed silencing and its expression is regulated at multiple levels. Here, we report that the F-box protein FBW2 targets proteolysis of AGO1 by a CDC48-mediated mechanism. We found that FBW2 assembles an SCF complex that recognizes the MID-PIWI domain of AGO1 and requires its C-terminal domain containing a GW motif for AGO1 turnover. We showed that FBW2 prefers the unloaded and some mutated forms of AGO1 protein. WhileFBW2loss of function does not lead to strong growth or developmental defects, it significantly increases RNA silencing activity. Interestingly, under conditions in which small RNA production or accumulation is affected, the failure to degrade AGO1 infbw2mutants becomes more deleterious for the plant. Hence, the non-degradable AGO1 protein assembles high molecular weight complexes and binds illegitimate small RNA leading to the cleavage of new target genes that belong to stress responses and cellular metabolic processes. Therefore, the control of AGO1 homeostasis by ubiquitin ligases plays an important role in quality control to avoid off-target cleavage.
Phosphorylation-dependent mitotic SUMOylation drives nuclear envelope-chromatin interactions
Authors: Ptak Christopher , Saik Natasha O. , Premashankar Ashwini , Lapetina Diego L. , Aitchison John D. , Montpetit Ben , Wozniak Richard W.
Published: March 2021

In eukaryotes, chromatin binding to the inner nuclear membrane (INM) and nuclear pore complexes (NPCs) contributes to spatial organization of the genome and epigenetic programs important for gene expression. In mitosis, chromatin-nuclear envelope (NE) interactions are lost and then formed again as sister chromosomes segregate to post-mitotic nuclei. Investigating these processes inS. cerevisiae, we identified temporally and spatially controlled phosphorylation-dependent SUMOylation events that positively regulate post-metaphase chromatin association with the NE. Our work establishes a phosphorylation-mediated targeting mechanism of the SUMO ligase Siz2 to the INM during anaphase, where Siz2 binds to and SUMOylates the VAP protein Scs2. The recruitment of Siz2 through Scs2 is further responsible for a wave of SUMOylation along the INM that supports the assembly and anchorage of subtelomeric chromatin at the INM and localization of an active gene (INO1) to NPCs during the later stages of mitosis and into G1-phase.