bluuebunny/crossref_metadata_2025 huggingface dataset:
Development, evaluation and validation of machine learning algorithms to detect atypical and asymptomatic presentations of Covid-19 in hospital practice
Authors: Baktash V , Hosack T , Rule R , Patel N , Kho J , Sekhar R , Mandal A K J , Missouris C G
Published: June 2021

Background

Diagnostic methods for Covid-19 have improved, both in speed and availability. Because of atypical and asymptomatic carriage of the virus and nosocomial spread within institutions, timely diagnosis remains a challenge. Machine learning models trained on blood test results have shown promise in identifying cases of Covid-19.

Aims

To train and validate a machine learning model capable of differentiating Covid-19 positive from negative patients using routine blood tests and assess the model’s accuracy against atypical and asymptomatic presentations.

Design and methods

We conducted a retrospective analysis of medical admissions to our institution during March and April 2020. Participants were categorized into Covid-19 positive or negative groups based on clinical, radiological features or nasopharyngeal swab. A machine learning model was trained on laboratory parameters and validated for accuracy, sensitivity and specificity and externally validated at an unconnected establishment.

Results

An Ensemble Bagged Tree model was trained on data collected from 405 patients (212 Covid-19 positive) producing an accuracy of 81.79% (95% confidence interval (CI) 77.53–85.55%), the sensitivity of 85.85% (CI 80.42–90.24%) and specificity of 76.65% (CI 69.49–82.84%). Accuracy was preserved for atypical and asymptomatic subgroups. Using an external data set for 226 patients (141 Covid-19 positive) accuracy of 76.82% (CI 70.87–82.08%), sensitivity of 78.38% (CI 70.87–84.72%) and specificity of 74.12% (CI 63.48–83.01%) was achieved.

Conclusion

A machine learning model using routine laboratory parameters can detect atypical and asymptomatic presentations of Covid-19 and might be an adjunct to existing screening measures.
Digital pitting scars are associated with a severe disease course and death in systemic sclerosis: a study from the EUSTAR cohort
Authors: Hughes Michael , Heal Calvin , Henes Jörg , Balbir-Gurman Alexandra , Distler Jörg H W , Airò Paolo , Müller-Ladner Ulf , Hunzelmann Nicolas , Kerzberg Eduardo , Rudnicka Lidia , Truchetet Marie-Elise , Stebbings Simon , Tanaka Yoshiya , Hoffman-Vold Anna Maria , Gabrielli Armando , Distler Oliver , Matucci-Cerinic Marco ,   the EUSTAR Collaborators, Ananieva Lidia P , de Vries-Bouwstra Jeska , Bruni Cosimo , Cantatore Francesco Paolo , Castellví Ivan , Cutolo Maurizio , Damjanov Nemanja , Farge-Bancel Dominique , Gheorghiu Ana Maria , Hachulla Eric , Hsu Vivien M , Iannone Florenzo , Ingegnoli Francesca , Ionescu Ruxandra , de la Peña Lefebvre Paloma García , Li Mengtao , Mohamed Walid Ahmed Abdel Atty , Montecucco Carlomaurizio , Mouthon Luc , Pellerito Raffaele , Randone Silvia Bellando , Riccieri Valeria , Riemekasten Gabriela , Siegert Elise , Spertini François , Smith Vanessa , Stamenkovic Bojana , Tikly Mohammed , Ullman Susanne , Vanthuyne Marie , Walker Ulrich
Published: June 2021

Objective

Digital pitting scars (DPS) are frequent, but little studied in SSc to date.

Methods

An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality.

Results

A total of 9671 patients were included with reported DPS at any time point (n = 4924) or ‘never’ DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud’s duration (both P ≤ 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P ≤ 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51–24.87), active digital ischaemia: 6.30 (5.34–7.42) and death: 1.86 (1.48–2.36).

Conclusion

DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy.
Molecular Detection and Quantification ofXanthomonas albilineansin Juice from Symptomless Sugarcane Stalks Using a Real-Time Quantitative PCR Assay
Authors: Shi Yang , Zhao Jian-Ying , Zhou Jing-Ru , Ntambo Mbuya Sylvain , Xu Peng-Yuan , Rott Philippe C. , Gao San-Ji
Published: June 2021

Leaf scald, a bacterial disease caused by Xanthomonas albilineans (Ashby) Dowson, is a major limiting factor for sugarcane production worldwide. Accurate identification and quantification of X. albilineans is a prerequisite for successful management of this disease. A sensitive and robust quantitative PCR (qPCR) assay was developed in this study for detection and quantification of X. albilineans using TaqMan probe and primers targeting a putative adenosine triphosphate–binding cassette (ABC) transporter gene (abc). The novel qPCR assay was highly specific to the 43 tested X. albilineans strains belonging to different pulsed-field gel electrophoresis groups. The detection thresholds were 100 copies/µl of plasmid DNA, 100 fg/µl of bacterial genomic DNA, and 100 CFU/ml of bacterial suspension prepared from pure culture. This qPCR assay was 100 times more sensitive than a conventional PCR assay. The pathogen was detected by qPCR in 75.1% (410/546) of symptomless stalk samples, whereas only 28.4% (155/546) of samples tested positive by conventional PCR. Based on qPCR data, population densities of X. albilineans in symptomless stalks of the same varieties differed between two sugarcane production areas in China, Beihai (Guangxi Province) and Zhanjiang (Guangdong Province), and no significant correlation between these populations was identified. Furthermore, no relationship was found between these populations of the pathogen in asymptomatic stalks and the resistance level of the sugarcane varieties to leaf scald. The newly developed qPCR assay proved to be highly sensitive and reliable for the detection and quantification of X. albilineans in sugarcane stalks.
Point-of-Care Ultrasound for the Evaluation of Neck Masses in the Pediatric Emergency Department
Authors: Stem Christopher T. , Marin Jennifer R. , Perera AG Nuwan D. , Azhdam Devora B.
Published: June 2021

Point-of-care ultrasound can be an effective tool for pediatric emergency medicine providers in the evaluation of soft tissue lesions. We present a series of 4 pediatric patients with neck lesions in whom point-of-care ultrasound identified the type of lesion, guided decision-making on the need for computed tomography imaging, and led to definitive management.
The Risk of Postkidney Transplant Outcomes by Induction Choice Differs by Recipient Age
Authors: Ahn JiYoon B. , Bae Sunjae , Chu Nadia M. , Wang Lingyu , Kim Jongyeon , Schnitzler Mark , Hess Gregory P. , Lentine Krista L. , Segev Dorry L. , McAdams-DeMarco Mara A.
Published: June 2021

Background.

Among adult kidney transplant (KT) recipients, the risk of post-KT adverse outcomes differs by type of induction immunosuppression. Immune response to induction differs as recipients age; yet, choice of induction is barely tailored by age likely due to a lack of evidence of the risks and benefits.

Methods.

Using Scientific Registry of Transplant Recipients data, we identified 39336 first-time KT recipients (2010–2016). We estimated the length of stay (LOS), acute rejection (AR), graft failure, and death by induction type using logistic and Cox regression weighted by propensity score to adjust for confounders. We tested whether these estimates differed by age (65+ versus 18–64 y) using a Wald test.

Results.

Overall, rabbit antithymocyte globulin (rATG) was associated with a decreased risk of AR (odds ratio = 0.79, 95% confidence interval [CI], 0.72-0.85) compared with basiliximab. The effect of induction on LOS and death (interaction P = 0.03 and 0.003) differed by recipient age. Discharge was on average 11% shorter in rATG among younger recipients (relative time = 0.89; 95% confidence interval [CI], 0.81-0.99) but not among older recipients (relative time = 1.01; 95% CI, 0.95-1.08). rATG was not associated with mortality among older (hazard ratio = 1.05; 95% CI, 0.96-1.15), but among younger recipients (hazard ratio = 0.87; 95% CI, 0.80-0.95), it was associated with reduced mortality risk.

Conclusions.

rATG should be considered to prevent AR, especially among recipients with high-immunologic risk regardless of age; however, choice of induction should be tailored to reduce LOS and risk of mortality, particularly among younger recipients.
Nurse-facilitated reflective exercise post patient death in the ICU: a best practice implementation project
Authors: VanHorn Erica K. , Worobel-Luk Pamela , Tanner Ben , Jang Hannah
Published: June 2021

Introduction:

ICUs are stressful environments where patient care is complex and demanding; death is not an unusual outcome. Nurses can become emotionally distressed from experiencing multiple, unexpected, or traumatic patient deaths. Performing a reflective exercise immediately post death is one coping strategy which encourages healthcare staff and family to debrief their feelings in a timelier manner.

Objectives:

The aim of this project was to educate the nurses in the ICU with emotional coping skills pertaining to the effects of patient deaths. The objective was to implement a nurse-guided reflective exercise following each patient death in three adult ICUs in a quaternary academic medical center.

Methods:

The current change project used the Joanna Briggs Institute's Getting Research into Practice and Practical Application of Clinical Evidence Systems for auditing and strategy development. After standardizing the reflective exercise procedure, teaching methods were employed to support implementation. One follow-up audit measured compliance with completing a reflective exercise for all deaths occurring in the three ICUs. Contextual data were collected for completed exercises including type of death and words to describe nurses’ emotions.

Results:

The reflective exercise script was revised and the standard procedure posted to the intranet for easy access. All ICU nurses received education on the use of this reflective exercise. For each of the two ICUs where this practice was new, compliance with nurses initiating and completing a reflective exercise was at a rate of 17 and 2%, respectively. For the ICU where reflective exercise was reintroduced, compliance was 30%. All deaths included in this study were anticipated (e.g., patient on comfort care) and calm, with the exception of one post cardiac arrest death.

Conclusion:

Despite multipronged teaching for why, when, and how to use reflective exercise, there was minimal success in completing reflective exercises in the two units where the practice was new. This outcome was most likely due to higher than anticipated levels of needed support or the unpredictability of frequency of deaths on each unit. However, the main achievement was having the Minute of Silence procedure with a standardized script readily available at all times for nursing staff. Reimplementation success in the other ICU was attributed to more recently established reflective practices. Further exploration of barriers, such as type of death, and re-education are essential strategies to bolster and sustain practice and to provide support for our nursing staff to prevent emotional distress.
A tale of caution: prolonged Bacillus clausii bacteraemia after probiotic use in an immunocompetent child
Authors: Khatri Akshay M. , Rai Shipra , Shank Caroline , McInerney Alissa , Kaplan Blanka , Hagmann Stefan H. F. , Kainth Mundeep K.
Published: June 2021

Introduction.

Bacillus clausii

as a probiotic supplement is increasingly used in both adult and paediatric patient populations. There is limited awareness about potential adverse effects.

Case presentation. We report a case of prolonged (111 days)

B. clausii

bacteraemia after brief probiotic use in a 17-month-old immunocompetent child, without a definite focus of infection and in the absence of predisposing risk factors or underlying co-morbidities. We identified seven probiotic use-associated cases of prolonged

B. clausii

bacteraemia (mean duration [range] 64 days [14–93 days] where data were available) in the literature, all with underlying co-morbidities.

Conclusion.

B. clausii

probiotic preparations may cause prolonged bacteraemia, rendering patients with underlying co-morbidities as well as those with unrecognized risk factors vulnerable for significant infectious complications.
The Clinical Utility of Serial Procalcitonin and Procalcitonin Clearance in Predicting the Outcome of COVID-19 Patients
Authors: Taha Sara I. , Shata Aalaa K. , Baioumy Shereen A. , Fouad Shaimaa H. , Moussa Aya H. , Youssef Mariam K.
Published: June 2021

Background

The pandemic of coronavirus disease 2019 (COVID-19) represents a significant threat to global health. Sensitive tests that effectively predict the disease outcome are essentially required to guide proper intervention.

Objectives

To evaluate the predictive ability of serial procalcitonin (PCT) measurement to predict the outcome of COVID-19 patients, using PCT clearance (PCT-c) as a tool to reflect its dynamic changes.

Methods

A prospective observational study of inpatients diagnosed with COVID-19 at the Quarantine Hospitals of Ain-Shams University, Cairo, Egypt. During the first five days of hospitalization, serial PCT and PCT-c values were obtained and compared between survivors and non-survivors. Patients were followed up to hospital discharge or in-hospital mortality.

Results

Compared to survivors, serial PCT levels of non-survivors were significantly higher (p ≤ 0.001) and progressively increased during follow-up. In contrast, PCT-c values were significantly lower (p < 0.01) and progressively decreased. Receiver operating characteristic (ROC) curve analysis showed that using the initial PCT value alone, at a cut-off value of 0.80 ng/ml, the area under the curve for predicting in-hospital mortality was 0.81 with 61.1% sensitivity and 87.3% accuracy. Serial measurements showed better predictive performance, and the combined prediction value was better than the single prediction by the initial PCT alone.

Conclusions

Serial PCT measurement could be a helpful laboratory tool to predict the prognosis and outcome of COVID-19 patients. Moreover, PCT-c could be a reliable tool to assess PCT progressive kinetics.
A Unified Model for Entrainment by Circadian Clocks: Dynamic Circadian Integrated Response Characteristic (dCiRC)
Authors: An Zheming , Piccoli Benedetto , Merrow Martha , Lee Kwangwon
Published: June 2021

Circadian rhythm is a ubiquitous phenomenon, and it is observed in all biological kingdoms. In nature, their primary characteristic or phenotype is the phase of entrainment. There are two main hypotheses related to how circadian clocks entrain, parametric and non-parametric models. The parametric model focuses on the gradual changes of the clock parameters in response to the changing ambient condition, whereas the non-parametric model focuses on the instantaneous change of the phase of the clock in response to the zeitgeber. There are ample empirical data supporting both models. However, only recently has a unifying model been proposed, the circadian integrated response characteristic (CiRC). In the current study, we developed a system of ordinary differential equations, dynamic CiRC (dCiRC), that describes parameters of circadian rhythms and predicts the phase of entrainment in zeitgeber cycles. dCiRC mathematically extracts the underlying information of velocity changes of the internal clock that reflects the parametric model and the phase shift trajectory that reflects the non-parametric model from phase data under entraining conditions. As a proof of concept, we measured clock parameters of 26 Neurospora crassa ecotypes in both cycling and constant conditions using dCiRC. Our data showed that the morning light shortens the period of the clock while the afternoon light lengthens it. We also found that individual ecotypes have different strategies of integrating light effects to accomplish the optimal phase of entrainment, a model feature that is consistent with our knowledge of how circadian clocks are organized and encoded. The unified model dCiRC will provide new insights into how circadian clocks function under different zeitgeber conditions. We suggest that this type of model may be useful in the advent of chronotherapies.
Analysis of conditional colocalization relationships and hierarchies in three-color microscopy images
Authors: Vega-Lugo Jesus , da Rocha-Azevedo Bruno , Dasgupta Aparajita , Touret Nicolas , Jaqaman Khuloud
Published: June 2021

Colocalization analysis of multicolor microscopy images is a cornerstone approach in cell biology. It provides information on the localization of molecules within various subcellular compartments and allows the interrogation of molecular interactions in their cellular context. However, almost all colocalization analyses are designed for two-color images. This limits their applicability and the type of information that they reveal, leading to underutilization of multicolor microscopy images. Here we describe an approach, termed “conditional colocalization analysis,” for analyzing the colocalization relationships between three molecular entities in three-color microscopy images. Going beyond the question of whether colocalization is present or not, it addresses the question of whether the colocalization between two entities is influenced, positively or negatively, by their colocalization with a third entity. We showcase two applications of conditional colocalization analysis, one addressing the question of compartmentalization of molecular interactions, and one investigating the hierarchy of molecular interactions in a multimolecular complex. The software for conditional colocalization analysis is available at https://github.com/kjaqaman/conditionalColoc.
Emergent Statistical Laws in Single-Cell Transcriptomic Data
Authors: Lazzardi Silvia , Valle Filippo , Mazzolini Andrea , Scialdone Antonio , Caselle Michele , Osella Matteo
Published: June 2021

Large scale data on single-cell gene expression have the potential to unravel the specific transcriptional programs of different cell types. The structure of these expression datasets suggests a similarity with several other complex systems that can be analogously described through the statistics of their basic building blocks. Transcriptomes of single cells are collections of messenger RNA abundances transcribed from a common set of genes just as books are different collections of words from a shared vocabulary, genomes of different species are specific compositions of genes belonging to evolutionary families, and ecological niches can be described by their species abundances. Following this analogy, we identify several emergent statistical laws in single-cell transcriptomic data closely similar to regularities found in linguistics, ecology or genomics. A simple mathematical framework can be used to analyze the relations between different laws and the possible mechanisms behind their ubiquity. Importantly, treatable statistical models can be useful tools in transcriptomics to disentangle the actual biological variability from general statistical effects present in most component systems and from the consequences of the sampling process inherent to the experimental technique.

Author summary

Gene expression profiles represent how different cells use their genetic information. Similarly, books are specific collections of words chosen from a shared vocabulary, and many complex systems can be ultimately described by the statistics of their basic components. Leveraging on this analogy, we identified several emergent statistical laws in single-cell transcriptomic data that are universally found in complex component systems. A simple mathematical description sets these laws in a treatable quantitative framework and represents a useful tool for dissecting the different sources of gene expression variability.
Evolution of Drosophila buzzatii wings: Modular genetic organization, sex-biased integrative selection and intralocus sexual conflict
Authors: Iglesias PP , Machado FA , Llanes S , Hasson E , Soto EM
Published: June 2021

The Drosophila wing is a structure shared by males and females with the main function of flight. However, in males, wings are also used to produce songs, or visual displays during courtship. Thus, observed changes in wing phenotype depend on the interaction between sex-specific selective pressures and the genetic and ontogenetic restrictions imposed by a common genetic architecture. Here, we investigate these issues by studying how the wing has evolved in twelve populations of Drosophila buzzatii raised in common-garden conditions and using an isofemale line design. The between-population divergence shows that sexual dimorphism is greater when sex evolves in different directions. Multivariate Qst-Fst analyses confirm that male wing shape is the target for multiple selective pressures, leading males’ wings to diverge more than females’ wings. While the wing blade and the wing base appear to be valid modules at the genetic (G matrix) and among-population (D matrix) levels, the reconstruction of between-population adaptive landscapes (Ω matrix) shows selection as an integrative force. Also, cross-sex covariances reduced the predicted response to selection in the direction of the extant sexual dimorphism, suggesting that selection had to be intensified in order to circumvent the limitations imposed by G. However, such intensity of selection was not able to break the modularity pattern of the wing. The results obtained here show that the evolution of D. buzzatii wing shape is the product of a complex interplay between ontogenetic constraints and conflicting sexual and natural selections.
Parallel shifts of visual sensitivity and body colouration in replicate populations of extremophile fish
Authors: Owens Gregory L. , Veen Thor , Moxley Dylan R. , Arias-Rodriguez Lenin , Tobler Michael , Rennison Diana J.
Published: June 2021

Visual sensitivity and body pigmentation are often shaped by both natural selection from the environment and sexual selection from mate choice. One way of quantifying the impact of the environment is by measuring how traits have changed after colonization of a novel habitat. To do this, we studiedPoecilia mexicanapopulations that have repeatedly adapted to extreme sulphidic (H2S containing) environments. We measured visual sensitivity using opsin gene expression, as well as body pigmentation and water transmission for populations in four independent drainages. Both visual sensitivity and body pigmentation showed significant parallel shifts towards greater medium wavelength sensitivity and reflectance in sulphidic populations. The light spectrum was only subtly different between environments and overall, we found no significant correlations between the light environment and visual sensitivity or body pigmentation. Altogether we found that sulphidic habitats select for differences in visual sensitivity and pigmentation; our data suggest that this effect is unlikely to be driven purely by the water’s spectral properties and may instead be from other correlated ecological changes.
Enhancing the interoperability of glycan data flow between ChEBI, PubChem, and GlyGen.
Authors: Navelkar Rahi , Owen Gareth , Mutherkrishnan Venkatesh , Thiessen Paul , Bolton Evan , Cheng Tiejun , Edwards Nathan , Tiemeyer Michael , Campbell Matthew , Martin Maria , Vora Jeet , Kahsay Robel , Mazumder Raja
Published: June 2021

Glycans play a vital role in health, disease, bioenergy, biomaterials, and bio-therapeutics. As a result, there is keen interest to identify and increase glycan data in bioinformatics databases like ChEBI and PubChem, and connecting them to resources at the EMBL-EBI and NCBI to facilitate access to important annotations at a global level. GlyTouCan is a comprehensive archival database that contains glycans obtained primarily through batch upload from glycan repositories, glycoprotein databases, and individual laboratories. In many instances, the glycan structures deposited in GlyTouCan may not be fully defined or have supporting experimental evidence and citations. Databases like ChEBI and PubChem were designed to accommodate complete atomistic structures with well-defined chemical linkages. As a result, they cannot easily accommodate the structural ambiguity inherent in glycan databases. Consequently, there is a need to improve the organization of glycan data coherently to enhance connectivity across the major NCBI, EMBL-EBI, and glycoscience databases.

This paper outlines a workflow developed in collaboration between GlyGen, ChEBI, and PubChem to improve the visibility and connectivity of glycan data across these resources. GlyGen hosts a subset of glycans (~29,000) from the GlyTouCan database and has submitted valuable glycan annotations to the PubChem database and integrated over 10,500 (including ambiguously defined) glycans into the ChEBI database. The integrated glycans were prioritized based on links to PubChem and connectivity to glycoprotein data. The pipeline provides a blueprint for how glycan data can be harmonized between different resources. The current PubChem, ChEBI, and GlyTouCan mappings can be downloaded from GlyGen (https://data.glygen.org).
Satelight: Self-Attention-Based Model for Epileptic Spike Detection from Multi-Electrode EEG
Authors: Fukumori Kosuke , Yoshida Noboru , Sugano Hidenori , Nakajima Madoka , Tanaka Toshihisa
Published: June 2021

Objective

Because of the lack of highly skilled experts, automated technologies that support electroencephalogram (EEG)-based in epilepsy diagnosis are advancing. Deep convolutional neural network-based models have been used successfully for detecting epileptic spikes, one of the biomarkers, from EEG. However, a sizeable number of supervised EEG records are required for training.

Approach

This study introduces the Satelight model, which uses the self-attention (SA) mechanism. The model was trained using a clinical EEG dataset labeled by five specialists, including 16,008 epileptic spikes and 15,478 artifacts from 50 children. The SA mechanism is expected to reduce the number of parameters and efficiently extract features from a small amount of EEG data. To validate the effectiveness, we compared various spike detection approaches with the clinical EEG data.

Main results

The experimental results showed that the proposed method detected epileptic spikes more effectively than other models (accuracy = 0.876 and false positive rate = 0.133).

Significance

The proposed model had only one-tenth the number of parameters as the other effective model, despite having such a high detection performance. Further exploration of the hidden parameters revealed that the model automatically attended to the EEG’s characteristic waveform locations of interest.
Automated compound testing in zebrafish xenografts identifies combined MCL-1 and BCL-XL inhibition to be effective against Ewing sarcoma
Authors: Grissenberger Sarah , Sturtzel Caterina , Wenninger-Weinzierl Andrea , Scheuringer Eva , Bierbaumer Lisa , Pascoal Susana , Tötzl Marcus , Tomazou Eleni , Delattre Olivier , Surdez Didier , Kovar Heinrich , Halbritter Florian , Distel Martin
Published: June 2021

Ewing sarcoma is a pediatric bone and soft tissue cancer for which new therapies to improve disease outcome and to reduce adverse effects of current standard treatments are urgently needed. To identify new and effective drugs, phenotypic drug screening has proven to be a powerful method and a cancer model ideally suited for this approach is the larval zebrafish xenograft system. Complementing mouse xenografts, zebrafish offer high-througput screening possibilities in an intact complex vertebrate organism. Here, we generated Ewing sarcoma xenografts in zebrafish larvae and established a workflow for automated imaging of xenografts, tumor cell recognition within transplanted zebrafish and quantitative tumor size analysis over consecutive days by high-content imaging. The increased throughput of our in vivo screening setup allowed us to identify combination therapies effective against Ewing sarcoma cells. Especially, combined inhibition of MCL-1 and BCL-XL, two anti-apoptotic proteins, was highly efficient at eradicating tumor cells in our zebrafish xenograft assays with two Ewing sarcoma cell lines and with patient-derived cells. Transcriptional analysis across Ewing sarcoma cell lines and tumors revealed that MCL-1 and BCL2L1, coding for BCL-XL, are the most abundantly expressed anti-apoptotic genes, suggesting that combined MCL-1/BCL-XL inhibition might be a broadly applicable strategy for Ewing sarcoma treatment.
SPEAR: a proteomics approach for simultaneous protein expression and redox analysis
Authors: Doron Shani , Lampl Nardy , Savidor Alon , Katina Corine , Gabashvili Alexandra , Levin Yishai , Rosenwasser Shilo
Published: June 2021

Oxidation and reduction of protein cysteinyl thiols serve as molecular switches, which is considered the most central mechanism for redox regulation of biological processes, altering protein structure, biochemical activity, subcellular localization, and binding affinity. Redox proteomics allows for the global identification of redox-modified cysteine (Cys) sites and quantification of their oxidation/reduction responses, serving as a hypothesis-generating platform to stimulate redox biology mechanistic research. Here, we developed Simultaneous Protein Expression and Redox (SPEAR) analysis, a new redox-proteomics approach based on differential labeling of oxidized and reduced cysteines with light and heavy isotopic forms of commercially available isotopically-labeled N-ethylmaleimide (NEM). The presented method does not require enrichment for labeled peptides, thus enabling simultaneous quantification of Cys oxidation state and protein abundance. Using SPEAR, we were able to quantify the in-vivo oxidation state of thousands of cysteines across theArabidopsisproteome under steady-state and oxidative stress conditions. Functional assignment of the identified redox-sensitive proteins demonstrated the widespread effect of oxidative conditions on various cellular functions and highlighted the enrichment of chloroplast-targeted proteins. SPEAR provides a simple, straightforward, and cost-effective means of studying redox proteome dynamics. The presented data provide a global quantitative view of cysteine oxidation of well-known redox-regulated active sites and many novel redox-sensitive sites whose role in plant acclimation to stress conditions remains to be further explored.
Inertia triggers nonergodicity of fractional Brownian motion
Authors: Cherstvy Andrey G. , Wang Wei , Metzler Ralf , Sokolov Igor M.
Published: June 2021

How related are the ergodic properties of the over- and underdamped Langevin equations driven by fractional Gaussian noise? We here find that for massive particles performing fractional Brownian motion (FBM) inertial effects not only destroy the stylized fact of the equivalence of the ensemble-averaged mean-squared displacement (MSD) to the time-averaged MSD (TAMSD) of overdamped or massless FBM, but also concurrently dramatically alter the values of the ergodicity breaking parameter (EB). Our theoretical results for the behavior of EB for underdamped ot massive FBM for varying particle mass m, Hurst exponent H, and trace length T are in excellent agreement with the findings of extensive stochastic computer simulations. The current results can be of interest for the experimental community employing various single-particle-tracking techniques and aiming at assessing the degree of nonergodicity for the recorded time series (studying e.g. the behavior of EB versus lag time). To infer FBM as a realizable model of anomalous diffusion for a set single-particle-tracking data when massive particles are being tracked, the EBs from the data should be compared to EBs of massive (rather than massless) FBM.
Glial AP1 promotes early TBI recovery but chronically drives tauopathy
Authors: Byrns China N. , Saikumar Janani , Bonini Nancy M.
Published: June 2021

The emergence of degenerative disease after traumatic brain injury is often described as an acceleration of normal age-related processes. Whether similar molecular processes occur in injury and in age is unclear. Here we identify a functionally dynamic and lasting transcriptional response in glia, mediated by the conserved transcription factor AP1. In the early post-TBI period, glial AP1 is essential for recovery, ensuring brain integrity and animal survival. In sharp contrast, chronic AP1 activation promotes human tau pathology, tissue loss, and mortality. We show a similar process activates in healthy brains with age. Importantly, AP1 activity is present in moderate human TBI, decades after injury, and associates with microglial activation and tauopathy. Our data provide key molecular insight into glia, highlighting that the same molecular process drives dynamic and contradictory glia behavior in TBI, first acting to protect but chronically promoting disease.
SARS-CoV-2 spike P681R mutation, a hallmark of the Delta variant, enhances viral fusogenicity and pathogenicity
Authors: Saito Akatsuki , Irie Takashi , Suzuki Rigel , Maemura Tadashi , Nasser Hesham , Uriu Keiya , Kosugi Yusuke , Shirakawa Kotaro , Sadamasu Kenji , Kimura Izumi , Ito Jumpei , Wu Jiaqi , Iwatsuki-Horimoto Kiyoko , Ito Mutsumi , Yamayoshi Seiya , Ozono Seiya , Butlertanaka Erika P , Tanaka Yuri L , Shimizu Ryo , Shimizu Kenta , Yoshimatsu Kumiko , Kawabata Ryoko , Sakaguchi Takemasa , Tokunaga Kenzo , Yoshida Isao , Asakura Hiroyuki , Nagashima Mami , Kazuma Yasuhiro , Nomura Ryosuke , Horisawa Yasuhito , Yoshimura Kazuhisa , Takaori-Kondo Akifumi , Imai Masaki ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Nakagawa So , Ikeda Terumasa , Fukuhara Takasuke , Kawaoka Yoshihiro , Sato Kei
Published: June 2021

During the current SARS-CoV-2 pandemic, a variety of mutations have been accumulated in the viral genome, and currently, four variants of concerns (VOCs) are considered as the hazardous SARS-CoV-2 variants to the human society1. The newly emerging VOC, the B.1.617.2/Delta variant, closely associates with a huge COVID-19 surge in India in Spring 20212. However, its virological property remains unclear. Here, we show that the B.1.617.2/Delta variant is highly fusogenic, and notably, more pathogenic than prototypic SARS-CoV-2 in infected hamsters. The P681R mutation in the spike protein, which is highly conserved in this lineage, facilitates the spike protein cleavage and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity than the parental virus. Our data suggest that the P681R mutation is a hallmark that characterizes the virological phenotype of the B.1.617.2/Delta variant and is closely associated with enhanced pathogenicity.
Insight into the ecology of vaginal bacteria through integrative analyses of metagenomic and metatranscriptomic data
Authors: France M. T. , Fu L. , Rutt L. , Yang H. , Humphrys M. , Narina S. , Gajer P. , Ma B. , Forney L. J. , Ravel J.
Published: June 2021

Vaginal bacterial communities dominated by Lactobacillus species are associated with a reduced risk to various adverse health outcomes. However, somewhat unexpectedly many healthy women have microbiota that are not dominated by lactobacilli. To determine the factors that drive vaginal community composition we characterized the genetic composition and transcriptional activities of vaginal microbiota in healthy women. We demonstrated that the abundance of a species is not always indicative of its transcriptional activity and that impending changes in community composition can be predicted from metatranscriptomic data. Functional comparisons highlight differences in the metabolic activities of these communities, notably in their degradation of host-produced mucin but not glycogen. Degradation of mucin by communities not dominated by Lactobacillus may play a role in their association with adverse health outcomes. Finally, we show that the transcriptional activities of L. crispatus, L. iners, and G. vaginalis vary with the taxonomic composition of the communities in which they reside. Notably, L. iners and G. vaginalis both demonstrated lower expression of their cholesterol-dependent cytolysins when co-resident with Lactobacillus spp. and higher expression when co-resident with other facultative and obligate anaerobes. The pathogenic potential of these species may depend on the communities in which they reside and thus could be modulated by interventional strategies. Our results provide insight to the functional ecology of vaginal microbiota and reveal strategies for management of these ecosystems.
A Dynamic Efficient Sensory Encoding Approach to Adaptive Tuning in Neural Models of Visual Motion Processing
Authors: Steinmetz Scott T. , Layton Oliver W. , Powell Nate V. , Fajen Brett R.
Published: June 2021

This paper introduces a self-tuning mechanism for capturing rapid adaptation to changing visual stimuli by a population of neurons. Building upon the principles of efficient sensory encoding, we show how neural tuning curve parameters can be continually updated to optimally encode a time-varying distribution of recently detected stimulus values. We implemented this mechanism in a neural model that produces human-like estimates of self-motion direction (i.e., heading) based on optic flow. The parameters of speed-sensitive units were dynamically tuned in accordance with efficient sensory encoding such that the network remained sensitive as the distribution of optic flow speeds varied. In two simulation experiments, we found that model performance with dynamic tuning yielded more accurate, shorter latency heading estimates compared to the model with static tuning. We conclude that dynamic efficient sensory encoding offers a plausible approach for capturing adaptation to varying visual environments in biological visual systems and neural models alike.
Pressure and curvature control of contact inhibition in epithelia growing under spherical confinement
Authors: Di Meglio Ilaria , Trushko Anastasiya , Guillamat Pau , Blanch-Mercader Carles , Roux Aurélien
Published: June 2021

Morphogenesis requires spatiotemporal regulation of cell shape and proliferation, both regulated by biochemical and mechanical cues. In epithelia, this regulation is called contact inhibition, but disentangling biochemical from mechanical cues remains challenging. Here, we show that epithelia growing under confinement accumulate pressure that inhibits proliferation above a threshold value, which depends on the β-catenin pathway. Before inhibition of proliferation, cell aspect ratio abruptly increased upon reaching confluency. This shape transition occurred at low, constant pressure and was mainly controlled by cell density and contractility, correlating with YAP/TAZ pathway inhibition. In our system, epithelia spontaneously buckle: we observed that folding transiently reactivates both the YAP/TAZ pathway and cell proliferation. Altogether, our results support that different mechanical cues part of contact inhibition regulate cell proliferation through different mechanosensing pathways. Proliferation is regulated by sustained, tissue-level pressure through the β-catenin pathway, and by local curvature and pressure changes through the YAP/TAZ pathway.
Mapping QTLs for phenotypic and morpho-physiological traits related to grain yield under late sown conditions conditions in wheat (Triticum aestivum L.)
Authors: Pankaj Yaswant Kumar , Pal Lalit , Nagarajan Ragupathi , Gill Kulvinder Singh , Kumar Vishnu , Sangwan Sonali , Panigrahi Sourav , Kumar Rajeev
Published: June 2021

The elevating temperature makes heat stress one of the major issues for wheat production globally. To elucidate genetic basis and map heat tolerance traits, a set of 166 doubled haploid lines (DHLs) derived from the cross between PBW3438/IC252874 was used. The population was evaluated under Normal sown (NS) and late sown (LS) conditions, by exposing to heat stress during rabi season. The canopy temperature (CT) showed positive correlations with grain yield, whereas Soil plant analysis development (SPAD) was not significantly correlated and associated with GY in both the normal and late sown conditions. Composite interval mapping (CIM) identified total 12 Quantitative trait loci (QTLs) viz., 2 (Normal sown), 10 (late sown) mapped on linkage groups 1A, 1D, 2B, 2D, 3B, 4D, 5B and 6D, during both the crop seasons 2017-18 and 2018-19. Combining the results of these QTLs revealed a major stable QTL for grain yield (GY) on chromosome 3B with 11.84% to 21.24% explaining phenotypic variance under both sowing conditions. QTL for CT and SPAD was detected on chromosome 1A while QTL for GY on chromosome 3B and 5B. The identified QTLs in the genomic regions could be targeted for genetic improvement and marker assisted selection for heat tolerance in wheat. The tools like SPAD and CT could be exploited to screen the large number of breeding lines.
Characterization of endogenous Rubus yellow net virus in raspberries
Authors: Ho Thien , Broome Janet C. , Buhler Jason P. , O’Donovan Wendy , Tian Tongyan , Diaz-Lara Alfredo , Martin Robert R. , Tzanetakis Ioannis E.
Published: June 2021

Rubus yellow net virus (RYNV) belongs to genus Badnavirus. Badnavirids are found in plants as endogenous, inactive sequences, and/or in episomal (infectious and active) forms. To assess the state of RYNV infections, we sequenced the genomes of various Rubus cultivars and mined eight additional published whole genome sequencing datasets. Sequence analysis revealed the presence of a diverse array of endogenous RYNV (endoRYNV) sequences that differ significantly in their structure; some lineages have nearly complete, yet non-functional genomes whereas others have rudimentary, small sequence fragments. We developed assays to genotype the six main endoRYNV lineages as well as the only known episomal lineage in commercial Rubus. This study discloses the widespread presence of endoRYNVs in commercial raspberries, likely because breeding programs have been using a limited pool of germplasm that harbored endoRYNVs.
Whole Genome Sequence and CAZyme distribution of the cellulase hyper producing filamentous fungus Penicillium janthinellum NCIM 1366
Authors: Christopher Meera , Sreeja-Raju Athiraraj , Kooloth-Valappil Prajeesh , Abraham Amith , Gokhale Digambar Vitthal , Sukumaran Rajeev K.
Published: June 2021

Penicillium janthinellum NCIM 1366, capable of secreting cellulases that are highly efficient in the hydrolysis of lignocellulosic biomass, was sequenced to understand its cellulolytic machinery. De novo sequencing and assembly revealed a 37.6 Mb genome encoding 11,848 putative proteins, 93% of which had significant BLAST-P hits. The majority of the top hits (those with over 60% UniProt identity) belonged to P. brasilianum. Carbohydrate active enzymes (CAZymes) and other enzymes involved in lignocellulose degradation were also predicted from this strain and compared with those of the industrial workhorse of cellulase production-Trichoderma reesei RUT-C30. The comparison showed that the fungus encodes a far higher number of CAZYmes (422) as compared to T. reesei RUT-C30 (244), which gives a plausible explanation for its overall effectiveness in biomass hydrolysis. An analysis of the secreted CAZymes and annotated ligninases identified 216 predicted proteins which may be directly involved in the breakdown of lignocellulose.
Metagenome-based comparisons of decay rates and host-specificity of fecal microbial communities for improved microbial source tracking
Authors: Suttner Brittany , Lindner Blake G. , Kim Minjae , Conrad Roth E. , Rodriguez Luis M. , Orellana Luis H. , Johnston Eric R. , Hatt Janet K. , Zhu Kevin J. , Brown Joe , Konstantinidis Konstantinos T.
Published: June 2021

Fecal material in the environment is a primary source of pathogens that cause waterborne diseases and affect over a billion people worldwide. Microbial source tracking (MST) assays based on single genes (e.g., 16S rRNA) do not always provide the resolution needed to attribute fecal contamination sources. In this work, we used dialysis bag mesocosms simulating a freshwater habitat that were spiked separately with cow, pig, or human feces to monitor the decay of host-specific fecal signals over time with metagenomics, traditional qPCR, and culture-based methods. Sequencing of the host fecal communities used as inocula recovered 79 non-redundant metagenome-assembled genomes (MAGs) whose abundance patterns showed that the majority of the fecal community signal was not detectable in the mesocosm metagenomes after four days. Several MAGs showed high host specificity, and thus are promising candidates for biomarkers for their respective host type. Traditional qPCR methods varied in their correlation with MAG decay kinetics. Notably, the human-specific Bacteroides assay, HF183/BFDRev, consistently under-estimated fecal pollution due to not being present in all hosts and/or primer mismatches. This work provides new insights on the persistence and decay kinetics of host-specific gut microbes in the environment and identifies several MAGs as putative biomarkers for improved MST.

SYNOPSIS

We track cow, pig, and human fecal pollution in lake water over time with metagenomics and benchmark these novel protocols against standard culture-based and qPCR tests for water quality monitoring.