bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative comparison of geological data and model simulations constrains early Cambrian geography and climate
Authors: Wong Hearing Thomas W. , Pohl Alexandre , Williams Mark , Donnadieu Yannick , Harvey Thomas H. P. , Scotese Christopher R. , Sepulchre Pierre , Franc Alain , Vandenbroucke Thijs R. A.
Published: June 2021

Marine ecosystems with a diverse range of animal groups became established during the early Cambrian (~541 to ~509 Ma). However, Earth’s environmental parameters and palaeogeography in this interval of major macro-evolutionary change remain poorly constrained. Here, we test contrasting hypotheses of continental configuration and climate that have profound implications for interpreting Cambrian environmental proxies. We integrate general circulation models and geological observations to test three variants of the ‘Antarctocentric’ paradigm, with a southern polar continent, and an ‘equatorial’ configuration that lacks polar continents. This quantitative framework can be applied to other deep-time intervals when environmental proxy data are scarce. Our results show that the Antarctocentric palaeogeographic paradigm can reconcile geological data and simulated Cambrian climate. Our analyses indicate a greenhouse climate during the Cambrian animal radiation, with mean annual sea-surface temperatures between ~9 °C to ~19 °C and ~30 °C to ~38 °C for polar and tropical palaeolatitudes, respectively.
Reconstruction of plant–pollinator networks from observational data
Authors: Young Jean-Gabriel , Valdovinos Fernanda S. , Newman M. E. J.
Published: June 2021

Empirical measurements of ecological networks such as food webs and mutualistic networks are often rich in structure but also noisy and error-prone, particularly for rare species for which observations are sparse. Focusing on the case of plant–pollinator networks, we here describe a Bayesian statistical technique that allows us to make accurate estimates of network structure and ecological metrics from such noisy observational data. Our method yields not only estimates of these quantities, but also estimates of their statistical errors, paving the way for principled statistical analyses of ecological variables and outcomes. We demonstrate the use of the method with an application to previously published data on plant–pollinator networks in the Seychelles archipelago and Kosciusko National Park, calculating estimates of network structure, network nestedness, and other characteristics.
Human cytomegalovirus-induced host protein citrullination is crucial for viral replication
Authors: Griffante Gloria , Gugliesi Francesca , Pasquero Selina , Dell’Oste Valentina , Biolatti Matteo , Salinger Ari J. , Mondal Santanu , Thompson Paul R. , Weerapana Eranthie , Lebbink Robert J. , Soppe Jasper A. , Stamminger Thomas , Girault Virginie , Pichlmair Andreas , Oroszlán Gábor , Coen Donald M. , De Andrea Marco , Landolfo Santo
Published: June 2021

Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation is implicated in the pathogenesis of various types of cancers and autoimmune diseases. Consistent with the ability of human cytomegalovirus (HCMV) to induce post-translational modifications of cellular proteins to gain a survival advantage, we show that HCMV infection of primary human fibroblasts triggers PAD-mediated citrullination of several host proteins, and that this activity promotes viral fitness. Citrullinome analysis reveals significant changes in deimination levels of both cellular and viral proteins, with interferon (IFN)-inducible protein IFIT1 being among the most heavily deiminated one. As genetic depletion of IFIT1 strongly enhances HCMV growth, and in vitro IFIT1 citrullination impairs its ability to bind to 5’-ppp-RNA, we propose that viral-induced IFIT1 citrullination is a mechanism of HCMV evasion from host antiviral resistance. Overall, our findings point to a crucial role of citrullination in subverting cellular responses to viral infection.
Single-component near-infrared optogenetic systems for gene transcription regulation
Authors: Kaberniuk Andrii A. , Baloban Mikhail , Monakhov Mikhail V. , Shcherbakova Daria M. , Verkhusha Vladislav V.
Published: June 2021

Near-infrared (NIR) optogenetic systems for transcription regulation are in high demand because NIR light exhibits low phototoxicity, low scattering, and allows combining with probes of visible range. However, available NIR optogenetic systems consist of several protein components of large size and multidomain structure. Here, we engineer single-component NIR systems consisting of evolved photosensory core module of Idiomarina sp. bacterial phytochrome, named iLight, which are smaller and packable in adeno-associated virus. We characterize iLight in vitro and in gene transcription repression in bacterial and gene transcription activation in mammalian cells. Bacterial iLight system shows 115-fold repression of protein production. Comparing to multi-component NIR systems, mammalian iLight system exhibits higher activation of 65-fold in cells and faster 6-fold activation in deep tissues of mice. Neurons transduced with viral-encoded iLight system exhibit 50-fold induction of fluorescent reporter. NIR light-induced neuronal expression of green-light-activatable CheRiff channelrhodopsin causes 20-fold increase of photocurrent and demonstrates efficient spectral multiplexing.
Single-cell transcriptomic analysis reveals disparate effector differentiation pathways in human Treg compartment
Authors: Luo Yuechen , Xu Changlu , Wang Bing , Niu Qing , Su Xiuhua , Bai Yingnan , Zhu Shuxian , Zhao Chunxiao , Sun Yunyan , Wang Jiali , Liu Maolan , Sun Xiaolei , Song Ge , Cui Haidong , Chen Xiaoli , Huang Huifang , Wang Haikun , Han Mingzhe , Jiang Erlie , Shi Lihong , Feng Xiaoming
Published: June 2021

Human FOXP3+ regulatory T (Treg) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate Treg cells into naïve, activated, and effector stages, and resolve the HLA-DRhi, LIMS1hi, highly suppressive FOXP3hi, and highly proliferative MKI67hi effector subsets. Trajectory analysis assembles Treg subsets into two differentiation paths (I/II) with distinctive phenotypic and functional programs, ending with the FOXP3hi and MKI67hi subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3hi and MKI67hi subsets and two differentiation pathways are conserved in transplanted patients, despite having functional and migratory impairments under aGVHD. These findings expand the understanding of Treg cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of Treg complexity in health and disease.
Pleistocene sediment DNA reveals hominin and faunal turnovers at Denisova Cave
Authors: Zavala Elena I. , Jacobs Zenobia , Vernot Benjamin , Shunkov Michael V. , Kozlikin Maxim B. , Derevianko Anatoly P. , Essel Elena , de Fillipo Cesare , Nagel Sarah , Richter Julia , Romagné Frédéric , Schmidt Anna , Li Bo , O’Gorman Kieran , Slon Viviane , Kelso Janet , Pääbo Svante , Roberts Richard G. , Meyer Matthias
Published: June 2021

Denisova Cave in southern Siberia is the type locality of the Denisovans, an archaic hominin group who were related to Neanderthals1–4. The dozen hominin remains recovered from the deposits also include Neanderthals5,6 and the child of a Neanderthal and a Denisovan7, which suggests that Denisova Cave was a contact zone between these archaic hominins. However, uncertainties persist about the order in which these groups appeared at the site, the timing and environmental context of hominin occupation, and the association of particular hominin groups with archaeological assemblages5,8–11. Here we report the analysis of DNA from 728 sediment samples that were collected in a grid-like manner from layers dating to the Pleistocene epoch. We retrieved ancient faunal and hominin mitochondrial (mt)DNA from 685 and 175 samples, respectively. The earliest evidence for hominin mtDNA is of Denisovans, and is associated with early Middle Palaeolithic stone tools that were deposited approximately 250,000 to 170,000 years ago; Neanderthal mtDNA first appears towards the end of this period. We detect a turnover in the mtDNA of Denisovans that coincides with changes in the composition of faunal mtDNA, and evidence that Denisovans and Neanderthals occupied the site repeatedly—possibly until, or after, the onset of the Initial Upper Palaeolithic at least 45,000 years ago, when modern human mtDNA is first recorded in the sediments.
Protective efficacy of Ad26.COV2.S against SARS-CoV-2 B.1.351 in macaques
Authors: Yu Jingyou , Tostanoski Lisa H. , Mercado Noe B. , McMahan Katherine , Liu Jinyan , Jacob-Dolan Catherine , Chandrashekar Abishek , Atyeo Caroline , Martinez David R. , Anioke Tochi , Bondzie Esther A. , Chang Aiquan , Gardner Sarah , Giffin Victoria M. , Hope David L. , Nampanya Felix , Nkolola Joseph , Patel Shivani , Sanborn Owen , Sellers Daniel , Wan Huahua , Hayes Tammy , Bauer Katherine , Pessaint Laurent , Valentin Daniel , Flinchbaugh Zack , Brown Renita , Cook Anthony , Bueno-Wilkerson Deandre , Teow Elyse , Andersen Hanne , Lewis Mark G. , Martinot Amanda J. , Baric Ralph S. , Alter Galit , Wegmann Frank , Zahn Roland , Schuitemaker Hanneke , Barouch Dan H.
Published: June 2021

The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines1,2. The Ad26.COV2.S vaccine expresses a stabilized spike protein from the WA1/2020 strain of SARS-CoV-2, and has recently demonstrated protective efficacy against symptomatic COVID-19 in humans in several geographical regions—including in South Africa, where 95% of sequenced viruses in cases of COVID-19 were the B.1.351 variant3. Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared to WA1/2020, but elicited comparable CD8 and CD4 T cell responses against the WA1/2020, B.1.351, B.1.1.7, P.1 and CAL.20C variants. B.1.351 infection of control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated macaques after B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern.
The COUGHVID crowdsourcing dataset, a corpus for the study of large-scale cough analysis algorithms
Authors: Orlandic Lara , Teijeiro Tomas , Atienza David
Published: June 2021

Cough audio signal classification has been successfully used to diagnose a variety of respiratory conditions, and there has been significant interest in leveraging Machine Learning (ML) to provide widespread COVID-19 screening. The COUGHVID dataset provides over 25,000 crowdsourced cough recordings representing a wide range of participant ages, genders, geographic locations, and COVID-19 statuses. First, we contribute our open-sourced cough detection algorithm to the research community to assist in data robustness assessment. Second, four experienced physicians labeled more than 2,800 recordings to diagnose medical abnormalities present in the coughs, thereby contributing one of the largest expert-labeled cough datasets in existence that can be used for a plethora of cough audio classification tasks. Finally, we ensured that coughs labeled as symptomatic and COVID-19 originate from countries with high infection rates. As a result, the COUGHVID dataset contributes a wealth of cough recordings for training ML models to address the world’s most urgent health crises.
Genome assembly using quantum and quantum-inspired annealing
Authors: Boev A. S. , Rakitko A. S. , Usmanov S. R. , Kobzeva A. N. , Popov I. V. , Ilinsky V. V. , Kiktenko E. O. , Fedorov A. K.
Published: June 2021

Recent advances in DNA sequencing open prospects to make whole-genome analysis rapid and reliable, which is promising for various applications including personalized medicine. However, existing techniques for de novo genome assembly, which is used for the analysis of genomic rearrangements, chromosome phasing, and reconstructing genomes without a reference, require solving tasks of high computational complexity. Here we demonstrate a method for solving genome assembly tasks with the use of quantum and quantum-inspired optimization techniques. Within this method, we present experimental results on genome assembly using quantum annealers both for simulated data and the $$\phi $$
ϕ
X 174 bacteriophage. Our results pave a way for an increase in the efficiency of solving bioinformatics problems with the use of quantum computing and, in particular, quantum annealing. We expect that the new generation of quantum annealing devices would outperform existing techniques for de novo genome assembly. To the best of our knowledge, this is the first experimental study of de novo genome assembly problems both for real and synthetic data on quantum annealing devices and quantum-inspired techniques.
Enhancement and analysis of Anthracene degradation by Tween 80 in LMS-HOBt
Authors: Yang Zuoyi , Mao Xingchen , Cui Jiahao , Wang Yujie , Zhang Yaping
Published: June 2021

This study examines the specific effect of Tween 80 on the conversion of anthracene (ANT) in laccase medium system regarding surfactant chemical changes and mechanism. The conversion rate and degradation products of ANT were investigated in different concentrations of Tween 80 solution. Between Tween 80 concentration 0–40 critical micelle concentrations (CMC), the kinetic parameter-k (h−1) and corresponding half-life T1/2 decreased with increasing concentration. When Tween 80 was above 20 CMC the laccase-medium system converted > 95% of ANT to anthraquinone within 12 h. During the entire enzymatic reaction, the laccase activity in the system increased with increasing Tween 80 concentration. Combined with GC/MS analysis of the product, it was speculated that hydrogens belonging to the ether-oxygen bond and carbon–carbon double bond α-CH of Tween 80, were removed by the laccase-media system, promoting its degradation. Additionally, enhanced activity caused by oxygen free radicals (ROS) such as RO• and ROO•, continuously oxidized Tween 80, which in turn produced free radicals while converting ANT. This study provides new theoretical support toward the application of surfactants in the elimination of polycyclic aromatic hydrocarbons.
A novel computer-aided diagnostic system for accurate detection and grading of liver tumors
Authors: Alksas Ahmed , Shehata Mohamed , Saleh Gehad A. , Shaffie Ahmed , Soliman Ahmed , Ghazal Mohammed , Khelifi Adel , Khalifeh Hadil Abu , Razek Ahmed Abdel , Giridharan Guruprasad A. , El-Baz Ayman
Published: June 2021

Liver cancer is a major cause of morbidity and mortality in the world. The primary goals of this manuscript are the identification of novel imaging markers (morphological, functional, and anatomical/textural), and development of a computer-aided diagnostic (CAD) system to accurately detect and grade liver tumors non-invasively. A total of 95 patients with liver tumors (M = 65, F = 30, age range = 34–82 years) were enrolled in the study after consents were obtained. 38 patients had benign tumors (LR1 = 19 and LR2 = 19), 19 patients had intermediate tumors (LR3), and 38 patients had hepatocellular carcinoma (HCC) malignant tumors (LR4 = 19 and LR5 = 19). A multi-phase contrast-enhanced magnetic resonance imaging (CE-MRI) was collected to extract the imaging markers. A comprehensive CAD system was developed, which includes the following main steps: i) estimation of morphological markers using a new parametric spherical harmonic model, ii) estimation of textural markers using a novel rotation invariant gray-level co-occurrence matrix (GLCM) and gray-level run-length matrix (GLRLM) models, and iii) calculation of the functional markers by estimating the wash-in/wash-out slopes, which enable quantification of the enhancement characteristics across different CE-MR phases. These markers were subsequently processed using a two-stages random forest-based classifier to classify the liver tumor as benign, intermediate, or malignant and determine the corresponding grade (LR1, LR2, LR3, LR4, or LR5). The overall CAD system using all the identified imaging markers achieved a sensitivity of 91.8%±0.9%, specificity of 91.2%±1.9%, and F$$_{1}$$

1

score of 0.91±0.01, using the leave-one-subject-out (LOSO) cross-validation approach. Importantly, the CAD system achieved overall accuracies of $$88\%\pm 5\%$$

88
%
±
5
%

, 85%±2%, 78%±3%, 83%±4%, and 79%±3% in grading liver tumors into LR1, LR2, LR3, LR4, and LR5, respectively. In addition to LOSO, the developed CAD system was tested using randomly stratified 10-fold and 5-fold cross-validation approaches. Alternative classification algorithms, including support vector machine, naive Bayes classifier, k-nearest neighbors, and linear discriminant analysis all produced inferior results compared to the proposed two stage random forest classification model. These experiments demonstrate the feasibility of the proposed CAD system as a novel tool to objectively assess liver tumors based on the new comprehensive imaging markers. The identified imaging markers and CAD system can be used as a non-invasive diagnostic tool for early and accurate detection and grading of liver cancer.
An optimality principle for locomotor central pattern generators
Authors: Ryu Hansol X. , Kuo Arthur D.
Published: June 2021

Two types of neural circuits contribute to legged locomotion:central pattern generators(CPGs) that produce rhythmic motor commands (even in the absence of feedback, termed “fictive locomotion”), andreflex circuitsdriven by sensory feedback. Each circuit alone serves a clear purpose, and the two together are understood to cooperate during normal locomotion. The difficulty is in explaining their relative balance objectively within a control model, as there are infinite combinations that could produce the same nominal motor pattern. Here we propose that optimization in the presence of uncertainty can explain how the circuits should best be combined for locomotion. The key is to re-interpret the CPG in the context of state estimator-based control: an internal model of the limbs that predicts their state, using sensory feedback to optimally balance competing effects of environmental and sensory uncertainties. We demonstrate use of optimally predicted state to drive a simple model of bipedal, dynamic walking, which thus yields minimal energetic cost of transport and best stability. The internal model may be implemented with neural circuitry compatible with classic CPG models, except with neural parameters determined by optimal estimation principles. Fictive locomotion also emerges, but as a side effect of estimator dynamics rather than an explicit internal rhythm. Uncertainty could be key to shaping CPG behavior and governing optimal use of feedback.
A new microfluidic method enabling the generation of multi-layered tissues-on-chips using skin cells as a proof of concept
Authors: Valencia L. , Canalejas-Tejero V. , Clemente M. , Fernaud I. , Holgado M. , Jorcano J. L. , Velasco D.
Published: June 2021

Microfluidic-based tissues-on-chips (TOCs) have thus far been restricted to modelling simple epithelia as a single cell layer, but likely due to technical difficulties, no TOCs have been reported to include both an epithelial and a stromal component despite the biological importance of the stroma for the structure and function of human tissues. We present, for the first time, a novel approach to generate 3D multilayer tissue models in microfluidic platforms. As a proof of concept, we modelled skin, including a dermal and an epidermal compartment. To accomplish this, we developed a parallel flow method enabling the deposition of bilayer tissue in the upper chamber, which was subsequently maintained under dynamic nutrient flow conditions through the lower chamber, mimicking the function of a blood vessel. We also designed and built an inexpensive, easy-to-implement, versatile, and robust vinyl-based device that overcomes some of the drawbacks present in PDMS-based chips. Preliminary tests indicate that this biochip will allow the development and maintenance of multilayer tissues, which opens the possibility of better modelling of the complex cell–cell and cell–matrix interactions that exist in and between the epithelium and mesenchyme, allowing for better-grounded tissue modelling and drug screening.
Acute and persistent symptoms in non-hospitalized PCR-confirmed COVID-19 patients
Authors: Bliddal Sofie , Banasik Karina , Pedersen Ole Birger , Nissen Janna , Cantwell Lisa , Schwinn Michael , Tulstrup Morten , Westergaard David , Ullum Henrik , Brunak Søren , Tommerup Niels , Feenstra Bjarke , Geller Frank , Ostrowski Sisse Rye , Grønbæk Kirsten , Nielsen Claus Henrik , Nielsen Susanne Dam , Feldt-Rasmussen Ulla
Published: June 2021

Reports of persistent symptoms after hospitalization with COVID-19 have raised concern of a “long COVID” syndrome. This study aimed at determining the prevalence of and risk factors for acute and persistent symptoms in non-hospitalized patients with polymerase chain reaction (PCR) confirmed COVID-19. We conducted a cohort study of non-hospitalized participants identified via the Danish Civil Registration System with a SARS-CoV-2-positive PCR-test and available biobank samples. Participants received a digital questionnaire on demographics and COVID-19-related symptoms. Persistent symptoms: symptoms > 4 weeks (in sensitivity analyses > 12 weeks). We included 445 participants, of whom 34% were asymptomatic. Most common acute symptoms were fatigue, headache, and sneezing, while fatigue and reduced smell and taste were most severe. Persistent symptoms, most commonly fatigue and memory and concentration difficulties, were reported by 36% of 198 symptomatic participants with follow-up > 4 weeks. Risk factors for persistent symptoms included female sex (women 44% vs. men 24%, odds ratio 2.7, 95% CI 1.4–5.1, p = 0.003) and BMI (odds ratio 1.1, 95% CI 1.0–1.2, p = 0.001). In conclusion, among non-hospitalized PCR-confirmed COVID-19 patients one third were asymptomatic while one third of symptomatic participants had persistent symptoms illustrating the heterogeneity of disease presentation. These findings should be considered in health care planning and policy making related to COVID-19.
CVD 103-HgR live, attenuated cholera vaccine strain viability in drinking waters from the US and Europe
Authors: Duffin R. Paul , Delbuono Michael , Nishioka Kylie , Shabram Paul , Patel Amish A.
Published: June 2021

CVD 103-HgR live, attenuated oral cholera vaccine strain is indicated for single dose immunization against Vibrio cholerae, the causative agent for cholera. The vaccine packets containing buffer powder and lyophilized CVD 103-HgR are reconstituted in water and consumed. Studies were performed to explore the viability of CVD 103-HgR in drinking waters from common sources. CVD 103-HgR vaccine was reconstituted in bottled and tap waters from the United States and Europe, and viability was measured via colony forming units assay. Chemical analysis of select water samples was used to identify chemicals that have a negative effect on CVD 103-HgR viability. CVD 103-HgR titers were stable in all bottled waters tested, including purified bottled water, bottled spring water, and sparkling waters. However, tap water from certain cities in the US and Europe affected viability and are not compatible with vaccine. Water chemistry revealed that these tap waters contained copper, likely leached from copper plumbing. These studies give high confidence in the stability of CVD 103-HgR reconstituted in a variety of bottled waters. Waters containing copper, including tap water, should not be used to reconstitute CVD 103-HgR strain oral vaccine due to the common use of copper plumbing.
Worldwide antipsychotic drug search intensities: pharmacoepidemological estimations based on Google Trends data
Authors: Ågren Richard
Published: June 2021

Prescription patterns of antipsychotic drugs (APDs) are typically sourced from country-specific data. In this study, a digital pharmacoepidemiological approach was used to investigate APD preferences globally. Publicly available data on worldwide web search intensities in Google for 19 typical and 22 atypical APDs were temporally and spatially normalized and correlated with reported prescription data. The results demonstrated an increasing global preference for atypical over typical APDs since 2007, with quetiapine, olanzapine, risperidone, and aripiprazole showing the largest search intensities in 2020. Cross-sectional analysis of 122 countries in 2020 showed pronounced differences in atypical/typical APD preferences that correlated with gross domestic product per capita. In conclusion, the investigation provides temporal and spatial assessments of global APD preferences and shows a trend towards atypical APDs, although with a relative preference for typical APDs in low-income countries. Similar data-sourcing methodologies allow for prospective studies of other prescription drugs.
Impaired auditory discrimination and auditory-motor integration in hyperfunctional voice disorders
Authors: Abur Defne , Subaciute Austeja , Kapsner-Smith Mara , Segina Roxanne K. , Tracy Lauren F. , Noordzij J. Pieter , Stepp Cara E.
Published: June 2021

Hyperfunctional voice disorders (HVDs) are the most common class of voice disorders, consisting of diagnoses such as vocal fold nodules and muscle tension dysphonia. These speech production disorders result in effort, fatigue, pain, and even complete loss of voice. The mechanisms underlying HVDs are largely unknown. Here, the auditory-motor control of voice fundamental frequency (fo) was examined in 62 speakers with and 62 speakers without HVDs. Due to the high prevalence of HVDs in singers, and the known impacts of singing experience on auditory-motor function, groups were matched for singing experience. Speakers completed three tasks, yielding: (1) auditory discrimination of voice fo; (2) reflexive responses to sudden fo shifts; and (3) adaptive responses to sustained fo shifts. Compared to controls, and regardless of singing experience, individuals with HVDs showed: (1) worse auditory discrimination; (2) comparable reflexive responses; and (3) a greater frequency of atypical adaptive responses. Atypical adaptive responses were associated with poorer auditory discrimination, directly implicating auditory function in this motor disorder. These findings motivate a paradigm shift for understanding development and treatment of HVDs.
Validation of an adipose-liver human-on-a-chip model of NAFLD for preclinical therapeutic efficacy evaluation
Authors: Slaughter Victoria L. , Rumsey John W. , Boone Rachel , Malik Duaa , Cai Yunqing , Sriram Narasimhan Narasimhan , Long Christopher J. , McAleer Christopher W. , Lambert Stephen , Shuler Michael L. , Hickman J. J.
Published: June 2021

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and strongly correlates with the growing incidence of obesity and type II diabetes. We have developed a human-on-a-chip model composed of human hepatocytes and adipose tissue chambers capable of modeling the metabolic factors that contribute to liver disease development and progression, and evaluation of the therapeutic metformin. This model uses a serum-free, recirculating medium tailored to represent different human metabolic conditions over a 14-day period. The system validated the indirect influence of adipocyte physiology on hepatocytes that modeled important aspects of NAFLD progression, including insulin resistant biomarkers, differential adipokine signaling in different media and increased TNF-α-induced steatosis observed only in the two-tissue model. This model provides a simple but unique platform to evaluate aspects of an individual factor’s contribution to NAFLD development and mechanisms as well as evaluate preclinical drug efficacy and reassess human dosing regimens.
Asymmetric physiological response of a reef-building coral to pulsed versus continuous addition of inorganic nutrients
Authors: van der Zande Rene M. , Mulders Yannick R. , Bender-Champ Dorothea , Hoegh-Guldberg Ove , Dove Sophie
Published: June 2021

Coral reefs, especially those located near-shore, are increasingly exposed to anthropogenic, eutrophic conditions that are often chronic. Yet, corals under unperturbed conditions may frequently receive natural and usually temporary nutrient supplementation through biological sources such as fishes. We compared physiological parameters indicative of long- and short-term coral health (day and night calcification, fragment surface area, productivity, energy reserves, and tissue stoichiometry) under continuous and temporary nutrient enrichment. The symbiotic coralAcropora intermediawas grown for 7 weeks under continuously elevated (press) levels of ammonium (14 µmol L−1) and phosphate (10 µmol L−1) as separate and combined treatments, to discern the individual and interactive nutrient effects. Another treatment exposedA. intermediatwice-daily to an ammonium and phosphatepulseof the same concentrations as thepresstreatments to simulate natural biotic supplementation.Pressexposure to elevated ammonium or phosphate produced mixed effects on physiological responses, with little interaction between the nutrients in the combined treatment. Overall, corals underpressexposure transitioned resources away from calcification. However, exposure to nutrientpulsesoften enhanced physiological responses. Our findings indicate that while continuous nutrient enrichment may pose a threat to coral health, episodic nutrient pulses that resemble natural nutrient supplementation may significantly benefit coral health and physiology.
Serum protein triplet TGF-β1, TIMP-1, and YKL-40 serve as diagnostic and prognostic profile for astrocytoma
Authors: Urbanavičiūtė Rūta , Zabitaitė Rūta , Kriščiukaitis Algimantas , Deltuva Vytenis-Pranas , Skiriutė Daina
Published: June 2021

Astrocytoma is the most common glial tumour of the CNS. The most malignant form is grade IV Astrocytoma, also called Glioblastoma. Due to its heterogeneity, aggressiveness and lethal nature scientists are trying to find less invasive methods for early prediction of tumour onset, recurrence, response to therapy and patients’ survival. Here, applying decision tree classification algorithm we performed astrocytoma specific protein profile analysis on serum proteins TIMP-1, active and latent form of TGF-β1, IP-10, ANGPT-1, OPN, and YKL-40 using enzyme-linked immunosorbent detection assay (ELISA). Results have demonstrated that astrocytoma specific profile consisted of three proteins—active form of TGF-β1, TIMP-1 and YKL-40 and was able to correctly classify 78.0% (103/132) of sample and 83.3% (60/72) of astrocytoma sample. Calculating decision tree algorithm associated with astrocytoma patient survival, prediction model reached an accuracy of 83.3% (60/72). All together these results indicate that glioma detection and prediction from patient serum using glioma associated proteins and applying mathematical classification tools could be achieved, and applying more comprehensive research further could be implemented in clinic.
Association between Meniere’s disease and air pollution in South Korea
Authors: Lee Dong-Han , Han Jiyeon , Jang Myoung-jin , Suh Myung-Whan , Lee Jun Ho , Oh Seung Ha , Park Moo Kyun
Published: June 2021

Meniere’s disease is thought to be a disorder of the inner ear function, affected by genetic and environmental factors. Several recent studies have shown that air pollution could affect middle and inner ear diseases. The purpose of this study was to investigate the relationship between the Meniere’s disease occurrence and air pollution status in Korea. This study used a time-stratified case-crossover design. Hospital visit data by Meniere’s disease were collected from the Korea National Health Insurance Service-National Sample Cohort (NHIS-NSC) database. Daily air pollution data for sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), and particulate matter (PM10: ≤ 10 μm in diameter, and PM2.5: ≤ 2.5 μm in diameter) were collected from the National Ambient air quality Monitoring Information System (NAMIS) database. We used two-stage analysis to assess the association between degree of air pollution and the occurrence of Meniere’s disease. In the first stage, region-specific analysis was conducted to estimate the odds ratios (ORs) of Meniere’s disease risk associated with each air pollutant exposure by using conditional logistic regression for matched case–control sets in 16 regions. In the second stage, region-specific ORs from the first stage were combined and the pooled effect estimates were derived through fixed and random effect meta-analysis. Subgroup analysis was conducted for age, sex, seasonality, and urbanization of residence. In total, 29,646 (32.1% males and 67.9% females) Meniere’s disease cases were identified from Korea NHIS-NSC database between 2008 and 2015. Overall, SO2, NO2, CO, and PM10showed significant correlation with Meniere’s disease risk at immediate lags, and weaker correlation at delayed lags, whereas O3showed slightly negative correlation at the immediate lag (lag0) and PM2.5did not show strong correlation (SO2: 1.04 [95% confidence interval: 1.01, 1.06]; NO2: 1.08 [1.06, 1.11]; CO: 1.04 [1.02, 1.06]; O3: 0.96 [0.93, 0.99]: statistically significant ORs at lag0 are listed). These positive and negative associations between Meniere’s disease and each air pollutant were generally stronger in the age of 40–64, female, summer (June–August) season, and urban subgroups. Our results showed that hospital visits for Meniere’s disease were associated with the measured concentrations of ambient air pollutants SO2, NO2, CO, and PM10. Further studies are required to confirm these associations and find their mechanisms.
Experimental evidence that apologies promote forgiveness by communicating relationship value
Authors: Forster Daniel E. , Billingsley Joseph , Burnette Jeni L. , Lieberman Debra , Ohtsubo Yohsuke , McCullough Michael E.
Published: June 2021

Robust evidence supports the importance of apologies for promoting forgiveness. Yet less is known about how apologies exert their effects. Here, we focus on their potential to promote forgiveness by way of increasing perceptions of relationship value. We used a method for directly testing these causal claims by manipulating both the independent variable and the proposed mediator. Namely, we use a 2 (Apology: yes vs. no) × 2 (Value: high vs. low) concurrent double-randomization design to test whether apologies cause forgiveness by affecting the same causal pathway as relationship value. In addition to supporting this causal claim, we also find that apologies had weaker effects on forgiveness when received from high-value transgressors, suggesting that the forgiveness-relevant information provided by apologies is redundant with relationship value. Taken together, these findings from a rigorous methodological paradigm help us parse out how apologies promote relationship repair.
MULTICOM2 open-source protein structure prediction system powered by deep learning and distance prediction
Authors: Wu Tianqi , Liu Jian , Guo Zhiye , Hou Jie , Cheng Jianlin
Published: June 2021

Protein structure prediction is an important problem in bioinformatics and has been studied for decades. However, there are still few open-source comprehensive protein structure prediction packages publicly available in the field. In this paper, we present our latest open-source protein tertiary structure prediction system—MULTICOM2, an integration of template-based modeling (TBM) and template-free modeling (FM) methods. The template-based modeling uses sequence alignment tools with deep multiple sequence alignments to search for structural templates, which are much faster and more accurate than MULTICOM1. The template-free (ab initio or de novo) modeling uses the inter-residue distances predicted by DeepDist to reconstruct tertiary structure models without using any known structure as template. In the blind CASP14 experiment, the average TM-score of the models predicted by our server predictor based on the MULTICOM2 system is 0.720 for 58 TBM (regular) domains and 0.514 for 38 FM and FM/TBM (hard) domains, indicating that MULTICOM2 is capable of predicting good tertiary structures across the board. It can predict the correct fold for 76 CASP14 domains (95% regular domains and 55% hard domains) if only one prediction is made for a domain. The success rate is increased to 3% for both regular and hard domains if five predictions are made per domain. Moreover, the prediction accuracy of the pure template-free structure modeling method on both TBM and FM targets is very close to the combination of template-based and template-free modeling methods. This demonstrates that the distance-based template-free modeling method powered by deep learning can largely replace the traditional template-based modeling method even on TBM targets that TBM methods used to dominate and therefore provides a uniform structure modeling approach to any protein. Finally, on the 38 CASP14 FM and FM/TBM hard domains, MULTICOM2 server predictors (MULTICOM-HYBRID, MULTICOM-DEEP, MULTICOM-DIST) were ranked among the top 20 automated server predictors in the CASP14 experiment. After combining multiple predictors from the same research group as one entry, MULTICOM-HYBRID was ranked no. 5. The source code of MULTICOM2 is freely available at https://github.com/multicom-toolbox/multicom/tree/multicom_v2.0.
Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations
Authors: Dudas Balint , Toth Daniel , Perahia David , Nicot Arnaud B. , Balog Erika , Miteva Maria A.
Published: June 2021

Sulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control the capability of SULT to bind large substrates. We employed molecular dynamics (MD) simulations and the recently developed approach of MD with excited normal modes (MDeNM) to elucidate molecular mechanisms guiding the recognition of diverse substrates and inhibitors by SULT1A1. MDeNM allowed exploring an extended conformational space of PAPS-bound SULT1A1, which has not been achieved up to now by using classical MD. The generated ensembles combined with docking of 132 SULT1A1 ligands shed new light on substrate and inhibitor binding mechanisms. Unexpectedly, our simulations and analyses on binding of the substrates estradiol and fulvestrant demonstrated that large conformational changes of the PAPS-bound SULT1A1 could occur independently of the co-factor movements that could be sufficient to accommodate large substrates as fulvestrant. Such structural displacements detected by the MDeNM simulations in the presence of the co-factor suggest that a wider range of drugs could be recognized by PAPS-bound SULT1A1 and highlight the utility of including MDeNM in protein–ligand interactions studies where major rearrangements are expected.
Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals
Authors: Mahajan Swapnil , Kode Vasumathi , Bhojak Keshav , Karunakaran Coral , Lee Kayla , Manoharan Malini , Ramesh Athulya , HV Sudheendra , Srivastava Ankita , Sathian Rekha , Khan Tahira , Kumar Prasanna , Gupta Ravi , Chakraborty Papia , Chaudhuri Amitabha
Published: June 2021

The COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild, or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. In this study, we identified immunodominant CD8 T-cell epitopes in the spike antigen using a novel TCR-binding algorithm. The predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing CD4 and CD8 T-cell immunity to SARS-CoV-2 antigen. The T-cell reactivity to the predicted epitopes was higher than the Spike-S1 and S2 peptide pools in the unexposed donors. A key finding of our study is that pre-existing T-cell immunity to SARS-CoV-2 is contributed by TCRs that recognize common viral antigens such as Influenza and CMV, even though the viral epitopes lack sequence identity to the SARS-CoV-2 epitopes. This finding is in contrast to multiple published studies in which pre-existing T-cell immunity is suggested to arise from shared epitopes between SARS-CoV-2 and other common cold-causing coronaviruses. However, our findings suggest that SARS-CoV-2 reactive T-cells are likely to be present in many individuals because of prior exposure to flu and CMV viruses.
Dopaminergic signaling supports auditory social learning
Authors: Paraouty Nihaad , Rizzuto Catherine R. , Sanes Dan H.
Published: June 2021

Explicit rewards are commonly used to reinforce a behavior, a form of learning that engages the dopaminergic neuromodulatory system. In contrast, skill acquisition can display dramatic improvements from a social learning experience, even though the observer receives no explicit reward. Here, we test whether a dopaminergic signal contributes to social learning in naïve gerbils that are exposed to, and learn from, a skilled demonstrator performing an auditory discrimination task. Following five exposure sessions, naïve observer gerbils were allowed to practice the auditory task and their performance was assessed across days. We first tested the effect of an explicit food reward in the observer’s compartment that was yoked to the demonstrator’s performance during exposure sessions. Naïve observer gerbils with the yoked reward learned the discrimination task significantly faster, as compared to unrewarded observers. The effect of this explicit reward was abolished by administration of a D1/D5 dopamine receptor antagonist during the exposure sessions. Similarly, the D1/D5 antagonist reduced the rate of learning in unrewarded observers. To test whether a dopaminergic signal was sufficient to enhance social learning, we administered a D1/D5 receptor agonist during the exposure sessions in which no reward was present and found that the rate of learning occurred significantly faster. Finally, a quantitative analysis of vocalizations during the exposure sessions suggests one behavioral strategy that contributes to social learning. Together, these results are consistent with a dopamine-dependent reward signal during social learning.
Measurements of periodically perturbed dewetting force fields and their consequences on the symmetry of the resulting patterns
Authors: Roumpos Konstantinos , Fontaine Sarah , Pfohl Thomas , Prucker Oswald , Rühe Jürgen , Reiter Günter
Published: June 2021

We studied the origin of breaking the symmetry for moving circular contact lines of dewetting polymer films suspended on a periodic array of pillars. There, dewetting force fields driving polymer flow were perturbed by elastic micro-pillars arranged in a regular square pattern. Elastic restoring forces of deformed pillars locally balance driving capillary forces and broke the circular symmetry of expanding dewetting holes. The observed envelope of the dewetting holes reflected the symmetry of the underlying pattern, even at sizes much larger than the characteristic period of the pillar array, demonstrating that periodic perturbations in a driving force field can establish a well-defined pattern of lower symmetry. For the presented system, we succeeded in squaring the circle.
Role of supersaturated Al-C phases in mechanical properties of Al/fullerene composites
Authors: Nam Seungjin , Lee Sooun , Roh Aeran , Son Hansol , Kim Miso , Choi Hyunjoo
Published: June 2021

We investigated the reinforcing effect of supersaturated Al-C phases on the mechanical properties of Al/C60composites produced via powder metallurgy followed by thermal treatment. We controlled the fractions of C60-fullerenes, nano-scale carbides, and Al-C supersaturated phases in the Al/C60composites by adjusting the heat-treatment temperature and duration. Furthermore, we examined the contribution of each phase on the elastic and plastic behavior of the composites using scanning acoustic microscopy (SAM) and hardness measurements. After heat treatment, a supersaturated Al-C phase and an Al carbide were formed in the Al/C composites by decomposition of individually dispersed C60. This led to enhancement of the hardness and elastic modulus of the Al/C composites heat-treated at 450 and 500 °C, while these properties were reduced in the 650 °C heat-treated composite. Notably, the 500 °C heat-treated composites showed significantly high hardness and elastic modulus (approximately 250 Hv and 77.8 GPa, respectively) owing to the substantially large contribution of the supersaturated Al-C phases, which was theoretically calculated to be 851 GPa/vol% and 227 GPa/vol%, respectively. This is possibly because the well-dispersed C in the atomic scale changed the elastic bonding characteristics of the metallic bonds between the Al atoms.
Pair-correlation ansatz for the ground state of interacting bosons in an arbitrary one-dimensional potential
Authors: Kościk Przemysław , Kuroś Arkadiusz , Pieprzycki Adam , Sowiński Tomasz
Published: June 2021

We derive and describe a very accurate variational scheme for the ground state of the system of a few ultra-cold bosons confined in one-dimensional traps of arbitrary shapes. It is based on assumption that all inter-particle correlations have two-body nature. By construction, the proposed ansatz is exact in the noninteracting limit, exactly encodes boundary conditions forced by contact interactions, and gives full control on accuracy in the limit of infinite repulsions. We show its efficiency in a whole range of intermediate interactions for different external potentials. Our results manifest that for generic non-parabolic potentials mutual correlations forced by interactions cannot be captured by distance-dependent functions.