bluuebunny/crossref_metadata_2025_split huggingface dataset:
An optimality principle for locomotor central pattern generators
Authors: Ryu Hansol X. , Kuo Arthur D. 
Published: June 2021

AbstractTwo 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

AbstractMicrofluidic-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

AbstractReports 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

AbstractCVD 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

AbstractPrescription 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

AbstractHyperfunctional 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

AbstractNonalcoholic 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

AbstractCoral 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

AbstractAstrocytoma 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

AbstractMeniere’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

AbstractRobust 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

AbstractProtein 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

AbstractSulfotransferases (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

AbstractThe 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.