bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Anatomy of Feeding Artery of the Submandibular Gland
Authors: Iwai Toshinori , Sugiyama Satomi , Minamiyama Shuhei , Oguri Senri , Mitsudo Kenji
Published: March 2022

The purpose of this study was to investigate the clinical anatomy of the feeding artery of the submandibular gland (SMG). A total of 199 SMG removals were performed in extraoral or intraoral approach with/without endoscopic assistance by a single surgeon. The feeding artery of the SMG was always identified intraoperatively and recorded in the operation record. The clinical anatomy of the feeding artery of the SMG was investigated based on the intraoperative findings. The facial artery was ligated and transected for the involvement of tumor or severe inflammation in 16 (8.0%) procedures. The feeding artery was investigated in the remaining 183 procedures. The mean number of the glandular branch was 1.5. There were 1 branch in 98 procedures (53.6%), 2 branches in 80 procedures (43.7%), and 3 branches in 5 procedures (2.7%). Detailed anatomical knowledge of the feeding artery of the SMG is useful for proper dissection of the SMG and preservation of the facial artery.
Adaptation of a Simulation Model and Checklist to Assess Pediatric Emergency Care Performance by Prehospital Teams
Authors: Boyle Tehnaz P. , Dugas Julianne N. , Liu James , Stapleton Stephanie N. , Medzon Ron , Walsh Barbara M. , Corey Pamela , Shubitowski Leonard , Horne John R. , O'Connell Richard , Williams Graham , Nelson Kerrie P. , Nadkarni Vinay M. , Camargo Carlos A. , Feldman James A.
Published: March 2022

Introduction

Simulation tools to assess prehospital team performance and identify patient safety events are lacking. We adapted a simulation model and checklist tool of individual paramedic performance to assess prehospital team performance and tested interrater reliability.

Methods

We used a modified Delphi process to adapt 3 simulation cases (cardiopulmonary arrest, seizure, asthma) and checklist to add remote physician direction, target infants, and evaluate teams of 2 paramedics and 1 physician. Team performance was assessed with a checklist of steps scored as complete/incomplete by raters using direct observation or video review. The composite performance score was the percentage of completed steps. Interrater percent agreement was compared with the original tool. The tool was modified, and raters trained in iterative rounds until composite performance scoring agreement was 0.80 or greater (scale <0.20 = poor; 0.21–0.39 = fair, 0.40–0.59 = moderate; 0.60–0.79 = good; 0.80–1.00 = very good).

Results

We achieved very good interrater agreement for scoring composite performance in 2 rounds using 6 prehospital teams and 4 raters. The original 175 step tool was modified to 171 steps. Interrater percent agreement for the final modified tool approximated the original tool for the composite checklist (0.80 vs. 0.85), cardiopulmonary arrest (0.82 vs. 0.86), and asthma cases (0.80 vs. 0.77) but was lower for the seizure case (0.76 vs. 0.91). Most checklist items (137/171, 80%) had good–very good agreement. Among 34 items with fair-moderate agreement, 15 (44%) related to patient assessment, 9 (26%) equipment use, 6 (18%) medication delivery, and 4 (12%) cardiopulmonary resuscitation quality.

Conclusions

The modified checklist has very good agreement for assessing composite prehospital team performance and can be used to test effects of patient safety interventions.
Genetic characterization of clonal complex sequence type 2057 (cc2057) serogroup B Neisseria meningitidis strains unique to Japan and identification of a capsular-switched serogroup Y isolate cc2057
Authors: Takahashi Hideyuki , Morita Masatomo , Kamiya Hajime , Nakamura-Miwa Haruna , Shimuta Ken , Ohnishi Makoto
Published: March 2022

Introduction. Only approximately 40 cases of invasive meningococcal diseases are reported annually in Japan, and the dominant strains are serogroup Y meningococci (MenY) followed by serogroup B meningococci (MenB). Within the last 10 years,

Neisseria meningitidis

strains belonging to clonal complex (cc)2057 have become dominant among Japanese MenB and have not been identified in countries other than Japan.

Hypothesis/Gap Statement. The uniqueness of cc2057

N. meningitidis

strains was considered to be epidemiologically of importance, and some genetic features could be hidden in the genome of cc2057 meningococci.

Method. We investigated 22 cc2057 MenB and one cc2057 MenY using whole genome sequencing (WGS) and also predicted the potential coverage of 4CMenB and bivalent rLP2086 vaccines in silico.

Results. cc2057

N. meningitidis

strains were phylogenetically assigned to two clades. Three hypothetical genes homologous to those in

Neisseria lactamica

and sequences related to a new CRISPR Cas9 system were found only in the genome of cc2057 strains. Moreover, one cc2057 MenY strain was presumed to be capsular-switched at the capsule synthesis (cps) locus. The potential coverage of 4CMenB and rLP2086 for cc2057 MenB strains was estimated to be very low.

Conclusion. To the best of our knowledge, this is the first study to provide genetic insights from epidemiologically unique

N. meningitidis

cc2057 strains isolated only in Japan, an island country.
Vaccine effectiveness and duration of protection against symptomatic and severe Covid-19 during the first year of vaccination in France
Authors: Castillo Milena Suarez , Khaoua Hamid , Courtejoie Noémie
Published: March 2022

Background

SARS-CoV-2 continues to spread despite fast vaccine rollout, which could be attributed to waning immunity or to a reduced protection against some variants. A thorough characterization of vaccine protection and its duration in time is needed to inform vaccination policies and enhance public trust.

Methods

We matched three national databases with exhaustive information on screening, vaccination and hospitalizations in France over the year 2021. We performed a two-step analysis to estimate vaccine effectiveness against severe forms of Covid-19 in people aged 50 years or over, combining: (i) a test-negative case–control design to assess vaccine effectiveness against symptomatic infections; and (ii) a survival analysis to assess the additional protection against severe outcomes (hospitalizations and inpatient deaths) in infected individuals.

Results

We found a high vaccine effectiveness in people aged 50 years or more, reaching 82% against symptomatic infections and 94% against severe outcomes, after a full vaccination scheme.

Vaccine effectiveness against symptomatic infections strongly decreased over time, dropping to 53% after six months, but remained high against severe forms (90% after six months). The booster dose allowed restoring high protection levels. Vaccine protection and its evolution in time, showed little difference against the variants that circulated prior to December 2021 in France, including the Delta variant.

Conclusion

Though vaccine immunity decreases over time, vaccination remains crucial to provide individual protection against severe diseases. This decline can be reversed by the injection of a booster dose.
Electronic Nicotine Delivery Systems (ENDS) use during a five-year period is not associated with self-reported chronic obstructive pulmonary disease (COPD) after adjustment of cigarette smoking history: A longitudinal analysis of PATH data
Authors: Cook Steven F. , Hirschtick Jana L. , Fleischer Nancy L. , Arenberg Douglas A. , Barnes Geoffrey D. , Levy David T. , Sanchez-Romero Luz Maria , Jeon Jihyoun , Meza Rafael
Published: March 2022

Background

Understanding the relationship between electronic nicotine delivery systems (ENDS) use and chronic obstructive pulmonary disease (COPD) and other respiratory conditions is critical. However, previous studies have not adequately controlled for history of cigarette smoking.

Research Question

To examine the prospective association between ENDS use and self-reported incident COPD after adjusting for cigarette smoking history.

Study Design and Methods

Using waves 1-5 of the US Population Assessment of Tobacco and Health (PATH) study, we examined the association between ENDS use and self-reported incident COPD among adults aged 40+ using discrete time survival models. Current ENDS use was measured as a time-varying covariate, lagged by one wave, defined as established daily or some days use. We controlled for baseline demographics (age, sex, race/ethnicity, education), health characteristics (asthma, obesity, exposure to second-hand smoke), and smoking history (smoking status and cigarette pack-years).

Results

Incident COPD was self-reported by 925 respondents during the five-year follow-up period. Prior to adjusting for other covariates, time-varying ENDS use appeared to nearly double the risk of incident COPD (HR 1.98, 95% CI 1.44-2.74). However, ENDS use was no longer significantly associated with COPD (aHR 1.10, 95% CI 0.78-1.57) after adjusting for current cigarette smoking and cigarette pack-years. The risk of self-reported incident COPD increased with cigarette pack-years and was higher for respondents who were older, female, less educated, and had baseline asthma or obesity.

Interpretation

ENDS use did not significantly increase the risk of self-reported incident COPD over a five-year period once current smoking status and cigarette pack-years were taken into account. Cigarette pack-years, on the other hand, remained associated with a net increase in the risk of self-reported incident COPD. These findings highlight the importance of using prospective longitudinal data and properly controlling for cigarette smoking history to assess the independent health effects of ENDS.
Pulsatile Gaussian-Enveloped Tones (GET) Vocoders for Cochlear-Implant Simulation
Authors: Meng Qinglin , Zhou Huali , Lu Thomas , Zeng Fan-Gang
Published: March 2022

Acoustic simulations of cochlear implants (CIs) allow for studies of perceptual performance with minimized effects of large CI individual variability. Different from conventional simulations using continuous sinusoidal or noise carriers, the present study employs pulsatile Gaussian-enveloped tones (GETs) to simulate several key features in modern CIs. Subject to the time-frequency uncertainty principle, the GET has a well-defined tradeoff between its duration and bandwidth. Two types of GET vocoders were implemented and evaluated in normal-hearing listeners. In the first implementation, constant 100-Hz GETs were used to minimize within-channel temporal overlap while different GET durations were used to simulate electric channel interaction. This GET vocoder could produce vowel and consonant recognition similar to actual CI performance. In the second implementation, 900-Hz/channel pulse trains were directly mapped to 900-Hz GET trains to simulate the maxima selection and amplitude compression of a widely-usedn-of-m processing strategy, or the Advanced Combination Encoder. The simulated and actual implant performance of speech-in-noise recognition was similar in terms of the overall trend, absolute mean scores, and standard deviations. The present results suggest that the pulsatile GET vocoders can be used as alternative vocoders to simultaneously simulate several key CI processing features and result in similar speech perception performance to that with modern CIs.
Genomic epidemiology offers high resolution estimates of serial intervals for COVID-19
Authors: Stockdale Jessica E. , Susvitasari Kurnia , Tupper Paul , Sobkowiak Benjamin , Mulberry Nicola , Gonçalves da Silva Anders , Watt Anne E. , Sherry Norelle , Minko Corinna , Howden Benjamin P. , Lane Courtney R. , Colijn Caroline
Published: March 2022

Estimating key aspects of transmission is crucial in infectious disease control. Serial intervals – the time between symptom onset in an infector and infectee – are fundamental, and help to define rates of transmission, estimates of reproductive numbers, and vaccination levels needed to prevent transmission. However, estimating the serial interval requires knowledge of individuals’ contacts and exposures (who infected whom), which is typically obtained through resource-intensive contact tracing efforts. We develop an alternate framework that uses virus sequences to inform who infected whom and thereby estimate serial intervals. The advantages are many-fold: virus sequences are often routinely collected to support epidemiological investigations and to monitor viral evolution. The genomic approach offers high resolution and cluster-specific estimates of the serial interval that are comparable with those obtained from contact tracing data. Our approach does not require contact tracing data, and can be used in large populations and over a range of time periods. We apply our techniques to SARS-CoV-2 sequence data from the first two waves of COVID-19 in Victoria, Australia. We find that serial interval estimates vary between clusters, supporting the need to monitor this key parameter and use updated estimates in onward applications. Compared to an early published serial interval estimate, using cluster-specific serial intervals can cause estimates of the effective reproduction number Rt to vary by a factor of up to 2–3. We also find that serial intervals estimated in settings such as schools and meat processing/packing plants tend to be shorter than those estimated in healthcare facilities.
Increased core body temperature exacerbates defective protein prenylation in mouse avatars of mevalonate kinase deficiency
Authors: Munoz Marcia A. , Skinner Oliver P. , Masle-Farquhar Etienne , Jurczyluk Julie , Xiao Ya , Fletcher Emma , Kristianto Esther , Hodson Mark P. , O’Donoghue Seán I. , Kaur Sandeep , Brink Robert , Zahra David , Deenick Elissa K. , Perry Kristen , Robertson Avril A.B. , Mehr Sam , Hissaria Pravin , Mulders-Manders Catharina M. , Simon Anna , Rogers Michael J.
Published: March 2022

Mevalonate kinase deficiency (MKD) is caused by biallelic loss-of-function mutations in MVK, leading to recurrent fevers and systemic inflammation. We describe new mouse avatars of MKD bearing p.Val377Ile (the commonest variant) or deletions in Mvk. Compound heterozygous mice recapitulated the biochemical phenotype of MKD, with build-up of unprenylated GTPases and increased plasma mevalonic acid. Mice with different deficiencies in mevalonate kinase revealed new insights into the genotype-phenotype relationship and mirrored the variability in the prenylation defect in human MKD, with p.V377I homozygous mice having a milder phenotype than compound heterozygous animals. The inflammatory response to LPS was enhanced in compound heterozygous mice in vivo and elevated serum interleukin-1β was abrogated by NLRP3 inflammasome inhibition. Increased temperature dramatically but reversibly exacerbated the deficit in the mevalonate pathway and defective prenylation in vitro and in vivo, highlighting increased body temperature as a likely trigger of inflammatory flares and an additional potential target for future therapeutic approaches.
Knowledge of theory of evolution and beliefs as determinants of dualism in health science students
Authors: Zappala María Alejandra Petino , López Pablo Luis , Aguirre Felipe , Richly Pablo
Published: March 2022

It has been proposed that dualistic conceptions on the mind and the body can affect the practice of health professionals. Religious beliefs have already been described as affecting mind-body dualistic thinking. Another factor that may play a role is knowledge of evolutionary theory, but this relationship has not been explored. In this work, data on knowledge of evolutionary theory and supernatural and dualistic beliefs of 287 Argentinian students of psychology and medicine majors. were collected through a cross-sectional online survey. Information was analyzed to determine whether an association exists between knowledge of evolutionary theory, supernatural beliefs and dualism. We found significant statistical associations between supernatural beliefs and dualism (positive) and between both and knowledge of evolutionary theory (negative). Also, some heterogeneity was found within dualistic questions between theoretical ones and a hypothetical case. Our results are consistent with the hypothesis that knowledge of evolutionary theory could challenge mind-body dualistic conceptions.
Multi-channel deep learning with intracranial neurostimulation can localize seizure onset zones in humans
Authors: Johnson Graham W. , Cai Leon Y. , Doss Derek J. , Jiang Jasmine W. , Negi Aarushi S. , Narasimhan Saramati , Paulo Danika L. , González Hernán F. J. , Roberson Shawniqua Williams , Bick Sarah K. , Chang Catie E. , Morgan Victoria L. , Wallace Mark T. , Englot Dario J.
Published: March 2022

In drug resistant temporal lobe epilepsy, automated tools for seizure onset zone (SOZ) localization using brief interictal recordings would supplement presurgical evaluations and improve care. Thus, we sought to localize SOZs by training a multi-channel convolutional neural network on stereo-EEG (SEEG) cortico-cortical evoked potentials. We performed single pulse electrical stimulation with 10 drug resistant temporal lobe epilepsy patients implanted with SEEG. Using the 500,000 unique post-stimulation SEEG epochs, we trained a multi-channel one-dimensional convolutional neural network to determine whether an SOZ was stimulated. SOZs were classified with a mean leave-one-patient-out testing sensitivity of 78.1% and specificity of 74.6%. To achieve maximum accuracy, the model requires a 0-350 ms post stimulation time period. Post-hoc analysis revealed that the model accurately classified unilateral vs bilateral mesial temporal lobe seizure onset, and neocortical SOZs. This is the first demonstration, to our knowledge, that a deep learning framework can be used to accurately classify SOZs using cortico-cortical evoked potentials. Our findings suggest accurate classification of SOZs relies on a complex temporal evolution of evoked potentials within 350 ms of stimulation. Validation in a larger dataset could provide a practical clinical tool for the presurgical evaluation of drug resistant epilepsy.
Aging the Brain: Multi-Region Methylation Principal Component Based Clock in the Context of Alzheimer’s Disease
Authors: Thrush Kyra L. , Bennett David A. , Gaiteri Christopher , Horvath Steve , van Dyck Christopher H. , Higgins-Chen Albert T. , Levine Morgan E.
Published: March 2022

Alzheimer’s disease (AD) risk increases exponentially with age and is associated with multiple molecular hallmarks of aging, one of which is epigenetic alterations. Epigenetic age predictors based on 5’ cytosine methylation (DNAm) have previously suggested that biological age acceleration may occur in AD brain tissue. To further investigate brain epigenetic aging in AD, we generated a novel age predictor termed PCBrainAge that was trained solely in cortical samples. This predictor utilizes a combination of principal components analysis and regularized regression, which reduces technical noise and greatly improves test-retest reliability. For further testing, we generated DNAm data from multiple brain regions in a sample from the Religious Orders Study and Rush Memory & Aging Project. PCBrainAge captures meaningful heterogeneity of aging, calculated according to an individual’s age acceleration beyond expectation. Its acceleration demonstrates stronger associations with clinical AD dementia, pathologic AD, and APOE ε4 carrier status compared to extant epigenetic age predictors. It does so across multiple cortical and subcortical regions. Overall, PCBrainAge is useful for investigating heterogeneity in brain aging, as well as epigenetic alterations underlying AD risk and resilience.
Long-read sequencing characterizes mitochondrial and plastid genome variants in Arabidopsismsh1mutants
Authors: Zou Yi , Zhu Weidong , Sloan Daniel B. , Wu Zhiqiang
Published: March 2022

The abundant repeats in plant mitochondrial genomes can cause rapid genome rearrangements and are also a major obstacle in short-read sequencing studies. Nuclear-encoded proteins such as MSH1 are known to suppress the generation of repeat-associated mitochondrial genome variants, but our understanding of these mechanisms has been constrained by the limitations of short-read technologies. Here, we used highly accurate long-read sequencing (PacBio HiFi) to characterize mitochondrial and plastid genome variants inArabidopsis thaliana msh1mutant individuals. The HiFi reads provided a global view of recombination dynamics with detailed quantification of parental and crossover recombination products for both large and small repeats. We found that recombination breakpoints were distributed relatively evenly across the length of repeated sequences and detected widespread internal exchanges of sequence variants between pairs of imperfect repeats in the mitochondrial genome ofmsh1mutants. Long-read assemblies of mitochondrial genomes from seven otherArabidopsis thalianawild-type accessions differed by repeat-mediated structural rearrangements similar to those observed inmsh1mutants, but they were all in a simple low-heteroplasmy state. TheArabidopsisplastid genome generally lacks small repeats and exhibited a very different pattern of variant accumulation inmsh1mutants compared with the mitochondrial genome. Our data illustrate the power of HiFi technology in studying repeat-mediated recombination in plant organellar genomes and improved the sequence resolution for recombinational processes suppressed by MSH1.

Significance

Plant organellar genomes can undergo rapid rearrangements. Long-read sequencing provides a detailed and quantitative view of mitochondrial and plastid genome variants normally suppressed by MSH1, advancing our understanding of plant organellar genome dynamics.
Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy and improves prediction
Authors: Hindley Guy , Shadrin Alexey , der Meer Dennis van , Parker Nadine , Cheng Weiqiu , O’Connell Kevin S. , Bahrami Shahram , Lin Aihua , Karadag Naz , Holen Børge , Bjella Thomas , Fan Chun C , Ueland Torill , Djurovic Srdjan , Smeland Olav B. , Frei Oleksandr , Dale Anders M. , Andreassen Ole A.
Published: March 2022

Personality and cognition are heritable mental traits, and their genetic determinants may be distributed across interconnected brain functions. However, previous studies have employed univariate approaches which reduce complex traits to summary measures. We applied the “pleiotropy-informed” multivariate omnibus statistical test (MOSTest) to genome-wide association studies (GWAS) of 35 item and task-level measures of neuroticism and cognition from the UK Biobank (n=336,993). We identified 431 significant genetic loci and found evidence of abundant pleiotropy across personality and cognitive domains. Functional characterisation implicated genes with significant tissue-specific expression in all tested brain tissues and enriched in brain-specific gene-sets. We conditioned independent GWAS of the Big 5 personality traits and cognition on our multivariate findings, which boosted genetic discovery in other personality traits and improved polygenic prediction. These findings advance our understanding of the polygenic architecture of complex mental traits, indicating a prominence of pleiotropic genetic effects across higher-order domains of mental function.

Graphical abstract
Identification of highly cross-reactive mimotopes for a public T cell response in murine melanoma
Authors: Grace Beth E. , Backlund Coralie M. , Morgan Duncan M. , Kang Byong H. , Singh Nishant K. , Huisman Brooke D. , Rappazzo C. Garrett , Moynihan Kelly D. , Maiorino Laura , Dobson Connor S. , Kyung Taeyoon , Gordon Khloe S. , Holec Patrick V. , Takou Mbah Overbeck C. , Garafola Daniel , Wu Shengwei , Love J. Christopher , Wittrup K. Dane , Irvine Darrell J. , Birnbaum Michael E.
Published: March 2022

While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8+T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell responsein vivo, engineered antigen mimotopes induced a significant expansion of CD8+T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cellsin vivoyet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals.
Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds
Authors: Boateng Samuel T. , Roy Tithi , Agbo Mercy E. , Banang-Mbeumi Sergette , Chamcheu Roxane-Cherille N. , Bramwell Marion , Pham Long K. , Jackson Keith E. , Hill Ronald A. , Nagalo Bolni Marius , Efimova Tatiana , Fotie Jean , Chamcheu Jean Christopher
Published: March 2022

Melanoma and non-melanoma skin cancers are the most-lethal and commonest forms of skin cancers, that affecting one-fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost-effective therapies, a small library of about 90 molecules was screenedin vitroagainst A375, SKMEL-28, A431, SCC-12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, C–C and C–N linked biphenyls, and substituted methylgallate or aniline derivatives, displayed low-micromolar range activities, primarily against the A431 and SCC-12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL-28 melanoma cell lines. Compounds11(A431: IC50= 5.0 µM, SCC-12: IC50= 2.9 µM, SKMEL-28: IC50= 4.9 µM, A375: IC50= 6.7 µM) and13(A431: IC50= 5.0 µM, SCC-12: IC50= 3.3 µM, SKMEL-28: IC50= 13.8 µM, A375: IC50= 17.1 µM) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds11and13significantly and dose-dependently induced apoptosis of SCC-12 and SK-MEL-28 cells as evidenced by the downregulation of Bcl-2 and upregulation of Bax protein expression levels, and by cleaved caspase-3, caspase-9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in-silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure-activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and non-melanoma skin cancers.
Greening conceals evergreening: contrasting trends for a socio-ecological system in Arctic Europe
Authors: Tuomi M.W. , Utsi T.Aa. , Yoccoz N.G. , Armstrong C.W. , Gonzalez V. , Hagen S.B. , Jónsdóttir I.S. , Pugnaire F.I. , Shea K. , Wardle D.A. , Zielosko S. , Bråthen K.A.
Published: March 2022

Ongoing Arctic greening can increase productivity and reindeer pasture quality in the tundra. However, greening may also entail proliferation of unpalatable species, with distinct consequences for pastoral socio-ecological systems (SES).

We show extensive greening across 20 reindeer districts in northern Norway between 2003 and 2020. The allelopathic, evergreen dwarf-shrub crowberry biomass increased by 60%, contrasted by smaller increases of deciduous dwarf-shrubs and stagnating forb and graminoid biomass.

We found evidence, although uncertain, of a negative relationship between biomass and reindeer densities, but only among forbs, the least abundant plant group.

Our results challenge the management decision-making, which aims at sustainable pasture management, but which assumes stationary density-dependent relationships. Changes in temporal vs. spatial relationships should be included as management criteria, to avoid mismanaging a SES in transition.

Large-scale shift towards increased allelopathy may undermine the resource base of a key Arctic herbivore and pastoral SES.
Genome-wide association and genomic prediction of resistance to Flavobacterium columnare in a farmed rainbow trout population
Authors: Fraslin Clémence , Koskinen Heikki , Nousianen Antti , Houston Ross D. , Kause Antti
Published: March 2022

Columnaris disease is an emerging disease affecting farmed rainbow trout (Oncorhynchus mykiss) globally. In aquaculture breeding, genomic selection has been increasingly used to improve traits that are difficult to measure on candidate fish (such as disease resistance traits). Following a natural outbreak of columnaris disease, 3,054 exposed fish and their 81 parents (33 dams and 48 sires) were genotyped with the 57K SNP Axiom™ trout genotyping array. Genetic parameters of host resistance (measured as a binary survival trait) were estimated, a genome wide association study was performed, and the accuracy of pedigree-based and genomic prediction was estimated. After quality controls, 2,874 challenged fish (1,403 dead fish and 1,471 alive fish) and 78 parents genotyped for 27,907 SNPs remained. Pedigree based heritability was estimated to be 0.18 and 0.35 on the observed and underlying scale, respectively. Genomic heritability was estimated to be 0.21 and 0.43 on the observed and underlying scale, respectively. A quantitative trait loci (QTL) was detected on chromosome Omy3, significant at the genome-wide level, along with several suggestive QTLs on two other chromosomes. The additive effect on mortality proportion of the peak SNP from Omy3 was estimated to be 0.11 (0.018; se). Pedigree-based prediction accuracy was 0.59, and the use of genomic evaluation increased the prediction accuracy by at least 13.6%. Using the second iteration of a weighted genomic-based evaluation increased the prediction accuracy by 18.6% compared to the pedigree-based model. These results suggest that resistance is a suitable target trait for genetic improvement by selective breeding, and genomic selection may be a useful approach to speed up this process.
Regulation strategies for two-output biomolecular networks
Authors: Alexis Emmanouil , Schulte Carolin CM , Cardelli Luca , Papachristodoulou Antonis
Published: March 2022

Feedback control theory facilitates the development of self-regulating systems with desired performance which are predictable and insensitive to disturbances. Feedback regulatory topologies are found in many natural systems and have been of key importance in the design of reliable synthetic bio-devices operating in complex biological environments. Here, we study control schemes for biomolecular processes with two outputs of interest, expanding previous traditional concepts describing one-output systems. Regulation of such processes may unlock new design possibilities but can be challenging due to coupling interactions; also potential disturbances applied on one of the outputs may affect both. We therefore propose architectures for robustly manipulating the ratio and linear combinations of the outputs as well as each of the outputs independently. To demonstrate their characteristics, we apply these architectures to a simple process of two mutually activated biomolecular species. We also highlight the potential for experimental implementation by exploring synthetic realizations bothin vivoandin vitro. This work presents an important step forward in building bio-devices capable of sophisticated functions.
IFT20 governs mesenchymal stem cell fate through positively regulating TGF-β-Smad2/3-Glut1 signaling mediated glucose metabolism
Authors: Li Yang , Yang Shuting , Liu Yang , Qin Ling , Yang Shuying
Published: March 2022

Aberrant lineage allocation of mesenchymal stem cells (MSCs) could cause bone marrow osteoblast-adipocyte imbalance, and glucose as an important nutrient is required for the maintenance of the MSCs’ fate and function. Intraflagellar transport 20 (IFT20) is one of the IFT complex B protein which regulates osteoblast differentiation, and bone formation, but how IFT20 regulates MSCs’ fate remains undefined. Here, we demonstrated that IFT20 controls MSC lineage allocation through regulating glucose metabolism during skeletal development. IFT20 deficiency in the early stage of MSCs caused significantly shortened limbs, decreased bone mass and significant increase in marrow fat. However, deletion of IFT20 in the later stage of MSCs and osteocytes just slightly decreased bone mass and bone growth and increased marrow fat. Additionally, we found that loss of IFT20 in MSCs promotes adipocyte formation, which enhances RANKL expression and bone resorption. Conversely, ablation of IFT20 in adipocytes reversed these phenotypes. Mechanistically, loss of IFT20 in MSCs significantly decreased glucose tolerance and suppressed glucose uptake and lactate and ATP production. Moreover, loss of IFT20 significantly inhibited TGF-β-Smad2/3 signaling and decreased the binding activity of Smad2/3 toGlut1promoter to downregulate Glut1 expression. These findings indicate that IFT20 plays essential roles for preventing MSC lineage allocation into adipocytes through controlling TGF-β-Smad2/3-Glut1 mediated glucose metabolism.
In vivo chromatic and spatial tuning of foveolar retinal ganglion cells in Macaca fascicularis
Authors: Godat Tyler , Cottaris Nicolas P. , Patterson Sara , Kohout Kendall , Parkins Keith , Yang Qiang , Strazzeri Jennifer M. , McGregor Juliette E. , Brainard David H. , Merigan William H. , Williams David R.
Published: March 2022

The primate fovea is specialized for high acuity chromatic vision, with the highest density of cone photoreceptors and a disproportionately large representation in visual cortex. The unique visual properties conferred by the fovea are conveyed to the brain by retinal ganglion cells, the somas of which lie at the margin of the foveal pit. Microelectrode recordings of these centermost retinal ganglion cells have been challenging due to the fragility of the fovea in the excised retina. Here we overcome this challenge by combining high resolution fluorescence adaptive optics ophthalmoscopy with calcium imaging to optically record functional responses of foveal retinal ganglion cells in the living eye. We use this approach to study the chromatic responses and spatial transfer functions of retinal ganglion cells using spatially uniform fields modulated in different directions in color space and monochromatic drifting gratings. We recorded from over 350 cells across three Macaca fascicularis primates over a time period of weeks to months. We find that the majority of the L vs. M cone opponent cells serving the most central foveolar cones have spatial transfer functions that peak at high spatial frequencies (20-40 c/deg), reflecting strong surround inhibition that sacrifices sensitivity at low spatial frequencies but preserves the transmission of fine detail in the retinal image. In addition, we fit to the drifting grating data a detailed model of how ganglion cell responses draw on the cone mosaic to derive receptive field properties of L vs. M cone opponent cells at the very center of the foveola. The fits are consistent with the hypothesis that foveal midget ganglion cells are specialized to preserve information at the resolution of the cone mosaic. By characterizing the functional properties of retinal ganglion cells in vivo through adaptive optics, we characterize the response characteristics of these cells in situ.
Genomic analyses identify biological processes and functions between M1 and M2 macrophages
Authors: Chang Tingxiang , Zhang Tingting , Gu Hanming , Wang Jing
Published: March 2022

Macrophages can be induced by a variety of factors to change their phenotype and functions. M1 and M2 macrophages play converse roles during inflammation or other diseases. However, the mechanism and function of M1 and M2 macrophages are still not clear. This study aims to identify the different molecules and functions by analyzing the RNA-seq data. The GSE189354 was created by the Illumina HiSeq 4000 (Mus musculus). The KEGG and GO analyses indicated the Phagosome and Hematopoietic cell lineage are the major biological processes between M1 and M2 macrophages. Moreover, we further identified ten molecules including Il6, Il1b, Tlr2, Myc, Fn1, Itgax, Cxcl10, Ccl5, Cxcr4, and Pparg. Therefore, our study may provide novel knowledge of innate immunity.
Cytologic Scoring of Equine Exercise-Induced Pulmonary Hemorrhage (EIPH): Performance of Human Experts and a Deep Learning-Based Algorithm
Authors: Bertram Christof A. , Marzahl Christian , Bartel Alexander , Stayt Jason , Bonsembiante Federico , Beeler-Marfisi Janet , Barton Ann K. , Brocca Ginevra , Gelain Maria E. , Gläsel Agnes , Preez Kelly du , Weiler Kristina , Weissenbacher-Lang Christiane , Breininger Katharina , Aubreville Marc , Maier Andreas , Klopfleisch Robert , Hill Jenny
Published: March 2022

Exercise-induced pulmonary hemorrhage (EIPH) is a relevant respiratory disease in sport horses which can be diagnosed by examination of bronchoalveolar lavage fluid (BALF) cells using the total hemosiderin score (THS). The aim of this study was to evaluate the diagnostic accuracy and reproducibility of trained annotators and to validate a deep learning-based algorithm for the THS. Digitized, iron-stained cytological specimens were prepared from 52 equine BALF samples. Ten annotators produced a THS for each slide according to published methods. The reference methods for comparing annotator’s and algorithmic performance included a ground truth dataset, the mean annotators’ THSs, and chemical iron measurements. Results of the study showed that annotators had marked inter-observer variability of the THS, which was mostly due to a systematic error between annotators in grading the intracytoplasmatic hemosiderin content of individual macrophages. Regarding overall measurement error between the annotators, 87.7% of the variance of the could be reduced by using standardized grades based on the ground truth. The algorithm was highly consistent with the ground truth in assigning hemosiderin grades. Compared to the ground truth THS, annotators had an accuracy of diagnosing EIPH (THS of < or ≥ 75) of 75.7% whereas the algorithm had an accuracy of 92.3% with no marked difference in correlation to chemical iron measurements. The results show that deep learning-based algorithms are useful for improving reproducibility and routine applicability of the THS. For THS by experts, a diagnostic uncertainty interval of 40 to 110 is proposed. THSs within this interval have insufficient reproducibility regarding the EIPH diagnosis.
A functional trait approach reveals the effects of landscape context on ecosystem services provided by urban birds
Authors: Swartz Timothy M. , Gleditsch Jason M. , Behm Jocelyn E.
Published: March 2022

Land use intensification in urban areas can have profound effects on biological communities that provide valuable ecosystem services to urban residents. We used a functional response and effect trait approach to determine how bird species’ responses to local and landscape-scale habitat of urban green spaces affects the supply of cultural and regulating ecosystem services. We sampled bird communities and habitat variables in urban green spaces that varied in local and landscape-scale habitat composition and compiled a dataset of species’ response and effect traits related to nesting, foraging, diet, and visual and acoustic aesthetic appeal. Overall, the landscape-scale context of a green space had a stronger influence on species’ abundances than local-scale habitat. Landscape-scale impervious surface surrounding our study sites interacted with response traits related to nesting in human-built structures, clutch size, and consumption of invertebrates to drive bird species’ abundances. Because correlations between response and effect traits can influence the effect traits available to provide ecosystem services at a site, we explored the correlation of these three response traits to a suite of effect traits and found the response traits were correlated with several effect traits related to diet and regulating services but correlated with few of the plumage and acoustic traits that produce cultural services. Finally, we found that effect traits associated with cultural and regulating ecosystem services varied strongly along the landscape-scale gradient of urbanization. Sites with high impervious surface cover are expected to have low levels of invertebrate pest control and visual appeal but high levels of acoustic appeal, diet evenness (generalism), and granivory. Overall, our study highlights the key role of landscape-scale habitat in driving bird-mediated ecosystem services and underscores the importance of regional urban planning to create healthy and livable cities.
Using Biometric Data to Measure and Predict Emotional Engagement of Video Games
Authors: Vazquez Janette , Abdelrahman Samir , Wasden Chris , Jardine Stuart , Judd Colby , Davis Matthew , Facelli Julio C.
Published: March 2022

Measurement and prediction of engagement in video games are very important because these are indicators to guide the development of game applications. Existing methods to predict game engagement are mostly based on subjective evaluations. This paper presents results correlating subjective and biometric data to show the potential of using biometric measures for assessment and prediction of engagement. Using three different games, we measured the biometric responses of participants and analyzed the responses using statistical and data mining methods. We compared the results with those obtained using subjective evaluations. Our results show that biometric measurements do correlate with subjective measures and better predict the self-reported engagement of a game.
Data-driven large-scale genomic analysis reveals an intricate phylogenetic and functional landscape in J-domain proteins
Authors: Malinverni Duccio , Zamuner Stefano , Rebeaud Mathieu E. , Barducci Alessandro , Nillegoda Nadinath B. , De Los Rios Paolo
Published: March 2022

The 70 kDalton Heat shock protein (Hsp70) chaperone system is emerging as a central hub of the proteostasis network that helps maintain protein homeostasis in all organisms. The recruitment of Hsp70 to perform a vast array of different cellular functions is regulated by a family of co-chaperones known as J-domain proteins (JDP) that bear a small namesake J-domain, which is required to interact and drive the ATPase cycle of Hsp70s. Both prokaryotic and eukaryotic JDPs display staggering diversity in domain architecture (besides the ubiquitous J-domain), function, and cell localization. On the contrary, a relatively small number of Hsp70 paralogs exist in cells, suggesting a high degree of specificity, but also promiscuity, in the partnering between JDPs and Hsp70s. Very little is known about the JDP family, despite their essential role in cellular proteostasis, development, and the link to a broad range of human diseases. The number of JDP gene sequences identified across all kingdoms as a consequence of advancements in sequencing technology has exponentially increased, where it is now beyond the ability of careful manual curation. In this work, we first provide a broad overview of the JDP repertoire accessible from public databases, and then we use an automated classification scheme, based on Artificial Neural Networks (ANNs), to demonstrate that the sequences of J-domains carry sufficient discriminatory information to recover with high reliability the phylogeny, localization, and domain composition of the corresponding full-length JDP. By harnessing the interpretability of the ANNs, we find that many of the discriminatory sequence positions match to residues that form the interaction interface between the J-domain and Hsp70. This reveals that key residues within the J-domains have coevolved with their obligatory Hsp70 partners to build chaperone circuits for specific functions in cells.
Organism-wide mapping of MHC class I and II expression in mouse lemur cells and tissues
Authors: Guethlein Lisbeth A. , Ezran Camille , Liu Shixuan , Krasnow Mark A. , Parham Peter
Published: March 2022

The major histocompatibility complex (MHC) class I and II glycoproteins have been associated with numerous disease phenotypes, mechanisms and outcomes. These associations can be due to allotypic polymorphism or to altered levels of allotype expression. Although well studied in a range of cell types and microenvironments, no study has encompassed all cell-types present in an individual mouse lemur. In this study the droplet-based single cell RNA sequence data from the mouse lemur cell atlas, Tabula Microcebus, were used to examine the patterns of MHC class I and II expression. The cell atlas comprises data obtained from 27 organs from four mouse lemurs, enabling comparison of expression pattern between both cell types and the individual lemurs. Patterns of gene expression showed a good concordance among the four mouse lemurs. Three primary patterns of expression were identified and associated with different cell-types. Mapping MHC expression onto existing cell trajectories of cell development and spatial gradients revealed fine scale differences in expression level and pattern in single tissues. The bioinformatic pipeline developed here is applicable to other cell atlas projects.
A parametric logistic equation with light flux and medium concentration for cultivation planning of microalgae
Authors: Kambe Kazuki , Hirokawa Yasutaka , Koshi Asuka , Hori Yutaka
Published: March 2022

Microalgae are considered to be promising producers of bioactive chemicals, feeds, and fuels from carbon dioxide by photosynthesis. Thus, the prediction of microalgal growth profiles is important for the planning of cost-effective and sustainable cultivation-harvest cycles. This paper proposes a mathematical model capable of predicting the effect of light flux into culture and medium concentration on the growth profiles of microalgae by incorporating these growth-limiting factors into the logistic equation. The specific form of the equation is derived based on the experimentally measured growth profiles of Monoraphidium sp., a microalgal strain isolated by the authors, under 16 conditions consisting of the combinations of incident light fluxes into culture and initial medium concentrations. Using a cross-validation method, it is shown that the proposed model has the ability to predict necessary incident light flux into culture and initial medium concentration for harvesting target biomass at target time. Finally, the model-guided cultivation planning is performed and is evaluated by comparing the result with the experimental data.