bluuebunny/crossref_metadata_2025 huggingface dataset:
Benefits and barriers to implementing precision preventive care: results of a national physician survey
Authors: Vassy Jason L. , Kerman Benjamin J. , Harris Elizabeth J. , Lemke Amy A. , Clayman Marla L. , Antwi Ashley A. , MacIsaac Katharine , Yi Thomas , Brunette Charles A.
Published: September 2022

Background

Clinical implementation of polygenic risk scores (PRS) for precision prevention depends on the utility and barriers primary care physicians (PCPs) perceive to their use.

Methods

An online survey asked PCPs in a national database about the clinical utility of PRS they perceived for categories of medical decision-making and perceived benefits of and barriers to that use. Latent class analysis (LCA) was used to identify subgroups of PCPs based on response patterns.

Results

Among 367 respondents (email open rate 10.8%; participation rate 96.3%; completion rate 93.1%), mean (SD) age was 54.9 (12.9) years, 137 (37.3%) were female, and mean (SD) time since medical school graduation was 27.2 (13.3) years. Respondents reported greater perceived utility for more clinical action (e.g., earlier or more intensive screening, preventive medications, or lifestyle modification) for patients with high-risk PRS than for delayed or discontinued prevention actions for low-risk patients (p<0.001). Respondents most often chose out-of-pocket costs (48%), lack of clinical guidelines (24%), and patient insurance discrimination concerns (22%) as extreme barriers to PRS implementation. LCA identified 3 subclasses of respondents. Skeptics (n=83, 22.6%) endorsed less agreement with individual clinical utilities, saw patient anxiety and insurance discrimination as significant barriers, and agreed less often that PRS could help patients make better health decisions. Learners (n=134, 36.5%) and enthusiasts (n=150, 40.9%) expressed similar levels of agreement that PRS had utility for preventive actions and that PRS could be useful for patient decision-making. Compared with enthusiasts, however, learners perceived greater barriers to the clinical use of PRS.

Conclusion

PCPs generally endorsed using PRS to guide medical decision-making about preventive care, with a preference for more clinical action over less. Barriers identified suggest interventions to address the needs and concerns of PCPs along the spectrum of acceptance and uptake.
Associations of conservatism/jumping to conclusions biases with aberrant salience and default mode network
Authors: Miyata Jun , Sasamoto Akihiko , Ezaki Takahiro , Isobe Masanori , Kochiyama Takanori , Masuda Naoki , Mori Yasuo , Sakai Yuki , Sawamoto Nobukatsu , Tei Shisei , Ubukata Shiho , Aso Toshihiko , Murai Toshiya , Takahashi Hidehiko
Published: September 2022

Background and hypothesis

While the conservatism bias refers to the human need for more evidence for decision-making than rational thinking expects, people with schizophrenia and delusion require less evidence, known as the jumping to conclusions (JTC) bias. The midbrain-striatal aberrant salience of schizophrenia is postulated to form delusion; however, the association between conservatism/JTC and aberrant salience and their neural correlates are unclear.

Study design

Thirty-seven patients with schizophrenia and 33 healthy controls performed the beads task, with large/small numbers of bead draws to decision (DTD) used as an index of conservative/hasty (JTC) decisions, respectively. We performed meta-independent component analysis and thresholded dual regression of resting functional magnetic resonance imaging (MRI) data, and structural covariance network analysis (SCNA) of structural and diffusion MRI data. We investigated interactions between diagnosis and DTD, and main effects of DTD for each imaging modality.

Study results

We found no significant interactions. We identified main effects of DTD (positive correlation) for: 1) functional connectivity between the striatum and default mode network (DMN), 2) DMN-like structural SCNA network, and 3) the diffusion SCNA network connecting networks of 1) and 2) (all p < 0.05, family-wise error [FWE] correction). The functional connectivity between the striatum and DMN was also negatively correlated with delusion severity in patients (p < 0.05, FWE), indicating that the greater the anti-correlation, the stronger the JTC and delusion.

Conclusions

Our results support a novel concept that conservatism/JTC biases are associated with aberrant salience of schizophrenia and the default brain mode.
Mediterranean diet related metabolite profiles and cognitive performance in a Greek population
Authors: Papandreou Christopher , Papagiannopoulos Christos , Koutsonida Myrto , Kanellopoulou Afroditi , Markozannes Georgios , Polychronidis Georgios , Tzakos Andreas G , Fragkiadakis Georgios A. , Evangelou Evangelos , Ntzani Evangelia , Tzoulaki Ioanna , Aretouli Eleni , Tsilidis Konstantinos K.
Published: September 2022

Background

Evidence suggests that adherence to the Mediterranean diet (MedDiet) affects human metabolism and may contribute to better cognitive performance. However, the underlying mechanisms are not clear.

Objective

We generated a metabolite profile for adherence to MedDiet and evaluated its cross-sectional association with aspects of cognitive performance.

Methods

A total of 1,250 healthy Greek middle-aged adults from the Epirus Health Study cohort were included in the analysis. Adherence to the MedDiet was assessed using the 14-point Mediterranean Diet Adherence Screener (MEDAS); cognition was measured using the Trail Making Test, the Verbal Fluency test and the Logical Memory test. A targeted metabolite profiling (n = 250 metabolites) approach was applied, using a high-throughput nuclear magnetic resonance platform. We used elastic net regularized regressions, with a 10-fold cross-validation procedure, to identify a metabolite profile for MEDAS. We evaluated the associations of the identified metabolite profile and MEDAS with cognitive tests, using multivariable linear regression models.

Results

We identified a metabolite profile composed of 42 metabolites, mainly lipoprotein subclasses and fatty acids, significantly correlated with MedDiet adherence (Pearson r = 0.35, P-value = 5.5 × 10−37). After adjusting for known risk factors and accounting for multiple testing, the metabolite profile and MEDAS were not associated with the cognitive tests.

Conclusions

A plasma metabolite profile related to better adherence to the MedDiet was not associated with the tested aspects of cognitive performance, in a middle-aged Mediterranean population.
Magnitude and antibiogram of uropathogens and associated risk factors among asymptomatic female college students in Dessie town, Northeast Ethiopia
Authors: Reda Berhanu Kebede , Molla Genet , Gedefie Alemu , Gebretsadik Daniel , Tilahun Mihret , Belete Melaku Ashagrie , Shibabaw Agumas
Published: September 2022

Background

Asymptomatic Urinary Tract Infection (Asymptomatic bacteriuria and asymptomatic candiduria) in sexually active non-pregnant female’s population in most cases may not be routinely detected at the initial and reversible stages. This is due to the fact that most women may not feel compelled to seek medical help.

Objectives

to determine the prevalence, and factors associated with asymptomatic urinary tract infection, and antibiogram of the uropathogen isolates among asymptomatic female college students

Methods

An institutional based cross-sectional study was conducted at selected colleges found in Dessie from January 2021 to March 2021. A total of 422 reproductive age non-pregnant female students were included and socio-demographic and clinical characteristics data were collected using structured questionnaires. Ten ml freshly voided mid-stream urine specimen was collected, transported and processed according to standard operating procedure. Data were coded and entered for statistical analysis using SPSS version 22.0 and descriptive statistics, bivariate and multivariate logistic regression analysis were performed. P-value ≤0.05 with corresponding 95% confidence interval (CI) were considered statistically significant.

Result

The overall prevalence of UTI was 24.6%. The prevalence of asymptomatic UTI bacteriuria and candidiuria were 57 (13.5%) and 47 (11.1%) respectively. The predominant isolated uropathogens were S. saprophyticus 24 (23.07%) followed by Candida tropicalis 23 (22.1%), Candida albican 10 (9.61%), Candida krusei 9(8.65%) and E. coli 8 (7.69%). Gram negative bacterial isolates showed higher level of resistance to Amoxicillin-clavulanic acid 24 (92.3%). Gram positive bacterial uropathogens showed high level of resistance for penicillin 28 (96.6%) and Trimethoprim-Sulfamethoxazole 23 (79.3%). Gram positive bacterial isolates were sensitive to norfloxacin clindamycin and ciprofloxacin accounting 24 (82.7%), 20 (69.0%) and 19 (65.5%), respectively. Moreover, MDR was seen in 50 (87.7%) of all isolated bacterial uropathogens.

Frequency of sexual intercourse (> 3 per week) (AOR =7.907, 95% CI: (2.918, 21.425), (P=0.000) and genital area washing habit (during defecation) (AOR = 5.914, 95%CI: (1.860, 18.809), (P=0.0003) and every morning (AOR = 6.128, 95%CI: (1.602, 23.449), (P=0.0008) were found to have statistically significant association with the occurrence of UTI among asymptomatic female college students.

Conclusion

A significant prevalence of uropathogens, and high resistance of bacterial isolates to commonly prescribed drugs were observed. Therefore, routine UTI screening, regular health education on the risk of asymptomatic infectious diseases and antimicrobial susceptibility testing should be practiced to avoid the progression of asymptomatic infection into symptomatic UTI.
When Case Reporting Becomes Untenable: Can Sewer Networks Tell Us Where COVID-19 Transmission Occurs?
Authors: Wang Yuke , Liu Pengbo , VanTassell Jamie , Hilton Stephen P. , Guo Lizheng , Sablon Orlando , Wolfe Marlene , Freeman Lorenzo , Rose Wayne , Holt Carl , Browning Mikita , Bryan Michael , Waller Lance , Teunis Peter F.M. , Moe Christine L.
Published: September 2022

Monitoring SARS-CoV-2 in wastewater is a valuable approach to track COVID-19 transmission. Designing wastewater surveillance (WWS) with representative sampling sites and quantifiable results requires knowledge of the sewerage system and virus fate and transport. We developed a multi-level WWS system to track COVID-19 in Atlanta using an adaptive nested sampling strategy. From March 2021 to April 2022, 868 wastewater samples were collected from influent lines to wastewater treatment facilities and upstream community manholes. Variations in SARS-CoV-2 concentrations in influent line samples preceded similar variations in numbers of reported COVID-19 cases in the corresponding catchment areas. Community sites under nested sampling represented mutually-exclusive catchment areas. Community sites with high SARS-CoV-2 detection rates in wastewater covered high COVID-19 incidence areas, and adaptive sampling enabled identification and tracing of COVID-19 hotspots. This study demonstrates how a well-designed WWS provides actionable information including early warning of surges in cases and identification of disease hotspots.
Development and validation of a Context-sensitive Positive Health Questionnaire (CPHQ) to measure health
Authors: Doornenbal Brian M. , van Zutphen Tim , Vos Rimke C. , Haisma Hinke , van den Akker-van Marle M. Elske , Kiefte-de Jong Jessica C.
Published: September 2022

A valid context-specific measurement of health is critical for evaluating health policies and interventions. The Positive Health dialogue is a tool that is increasingly being used to evaluate health. However, this tool is meant to spark conversations about health rather than measure context-specific health. In this paper, we advance the Positive Health dialogue tool into a measurement instrument, that we denote as the Context-sensitive Positive Health Questionnaire (CPHQ). We build on previous efforts to create the CPHQ, using the Capability Approach as a theoretical framework. The measurement was developed in three stages: 1) focus groups, 2) expert consultations, and 3) validation among a representative panel of Dutch citizens. The goal of both the (1) focus groups and (2) expert consultations phases was to pilot test and refine previously proposed Positive Health questionnaires into an initial version of the CPHQ. The validation phase (3) sought to examine the initial CPHQ’s factorial validity, using Factor Analysis, and its concurrent validity, using Multivariate Regression Analysis. The developed questionnaire demonstrated adequate factorial and concurrent validity. Furthermore, it explicitly accounts for resilience, which is a key component of Positive Health. We introduced four benefits by aligning the CPHQ instrument with the Capability Approach. First, it embedded the measurement in a theoretical framework, which is required for theory development and testing. Second, it focused the questionnaire on a key concept of Positive Health - that is, on the “ability to adapt.” Third, it addressed issues of health equity by taking contextual factors into account. Fourth, it aided in developing more understandable measurement items. The introduced measurement (i.e., the CPHQ) includes 11 dimensions, which we labeled as follows: relaxation, autonomy, fitness, perceived environmental safety, exclusion, social support, financial resources, political representation, health literacy, resilience, and enjoyment.

Highlights

- The Context-sensitive Positive Health Questionnaire (CPHQ) was developed using items from Positive Health questionnaires and the Capability Approach, which were then refined through focus groups and professional advice.

- The questionnaire considers individuals’ unique environment, an aspect often overlooked in health measurements that can affect how someone feels.

- By aligning the CPHQ instrument with the Capability Approach, we embedded the measurement in a theoretical framework, which is required for theory development and testing.

- By embedding the measurement in the Capability Approach and including the Brief Resilience Scale into the initial questionnaire, we accounted for a key concept of Positive Health - that is, the “ability to adapt.”

- The developed scale showed adequate factorial validity and concurrent validity.
Effectiveness and Duration of Protection of a Fourth Dose of COVID-19 mRNA Vaccine among Long-Term Care Residents in Ontario, Canada
Authors: Grewal Ramandip , Nguyen Lena , Buchan Sarah A , Wilson Sarah E , Costa Andrew P , Kwong Jeffrey C
Published: September 2022

Background

As of December 30, 2021, Ontario long-term care (LTC) residents who received a third dose of COVID-19 vaccine ≥84 days previously were offered a fourth dose to prevent a surge in COVID-19-related morbidity and mortality due to the Omicron variant. Seven months have passed since fourth doses were implemented, allowing for the examination of fourth dose protection over time.

Methods

We used a test-negative design and linked databases to estimate the marginal effectiveness (4 versus 3 doses) and vaccine effectiveness (VE; 2, 3, or 4 doses versus no doses) of mRNA vaccines among Ontario LTC residents aged ≥60 years who were tested for SARS-CoV-2 between December 30, 2021 and August 3, 2022. Outcome measures included any Omicron infection, symptomatic infection, and severe outcomes (hospitalization or death).

Results

We included 21,275 Omicron cases and 273,466 test-negative controls. The marginal effectiveness of a fourth dose <84 days ago compared to a third dose received ≥84 days ago was 23% (95% Confidence Interval [CI] 17-29%), 36% (95%CI 26-44%), and 37% (95%CI 24-48%) against SARS-CoV-2 infection, symptomatic infection, and severe outcomes, respectively. Additional protection provided by a fourth dose compared to a third dose was negligible against all outcomes ≥168 days after vaccination. Compared to unvaccinated individuals, vaccine effectiveness (VE) of a fourth dose decreased from 49% (95%CI 44%-54%) to 18% (95%CI 5-28%) against infection, 69% (95%CI 62-75%) to 44% (95%CI 24-59%) against symptomatic infection, and 82% (95%CI 77-86%) to 74% (95%CI 62-82%) against severe outcomes <84 days versus ≥168 days after vaccination.

Conclusions

Our findings suggest that fourth doses of mRNA COVID-19 vaccines provide additional protection against Omicron-related outcomes in LTC residents, but the protection wanes over time, with more waning seen against infection than severe outcomes.
Differential Lifespan Impacts on Veterans by War Exposure in the First World War
Authors: Wilson Nick , Clement Christine , Summers Jennifer A , Thomson George , Harper Glyn
Published: September 2022

Introduction

There remains uncertainty around the impact of war on the lifespan of First World War (WW1) veterans.

Methods

We obtained lifespan data on a random sample of 857 war-exposed New Zealand WW1 veterans and compared this with lifespans of a non-war military cohort (n=1039). This comparison was possible as the non-war-cohort arrived in Europe too late to participate in the war, allowing a “natural experiment” that avoided the “healthy solider effect”.

Results

The lifespan comparisons indicated lower mean lifespan in the war-exposed veteran cohort compared to the non-war veteran cohort (69.7 vs 71.1 years; p=0.0405). This gap persisted (range: 0.8 to 1.1 years) but was no longer statistically significant when only considering the non-Māori ethnic grouping (nearly all European/Pākehā personnel), when excluding additional deaths in the immediate post-war period up to 31 December 1923, and when excluding participation in any other wars. Within the war-exposed cohort there were suggestive patterns of increasing lifespan with increasing occupational status and military rank (eg, 69.5, 70.0 and 70.7 mean years as group-level occupational status progressively increased). There were also stark differences in lifespan of 8.3 years between Māori (Indigenous) and non-Māori veterans (p=0.0083).

Conclusions

The pattern of reduced lifespan in war-exposed vs non-war-exposed veterans, was compatible with a smaller previous New Zealand study. There are a number of feasible avenues to further improve this type of work with existing data sources.

Key messages

➢

There is still uncertainty around the impact of the First World War on premature death and lifespan in veterans internationally.

➢

This study of New Zealand veterans found lower mean lifespan in the war-exposed cohort compared to the non-war cohort (69.7 vs 71.1 years). This gap persisted, but was no longer statistically significant, when considering such factors as ethnicity of personnel and participation in any other wars.

➢

The pattern of reduced lifespan in war-exposed veterans was compatible with a smaller previous New Zealand study.

➢

There are a number of feasible avenues to further improve this type of work with existing data sources.
Contributions of neighborhood social environment and air pollution exposure to Black-White disparities in epigenetic aging
Authors: Yannatos Isabel , Brown Rebecca T. , McMillan Corey T.
Published: September 2022

Racial disparities in many aging-related health outcomes are persistent and pervasive among older Americans, reflecting accelerated biological aging for Black Americans compared to White, known as weathering. Environmental determinants that contribute to weathering are poorly understood. Having a higher biological age, measured by DNA methylation (DNAm), than chronological age is robustly associated with worse age-related outcomes and higher social adversity. We hypothesize that individual socioeconomic status (SES), neighborhood social environment, and air pollution exposures contribute to racial disparities in DNAm aging according to GrimAge and Dunedin Pace of Aging methylation (DPoAm). We perform retrospective cross-sectional analyses among 2,960 non-Hispanic participants (82% White, 18% Black) in the Health and Retirement Study whose 2016 DNAm age is linked to survey responses and geographic data. DNAm aging is defined as the residual after regressing DNAm age on chronological age. We observe Black individuals have significantly accelerated DNAm aging on average compared to White individuals according to GrimAge (239%) and DPoAm (238%). We implement multivariable linear regression models and threefold decomposition to identify exposures that contribute to this disparity. Exposure measures include individual-level SES, census-tract-level socioeconomic deprivation and air pollution (fine particulate matter, nitrogen dioxide, and ozone), and perceived neighborhood social and physical disorder. Race and gender are included as covariates. Regression and decomposition results show that individual-level SES is strongly associated with and accounts for a large portion of the disparity in both GrimAge and DPoAm aging. Higher neighborhood deprivation for Black participants significantly contributes to the disparity in GrimAge aging. Black participants are more vulnerable to fine particulate matter exposure for DPoAm, perhaps due to individual- and neighborhood-level SES, which may contribute to the disparity in DPoAm aging. DNAm aging may play a role in the environment “getting under the skin”, contributing to age-related health disparities between older Black and White Americans.
Dopamine regulates decision thresholds in human reinforcement learning
Authors: Chakroun Karima , Wiehler Antonius , Wagner Ben , Mathar David , Ganzer Florian , vanEimeren Thilo , Sommer Tobias , Peters Jan
Published: September 2022

Dopamine fundamentally contributes to reinforcement learning by encoding prediction errors, deviations of an outcome from expectation. Prediction error coding in dopaminergic regions in human functional neuroimaging studies is well replicated. In contrast, replications of behavioral and neural effects of pharmacological modulations of the dopamine system in human reinforcement learning are scarce. Additionally, dopamine contributes to action selection, but direct evidence and process-specific accounts in human reinforcement learning are lacking. Here we examined dopaminergic mechanisms underlying human reinforcement learning in a within-subjects pharmacological approach in male human volunteers (n=31, within-subjects design; Placebo, 150mg L-dopa, 2mg Haloperidol) in combination with functional magnetic resonance imaging and a stationary reinforcement learning task. We had two aims. First, we aimed to replicate previously reported beneficial effects of L-dopa vs. Haloperidol on reinforcement learning from gains. This replication was not successful. We observed no performance benefit of L-Dopa vs. Haloperidol, and no evidence for alterations in neural prediction error signaling. In contrast, Bayesian analyses provided moderate evidence in favor of the null hypothesis. This unsuccessful replication is likely at least partly due to a number of differences in experimental design. Second, using combined reinforcement learning drift diffusion models, we tested the recent proposal that dopamine contributes to action selection by regulating decision thresholds. Model comparison revealed that the data were best accounted for by a reinforcement learning drift diffusion model with separate learning rates for positive and negative prediction errors. The model accounted for both reductions in RTs and increases in accuracy over the course of learning. The only parameter showing robust drug effects was the boundary separation parameter, which revealed reduced decision thresholds under both L-Dopa and Haloperidol, compared to Placebo, and the degree of threshold reduction accounted for individual differences in RTs between conditions. Results are in line with the idea that striatal dopamine regulates decision thresholds during action selection, and that lower dosages of D2 receptor antagonists increase striatal DA release via an inhibition of autoreceptor-mediated feedback mechanisms.
Molecular Dynamics Simulations of Ion Permeation in human NaV Channels
Authors: Alberini Giulio , Paz S. Alexis , Corradi Beatrice , Abrams Cameron , Benfenati Fabio , Maragliano Luca
Published: September 2022

The recent determination of cryo-EM structures of voltage-gated sodium (Nav)channels has revealed many details of these proteins. However, knowledge of ionic permeation through the Nav pore remains limited. In this work, we performed atomistic molecular dynamics simulations to study the structural features of various neuronal Nav channels based on homology modeling of the cryo-EM structure of the human Nav1.4 channel and, in addition, on the more recent resolved configuration for Nav1.2.
In particular, single Na+ permeation events during standard MD runs suggest that the ion resides in the inner part of the Nav selectivity filter (SF). On-the-fly free-energy parametrization (OTFP) temperature accelerated molecular dynamics (TAMD) was also used to calculate two-dimensional free energy surfaces (FESs) related to single/double Na+ translocation through the SF of the Nav1.2 homology model. The same thermodynamic analysis was performed on the cryo-EM based Nav1.2 configuration. These additional simulations revealed distinct mechanisms for single and double Na+ permeation through the wild-type SF, which has a charged lysine in the DEKA ring. In particular, the extracted protein-ion configurations are not accessible by the other modified SFs tested by TAMD/OTFP. Overall, the description of these mechanisms gives us new insights into ion conduction in human Nav cryo-EM based configurations, that could advance understanding of these systems and how they differ from potassium and bacterial Nav channels.
Methotrexate inhibition of muropeptide transporter SLC46A2 controls psoriatic skin inflammation
Authors: Bharadwaj Ravi , Lusi Christina F. , Mashayekh Siavash , Nagar Abhinit , Subbarao Malireddi , Kane Griffin I. , Wodzanowski Kimberly , Brown Ashley , Okuda Kendi , Monahan Amanda , Paik Donggi , Nandy Anubhab , Anonick Madison , Goldman William E. , Kanneganti Thirumala-Devi , Orzalli Megan H. , Grimes Catherine Leimkuhler , Atukorale Prabhani U. , Silverman Neal
Published: September 2022

Cytosolic innate immune sensing is critical for protecting barrier tissues. NOD1 and NOD2 are cytosolic sensors of small peptidoglycan fragments (muropeptides) derived from the bacterial cell wall. These muropeptides enter cells, especially epithelial cells, through unclear mechanisms. We previously implicated SLC46 transporters in muropeptide transport in Drosophila immunity. Here we focus on Slc46a2, which is highly expressed in mammalian epidermal keratinocytes, and show that it is critical for delivery of DAP-muropeptides and activation of NOD1 in keratinocytes, while the related transporter Slc46a3 is critical for responding to MDP, the NOD2 ligand. In a mouse model, Slc46a2 and Nod1 deficiency strongly suppressed psoriatic inflammation, while methotrexate, a commonly used psoriasis therapeutic, inhibited Slc46a2-dependent transport of DAP-muropeptides. Collectively these studies define SLC46A2 as a transporter of NOD1 activating muropeptides, with critical roles in the skin barrier, and identify this transporter as an important target for anti-inflammatory intervention.
The trait coding rule in phenotype space
Authors: Wang Jianguo , He Xionglei
Published: September 2022

Genotype and phenotype are both the themes of modern biology. Despite the elegant protein coding rules recognized decades ago in genotype, little is known on how traits are coded in a phenotype space (P). Mathematically, P can be partitioned into a subspace determined by genetic factors (PG) and a subspace affected by non-genetic factors (PNG). Evolutionary theory predicts PG is composed of limited dimensions while PNG may have infinite dimensions, which suggests a dimension decomposition method, termed as uncorrelation-based high-dimensional dependence (UBHDD), to separate them. We applied UBHDD to a yeast phenotype space comprising ~400 traits in ~1,000 individuals. The obtained tentative PG matches the actual genetic components of the yeast traits, explains the broad-sense heritability, and facilitates the mapping of quantitative trait loci, suggesting the tentative PG be the yeast genetic subspace. A limited number of latent dimensions in the PG were found to be recurrently used for coding the diverse yeast traits, while dimensions in the PNG tend to be trait specific and increase constantly with trait sampling. A similar separation success was achieved when applying UBHDD to the UK Biobank human brain phenotype space that comprises ~700 traits in ~26,000 individuals. The obtained PG helped elucidate the genetic versus non-genetic origins of the left-right asymmetry of human brain, and reveal several hundred novel genetic correlations between brain regions and dozens of mental traits/diseases. In sum, by developing a dimension decomposition method we show that phenotypic traits are coded by a limited number of genetically determined common dimensions and unlimited trait-specific dimensions shaped by non-genetic factors, a rule fundamental to the emerging field of phenomics.
Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1
Authors: Dwivedi Devashish , Harry Daniela , Meraldi Patrick
Published: September 2022

A tight synchrony between the DNA and centrosome cycle is essential for genomic integrity. Centriole disengagement, which licenses centrosomes for duplication, occurs normally during mitotic exit. We recently demonstrated that mild DNA replication stress in untransformed human cells causes premature centriole disengagement at mitotic entry, leading to transient multipolar spindles that favour chromosome mis-segregation. How mild replication stress accelerate the centrosome cycle at the molecular level remained, however, unclear. Using expansion microscopy, we show that mild replication stress already induces premature centriole disengagement in G2 via the ATR-Chk1 axis of the DNA damage repair pathway. We demonstrate that this results in a subcritical Plk1 kinase activity that is insufficient for rapid mitotic entry. Nevertheless, it primes the pericentriolar matrix for Separase-dependent disassembly causing premature centriole disengagement in G2. We postulate that the differential requirement of Plk1 activity in the DNA and centrosome cycles explains how mild replication stress disrupts the synchrony between both processes and contributes to genomic instability.
YAP1 is essential for self-organized differentiation of pluripotent stem cells
Authors: Zeevaert Kira , Goetzke Roman , Elsafi Mabrouk Mohamed H. , Schmidt Marco , Maaßen Catharina , Henneke Ann-Christine , He Chao , Gillner Arnold , Zenke Martin , Wagner Wolfgang
Published: September 2022

The Yes-associated protein 1 (YAP1) is a downstream effector of the Hippo pathway and essential mechanotransducer. It has been suggested to play a crucial role for early embryo development, but the relevance for early germ layer commitment of human induced pluripotent stem cells (iPSCs) remains largely unclear. To gain better insight into the function of YAP1 in these early cell-fate decisions, we generated iPSC lines with YAP1 knockout (YAP-/-) with CRISPR/Cas9 technology and analyzed transcriptomic and epigenetic modifications. In YAP-/- iPSCs the expression of several YAP1 targets changed and NODAL, which is an important regulator of cell differentiation, was upregulated. Furthermore, YAP1 deficiency evoked global DNA methylation changes. Directed differentiation of adherent iPSC colonies toward endoderm, mesoderm, and ectoderm could be induced, albeit endodermal and ectodermal differentiation showed transcriptomic and epigenetic changes in YAP-/- lines. Notably, in self-organized embryoid bodies (EBs) germ layer specification was clearly impaired. This phenotype was rescued via lentiviral overexpression of YAP1 and in tendency also by NODAL inhibitors. Our results demonstrate that YAP1 plays an important role during early germ layer specification of iPSCs, particularly for the non-directed self-organization of EBs, and this is at least partly attributed to activation of the NODAL pathway.
Cellular Factors Involved in Transcriptome Dynamics in Early Zebrafish Embryogenesis
Authors: Rauwerda Han , Pagano Johanna F.B. , de Leeuw Wim C. , Ensink Wim , van Olst Marina , Nehrdich Ulrike , Jonker Martijs J. , Spaink Herman P. , Breit Timo M.
Published: September 2022

At gastrulation in the zebrafish embryogenesis, the embryonic genome is switched on to produce transcripts that are used for the maintenance and development of the embryo. In a previous study from late blastula to mid gastrula on the transcriptomes of 179 individual embryos, we capture the transcriptome dynamics via ten gene-expression types. Here we study the factors that regulate these transcriptome dynamics by in extensive silico analyses and two small-RNA sequencing experiments. We analyzed mechanisms that would make it possible for the embryo to achieve the tight regulation of gene expression that was observed, not only during development, but also when individual embryos were compared. We found that many of the gene-expression regulatory factors that are available to the embryo are operational in the different gene-expression types and act concurrently with not one mechanism prevailing in this developmental phase. We also saw that at least one of the regulatory mechanisms, the expression of members of the miRNA-430 family again is very tightly regulated, both during development as well as when miRNA expression from individual embryos is compared.
The BeMoBIL Pipeline for automated analyses of multimodal mobile brain and body imaging data
Authors: Klug M. , Jeung S. , Wunderlich A. , Gehrke L. , Protzak J. , Djebbara Z. , Argubi-Wollesen A. , Wollesen B. , Gramann K.
Published: September 2022

Advancements in hardware technology and analysis methods allow more and more mobility in electroencephalography (EEG) experiments. Mobile Brain/Body Imaging (MoBI) studies may record various types of data such as motion or eye tracking in addition to neural activity. Although there are options available to analyze EEG data in a standardized way, they do not fully cover complex multimodal data from mobile experiments. We thus propose the BeMoBIL Pipeline, an easy-to-use pipeline in MATLAB that supports the time-synchronized handling of multimodal data. It is based on EEGLAB and fieldtrip and consists of automated functions for EEG preprocessing and subsequent source separation. It also provides functions for motion data processing and extraction of event markers from different data modalities, including the extraction of eye-movement and gait-related events from EEG using independent component analysis. The pipeline introduces a new robust method for region-of-interest-based group-level clustering of independent EEG components. Finally, the BeMoBIL Pipeline provides analytical visualizations at various processing steps, keeping the analysis transparent and allowing for quality checks of the resulting outcomes. All parameters and steps are documented within the data structure and can be fully replicated using the same scripts. This pipeline makes the processing and analysis of (mobile) EEG and body data more reliable and independent of the prior experience of the individual researchers, thus facilitating the use of EEG in general and MoBI in particular. It is an open-source project available for download at https://github.com/BeMoBIL/bemobil-pipeline which allows for community-driven adaptations in the future.
Atmospheric nitrogen fixation by eukaryotes: Should we reconsider the nitrogen cycle in nature?
Authors: Arapitsas Nikolaos , Christakis Christos A. , Angelakis George , Maragkoudakis Aristeidis , Kotzabasis Kiriakos , Sarris Panagiotis F.
Published: September 2022

Nitrogen is the most abundant element in our planet’s atmosphere. Approximately 78% of the atmosphere is made up of nitrogen gas (N2). It is essential for organisms, as a major component of biomolecules and cellular biochemistry. Until today, atmospheric N2 assimilation in eukaryotic organisms has been reported to occur only through specific symbiotic N2-fixing bacterial groups that make it available to plants, the base of the food chain.

In this work, using Gas Chromatography with Thermal Conductivity Detection, we proved the direct consumption of atmospheric N2 by eukaryotic organisms. Three yeast species: Debaryomyces hansenii, Metschnikowia reukaufii and model-species Saccharomyces cerevisiae are able to directly assimilate atmospheric nitrogen in various conditions, with a yet unknown mechanisms that are not based on the presence of known N2-fixation enzymes. Our findings could change the way we consider the N2-assimilation in nature, laying the basis for future focused studies on the molecular mechanism underling the biological phenomenon of eukaryotic N2-assimilation.
The paradoxical relationship between CRISPR-Cas and phage susceptibility in Pseudomonas aeruginosa
Authors: Lood Cédric , Verkinderen Emma , Fabijan Aleksandra Petrovic , Iredell Jonathan R. , Ceyssens Pieter-Jan , Lavigne Rob , van Noort Vera
Published: September 2022

CRISPR-Cas systems are part of the pan-immune system of Pseudomonas aeruginosa and have been shown to limit horizontal gene transfers in that species. Indeed, isolates equipped with these systems tend to have smaller genomes and CRISPR spacers targeting integrative conjugative elements, phages, and plasmids. In this work, we investigate the genomic effects and phenotypic consequences of CRISPR-Cas systems in P. aeruginosa. First, we establish that the population structure is a confounding factor of the relation between genome sizes and the presence of CRISPR-Cas systems in P. aeruginosa as isolates from group II are, on average, 200 kbp larger than those from group I, and have a lower likelihood of possessing CRISPR-Cas systems. Second, we show that the impact on the genome size of CRISPR deactivation by anti-CRISPR proteins differs between the various CRISPR-Cas types found in this species (I-C, I-E, and I-F). Finally, we highlight a paradoxical, positive correlation between the presence of CRISPR-Cas systems and the chances of the host being infected by a set of distinct, strictly virulent Pseudomonas phages. We propose that this increased phage susceptibility in the presence of CRISPR-Cas is linked to a depletion of other accessory defense system genes in isolates with CRISPR-Cas systems.

Note: This manuscript was published as a chapter in the doctoral dissertation of Cédric Lood [72]
Concomitant Vascular Calsequestrin 2 overexpression and leukocytes transmigration in a rat model of skeletal muscle traumatic inflammatory injury
Authors: Khalaf Noureddine Ben , Al-Mehatab Dalal , Fathallah Dahmani M.
Published: September 2022

The network of molecular mediators involved in the transmigration of leukocytes to inflamed tissues has been expanding with the identification of new molecules involved in the inflammatory response. We have previously shown using a rat model that Protein Disulfide Isomerase PDIA4 (ERP72) is involved in the inflammatory response to skeletal muscle traumatic injury. In this paper, we report observations suggesting that calsequestrin 2 (CASQ2), another member of the thioredoxin/PDI family, might contribute to the inflammatory response that leads to adhesion and transmigration of leukocytes into injured skeletal muscle. Indeed, real time PCR assay showed that the expression level CASQ2 is significantly enhanced [p<0.01] in the mechanically injured muscle. Immunohistological and immunofluorescence analysis showed that CASQ2 but not CASQ1 is expressed in the vessels present in the muscle-injured area. In addition, CASQ2 overexpression and PMN transmigration to the inflamed muscle injury are concomitant. This overexpression occurs most likely in the smooth muscle of the inflamed vessel. These observations together with the known Ca2+ buffering role of CASQ2 suggest that the protein contributes to the inflammatory process by providing the Ca2+ needed to activate the inflammasome and the leukocytes adhesion molecules which enhances transmigration of inflammatory cells into the injured muscle.
RACK1 may participate in placental development via regulating proliferation and migration of trophoblast cell in pigs following intrauterine growth restriction
Authors: Wu Zhimin , Hu Guangling , Gong Ting , Hu Qun , Hong Linjun , Zhang Yiyu , Ao Zheng
Published: September 2022

Intrauterine growth restriction (IUGR) is a severe complication in swine production. Placental insufficiency is responsible for inadequate fetal growth, but the specific etiology of placental dysfunction-induced IUGR in pigs remains poorly understood. In this work, placenta samples supplying the lightest-weight (LW) and mean-weight (MW) pig fetuses in the litter at day 65 (D65) of gestation were collected, and the relationship between fetal growth and placental morphologies and functions was investigated using histomorphological analysis, RNA sequencing, quantitative polymerase chain reaction, and in-vitro experiment in LW and MW placentas. Results showed that the folded structure of the epithelial bilayer of LW placentas followed a poor and incomplete development compared with that of MW placentas. A total of 632 differentially expressed genes (DEGs) were screened out between the LW and MW placentas, and RACK1 was found to be downregulated in LW placentas. The DEGs were mainly enriched in translation, ribosome, protein synthesis, and mTOR signaling pathway according to GO and KEGG enrichment analyses. In-vitro experiments indicated that the decreased RACK1 in LW placentas may be involved in abnormal development of placental folds (PFs) by inhibiting the proliferation and migration of porcine trophoblast cells. Taken together, these results revealed that RACK1 may be a vital regulator in the development of PFs via regulating trophoblast ribosome function, proliferation, and migration in pigs.
Cross-reactive single-domain antibodies to hemagglutinin stem region protect mice from group 1 influenza A virus infection
Authors: Voronina Darya V. , Bandelyuk Alina S. , Dzharullaeva Alina Sh. , Popova Olga , Kan Vladislav Yu. , Esmagambetov Ilias B. , Favorskaya Irina A. , Shcheblyakov Dmitry V. , Naroditskiy Boris S. , Gintsburg Aleksandr L.
Published: September 2022

The continued evolution of influenza viruses reduces the effectiveness of vaccination and antiviral drugs. The identification of novel and universal agents for influenza prophylaxis and treatment is an urgent need. We have previously described two potent single-domain antibodies (VHH), G2.3 and H1.2, which efficiently neutralize H1N1 and H5N2 influenza viruses in vivo. In this study, we modified these VHHs with Fc-fragment to enhance their antiviral activity. Reformatting of G2.3 into bivalent Fc-fusion molecule increased its in vitro neutralizing activity against H1N1 and H2N3 viruses up to 20-fold and, moreover, resulted in obtaining the ability to neutralize H5N2 and H9N2 subtypes. We demonstrated that a dose as low as 0.6 mg/kg of G2.3-Fc or H1.2-Fc administered systemically or locally before infection could protect mice from lethal challenges with both H1N1 and H5N2 viruses. Furthermore, G2.3-Fc reduced the lung viral load to an undetectable level. Both VHH-Fc showed in vivo therapeutic efficacy when delivered via systemic or local route. The findings support G2.3-Fc as a potential therapeutic agent for both prophylaxis and therapy of Group 1 influenza A infection.
Validity of Optical Heart Rate Measurement in Commercially Available Wearable Fitness Tracking Devices
Authors: Thomas Jason , Doyle Patrick , Doyle J. Andrew
Published: September 2022

Background

Wearable fitness tracking devices have risen in popularity for athletes and the general population and are increasingly integrated into smartwatch technology. Many devices incorporate optical heart rate (HR) measurement by photoplethysmography which provides data used to monitor and track exercise training intensities, progress, and other health and fitness related parameters.

Objective

To determine the validity of optical heart rate measurement in three fitness tracking devices while resting, walking, and running.

Methods

Twenty subjects (10 male, 10 female) completed the research study based on the ANSI/CTI standards for physical activity monitoring of heart rate under 4 different conditions: sedentary (SED), treadmill walking (WLK), running (RUN), and dynamic running/walking (DYN). Subjects wore 3 optical heart rate devices: Polar OH1 (OH1) on the right forearm, Apple Watch 4 (AW4) on the right wrist and Garmin Forerunner 945 (FR945) on the left wrist. A Polar H10 (H10), a chest strap device, was the criterion HR measurement device. SED, WLK, and RUN were all 7-minute protocols with 1 minute of standing, 5 minutes of prescribed activity, and 1 final minute of standing. The DYN protocol was a 12-minute protocol with 1 minute of standing, 10 minutes of variable intensity walking and running, and 1 minute of standing. Raw HR data was extracted from each device and temporally aligned with the criterion H10 HR data for analysis.

Results

The mean absolute deviation (MAD, measured in beats per minute) for the three experimental devices (OH1, AW4, FR945, respectively) for SED was 1.31, 1.33, and 2.03; for WLK was 2.79, 2.58, and 5.19; for RUN were 4.00, 4.29, and 6.51; and for DYN was 2.60, 2.44, and 2.44. The mean absolute percent error (MAPE) for the three experimental devices (OH1, AW4, FR945, respectively) for SED was 1.78%, 1.89%, and 2.81%; for WLK was 3.15%, 3.18%, and 5.93%; for RUN was 3.43%, 3.51%, and 5.25%; and for DYN was 2.05%, 1.95%, and 5.47%. The intraclass correlation for each device across all conditions was .991 (OH1), .984 (AW4), and .697 (FR945).

Conclusions

At rest, and during both steady-state and variable-speed treadmill walking and running, the Polar OH1, Garmin Forerunner 945, and Apple Watch 4 optical HR monitors demonstrated a level of accuracy well within that required by the ANSI/CTA Standard (2018) for physical activity monitoring devices for heart rate measurement (i.e., <10% Mean Absolute Percent Error). Therefore, consumers can have confidence that these devices provide HR data with accuracy that conforms to the performance criteria recommended for consumer electronics.
Nanoscale Friction of Biomimetic Hair Surfaces
Authors: Weiand Erik , Ewen James P. , Roiter Yuri , Koenig Peter H. , Page Steven H. , Rodriguez-Ropero Francisco , Angioletti-Uberti Stefano , Dini Daniele
Published: September 2022

We investigate the nanoscale friction between biomimetic hair surfaces using chemical colloidal probe atomic force microscopy experiments and nonequilibrium molecular dynamics simulations. In the experiments, friction is measured between water-lubricated silica surfaces functionalised with monolayers of either octadecyl or sulfonate groups, which are representative of the surfaces of virgin and ultimately bleached hair, respectively. In the simulations, friction is monitored between coarse-grained model hair surfaces with different levels of chemical damage, where different fractions of grafted lipid molecules are randomly replaced with sulfonate groups. The sliding velocity dependence of friction can be described using an extended stress-augmented thermally activation model. As the damage level increases, the friction generally increases, but its sliding velocity-dependence decreases. At low sliding speeds, which are closer to those encountered physiologically and experimentally, we observe a monotonic increase of friction with the damage ratio, which is consistent with our new experiments using biomimetic surfaces and previous ones using real hair. This observation demonstrates that modified surface chemistry, rather than roughness changes or subsurface damage, control the increase in nanoscale friction of damaged hair. We expect the experimental and computational model surfaces proposed here to be useful to screen the tribological performance of hair care formulations.