bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomic signatures of lipid-modifying therapies using drug target Mendelian randomization
Authors: Richardson Tom G , Leyden Genevieve M , Wang Qin , Bell Joshua A , Elsworth Benjamin , Smith George Davey , Holmes Michael V 
Published: August 2021

AbstractBackgroundLarge-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on the human metabolome.MethodsWe firstly constructed genetic risk scores for 8 drug targets on the basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9 & NPC1L1), high-density lipoprotein (HDL) cholesterol (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4 & LPL). We then used Mendelian randomization to evaluate the effect of each score on coronary artery disease (CAD) risk, and to systematically estimate their effects on 249 metabolic traits derived using blood samples from an unprecedented sample size of up to 115,082 UK Biobank participants.ResultsThere was strong evidence of an effect of drug-based genetic scores on CAD risk with the exception of ANGPTL3. Genetically predicted effects on the blood metabolome were generally consistent amongst drug targets which were intended to modify the same lipoprotein lipid trait. For example, the linear fit for the MR estimates on all 249 metabolic traits for genetically-predicted inhibition of LDL cholesterol lowering targets HMGCR and PCSK9 was r2=0.91. In contrast, comparisons between drug classes that were designed to modify discrete lipoprotein traits typically had very different effects on metabolic signatures (e.g. HMGCR vs all 4 triglyceride targets had r2<0.02), despite largely consistent effects on risk of CAD. Furthermore, we highlight this discrepancy for specific metabolic traits, for example finding that LDL cholesterol lowering therapies typically had a weak effect on glycoprotein acetyls, a marker of inflammation (e.g. PCSK9: Beta=0.01, 95 CI%=-0.06 to 0.08, P=0.78). In contrast, all of the triglyceride modifying therapies assessed provided evidence of a strong effect on lowering levels of this inflammatory biomarker (e.g. LPL: Beta=-0.43, 95 CI%=-0.37 to -0.48, P=9×10−50).ConclusionsMultiple lipid-modifying drug targets have therapeutically beneficial effects on CAD risk. Our findings indicate that genetically predicted perturbations of these drug targets on the blood metabolome can drastically differ, with potential implications for biomarkers in clinical development and measuring treatment response.
Titin switches from an extensible spring to a mechanical rectifier upon muscle activation
Authors: Squarci Caterina , Bianco Pasquale , Reconditi Massimo , Caremani Marco , Narayanan Theyencheri , Csizmadia Andras Málnási , Linari Marco , Lombardi Vincenzo , Piazzesi Gabriella 
Published: August 2021

SUMMARYIn contracting striated muscle titin acts as a spring in parallel with the array of myosin motors in each half-sarcomere and could prevent the intrinsic instability of thousands of serially linked half-sarcomeres, if its stiffness, at physiological sarcomere lengths (SL), were ten times larger than reported. Here we define titin mechanical properties during tetanic stimulation of single fibres of frog muscle by suppressing myosin motor responses with Para-Nitro-Blebbistatin, which is able to freeze thick filament in the resting state. We discover that thin filament activation switches I-band titin spring from the large SL-dependent extensibility of the OFF-state to an ON-state in which titin acts as a SL-independent mechanical rectifier, allowing free shortening while opposing stretch with an effective stiffness 4 pN nm−1 per half-thick filament. In this way during contraction titin limits weak half-sarcomere elongation to a few % and, also, provides an efficient link for mechanosensing-based thick filament activation.
Apoplastic effector candidates of a foliar forest pathogen trigger cell death in host and non-host plants
Authors: Hunziker Lukas , Tarallo Mariana , Gough Keiko , Guo Melissa , Hargreaves Cathy , Loo Trevor S. , McDougal Rebecca L. , Mesarich Carl H. , Bradshaw Rosie E. 
Published: August 2021

AbstractForests are under threat from pests, pathogens, and changing climate. One of the major forest pathogens worldwide isDothistroma septosporum, which causes dothistroma needle blight (DNB) of pines.D. septosporumis a hemibiotrophic fungus related to well-studied Dothideomycete pathogens, such asCladosporium fulvum. These pathogens use small secreted proteins, termed effectors, to facilitate the infection of their hosts. The same effectors, however, can be recognised by plants carrying corresponding immune receptors, resulting in resistance responses. Hence, effectors are increasingly being exploited to identify and select disease resistance in crop species. In gymnosperms, however, such research is scarce. We predicted and investigated apoplasticD. septosporumcandidate effectors (DsCEs) using bioinformatics and plant-based experiments. We discovered secreted proteins that trigger cell death in the angiospermNicotianaspp., suggesting their recognition by immune receptors in non-host plants. In a first for foliar forest pathogens, we also developed a novel protein infiltration method to show that tissue-cultured pine shoots can respond with a cell death response to one of our DsCEs, as well as to a reference cell death-inducing protein. These results contribute to our understanding of forest pathogens and may ultimately provide clues to disease immunity in both commercial and natural forests.
Endogenous auxin directs development of embryonic stem cells into somatic proembryos in Arabidopsis
Authors: Karami Omid , Philipsen Cheryl , Rahimi Arezoo , Nurillah Annisa Ratna , Boutilier Kim , Offringa Remko 
Published: August 2021

AbstractSomatic embryogenesis (SE) is the process by which embryos develop from in vitro cultured vegetative tissue explants. The synthetic auxin 2,4-dichlorophenoxyacetic acid (2,4-D) is widely used for SE induction, but SE can also be induced by overexpression of specific transcription factors, such as AT-HOOK MOTIF NUCLEAR LOCALIZED 15 (AHL15). 2,4-D and AHL15 both trigger the biosynthesis of the natural auxin indole-3-acetic acid (IAA). However, the role of this endogenously produced auxin in SE is yet not well understood. In this study we show that the induction of embryonic stem cells from explants does not require IAA biosynthesis, whereas an increase in IAA levels is essential to maintain embryo identity and for embryo formation from these stem cells. Further analysis showed that YUCCA (YUC) genes involved in the IPyA auxin biosynthesis pathway are up-regulated in embryo-forming tissues. Chemical inhibition of the IPyA pathway significantly reduced or completely inhibited the formation of somatic embryos in both 2,4-D-and AHL15-dependent systems. In the latter system, SE could be restored by exogenous IAA application, confirming that the biosynthesis-mediated increase in IAA levels is important. Our analyses also showed that PIN1 and AUX1 are the major auxin carriers that determine respectively auxin efflux and influx during SE. This auxin transport machinery is required for the proper transition of embryonic cells to proembryos and, later, for correct cell fate specification and differentiation. Taken together, our results indicate that auxin biosynthesis in conjunction with its polar transport are required during SE for multicellular somatic proembryo development and differentiation.One sentence summarySomatic embryogenesis in Arabidopsis requires auxin biosynthesis and polar auxin transport only after the acquisition of embryonic competence for somatic proembryo development and differentiation.
Hippocampal-hypothalamic circuit controls context-dependent innate defensive responses
Authors: Bang Jee Yoon , Sunstrum Julia , Garand Danielle , Parfitt Gustavo Morrone , Woodin Melanie , Inoue Wataru , Kim Jun Chul 
Published: August 2021

AbstractPreys use their memory - where they sensed a predatory threat and whether a safe shelter is nearby - to dynamically control their survival instinct to avoid harm and reach safety. However, it remains unknown which brain regions are involved, and how such top-down control of innate behaviour is implemented at the circuit level. Here, we show that the anterior hypothalamic nucleus (AHN) is best positioned to perform this task as an exclusive target of the hippocampus (HPC) within the medial hypothalamic defense system. Selective optogenetic stimulation and inhibition of hippocampal inputs to the AHN revealed that the HPC→AHN pathway not only mediates the contextual memory of predator threats but also controls the goal-directed escape by transmitting information about the surrounding environment. These results reveal a new mechanism for experience-dependent, top-down control of innate defensive behaviours.
Broad-spectrum in vitro antiviral activity of ODBG-P-RVn: an orally-available, lipid-modified monophosphate prodrug of remdesivir parent nucleoside (GS-441524)
Authors: Lo Michael K. , Shrivastava-Ranjan Punya , Chatterjee Payel , Flint Mike , Beadle James R. , Valiaeva Nadejda , Schooley Robert T. , Hostetler Karl Y. , Montgomery Joel M. , Spiropoulou Christina 
Published: August 2021

ABSTRACTThe intravenous administration of remdesivir for COVID-19 confines its utility to hospitalized patients. We evaluated the broad-spectrum antiviral activity of ODBG-P-RVn, an orally available, lipid-modified monophosphate prodrug of the remdesivir parent nucleoside (GS-441524) against viruses that cause diseases of human public health concern, including SARS-CoV-2. ODBG-P-RVn showed 20-fold greater antiviral activity than GS-441524 and had near-equivalent activity to remdesivir in primary-like human small airway epithelial cells. Our results warrant investigation of ODBG-P-RVn efficacy in vivo.
SARS-CoV-2 Suppression and Early Closure of Bars and Restaurants : A Longitudinal Natural Experiment
Authors: Takaku Reo , Yokoyama Izumi , Tabuchi Takahiro , Oguni Masaki , Fujiwara Takeo 
Published: August 2021

AbstractDespite severe economic damage, full-service restaurants and bars have been closed in hopes of suppressing the spread of SARS-CoV-2 worldwide. This paper explores whether the early closure of restaurants and bars in February 2021 reduced symptoms of SARS-CoV-2 in Japan. Using a large-scale nationally representative longitudinal survey, we found that the early closure of restaurants and bars decreased the utilization rate among young persons (OR 0.688; CI95 0.515-0.918) and those who visited these places before the pandemic (OR 0.754; CI95 0.594-0.957). However, symptoms of SARS-CoV-2 did not decrease in these active and high-risk subpopulations. Among the more inactive and low-risk subpopulations, such as elderly persons, no discernible impacts are observed in both the utilization of restaurants and bars and the symptoms of SARS-CoV-2. These results suggest that the early closure of restaurants and bars without any other concurrent measures does not contribute to the suppression of SARS-CoV-2.
Investigating heterogeneous genetic effects contributing to smoking behaviors
Authors: Funkhouser Scott A , Boardman Jason D , Hewitt John K , Stallings Michael C , Hopfer Christian J , Brown Sandra A , Wall Tamara L , Reynolds Chandra A , Keller Matthew C , Evans Luke M 
Published: August 2021

AbstractThe genetic architecture of numerous smoking behaviors is highly polygenic, but these genetic effects are heterogeneous and depend on moderating factors. Here, we used common SNPs from the UK Biobank to investigate heterogeneous genetic effects for smoking heaviness using cigarettes per day (CPD) records, smoking initiation (SI), and smoking cessation (SC). We assessed heterogeneous effects across levels of sex, age of smoking initiation, major depressive disorder (MDD) DSM-V-like diagnosis, generalized anxiety disorder (GAD) DSM-V-like diagnosis, and whether an individual has seen a psychiatrist for nerves, anxiety, tension, or depression. We observed suggestive evidence of heterogeneous genetic effects for CPD and SC, moderated by MDD and GAD, respectively [ (SE = 0.15) between MDD cases and controls, and (SE = 0.28) between GAD cases and controls, p < 0.05]. We detected 5 SNPs with genome-wide significant evidence of heterogeneous effects moderated by either MDD or GAD (p-value < 5×10-8) for CPD and SC. We also observed strong evidence for heterogeneous genetic effects for SI between sexes (between-sex , SE = 0.02). While we detected no individual SNPs that were moderated by sex at genome-wide significance (all p-value > 5×10-8), we observed evidence of novel genome-wide significant SI-SNP associations using sex-stratified GWAS; six loci were discovered in either men or women separately that were not identified in a previous smoking meta-analysis that had a 6-fold larger, sex-combined sample. Furthermore, using several independent testing samples, there was suggestive evidence that the prediction ability of a polygenic risk score (PRS) for smoking initiation improved through the utilization of sex-specific SNP effects. This work suggests that a more nuanced approach to GWAS analyses is warranted, as potential heterogeneous effects can complicate variant discovery and polygenic risk score accuracy.Author SummarySmoking imposes a heavy health burden and is highly polygenic in architecture. Consistent with most complex traits, many causal loci have yet to be identified, even when using the largest available samples. One possible reason for the difficulty in inferring genetic variants associated with such complex traits is that common genetic variants possess context-dependent (or heterogeneous) effects. Utilizing the UK Biobank, we find evidence for heterogeneous SNP effects on smoking initiation, heaviness, and cessation among psychiatric disorder cases and controls and between sexes. Failure to model such heterogeneity (when accounting for sample size) resulted in lower independent sample predictive ability. This work encourages a more nuanced approach to GWAS and polygenic risk prediction. The assumption that all genetic effects are homogeneous limits our understanding of complex traits when heterogeneous effects are present.
Powerful eQTL mapping through low coverage RNA sequencing
Authors: Schwarz Tommer , Boltz Toni , Hou Kangcheng , Bot Merel , Duan Chenda , Loohuis Loes Olde , Boks Marco P. , Kahn René S. , Ophoff Roel A. , Pasaniuc Bogdan 
Published: August 2021

ABSTRACTMapping genetic variants that regulate gene expression (eQTL mapping) in large-scale RNA sequencing (RNA-seq) studies is often employed to understand functional consequences of regulatory variants. However, the high cost of RNA-Seq limits sample size, sequencing depth, and therefore, discovery power. In this work, we demonstrate that, given a fixed budget, eQTL discovery power can be increased by lowering the sequencing depth per sample and increasing the number of individuals sequenced in the assay. We perform RNA-Seq of whole blood tissue across 1490 individuals at low-coverage (5.9 million reads/sample) and show that the effective power is higher than that of an RNA-Seq study of 570 individuals at high-coverage (13.9 million reads/sample). Next, we leverage synthetic datasets derived from real RNA-Seq data to explore the interplay of coverage and number individuals in eQTL studies, and show that a 10-fold reduction in coverage leads to only a 2.5-fold reduction in statistical power. Our study suggests that lowering coverage while increasing the number of individuals is an effective approach to increase discovery power in RNA-Seq studies.
The Cell Adhesion Molecule TMIGD1 Binds to Moesin and Regulates Tubulin Acetylation and Cell Migration
Authors: Rahimi Nader , Ho Rachel X-Y , Chandler Kevin Brown , De La Cena Kyle Oliver Corcino , Amraei Razie , Mitchel Ashley J , Engblom Nels , Costello Catherine E 
Published: August 2021

ABSTRACTBackgroundThe cell adhesion molecule transmembrane and immunoglobulin (Ig) domain containing1 (TMIGD1) is a novel tumor suppressor that plays important roles in regulating cell-cell adhesion, cell proliferation and cell cycle. However, the mechanisms of TMIGD1 signaling are not yet fully elucidated.ResultsTMIGD1 binds to the ERM family proteins moesin and ezrin, and an evolutionarily conserved RRKK motif on the carboxyl terminus of TMIGD1 mediates the interaction of TMIGD1 with the N-terminal ERM domains of moesin and ezrin. TMIGD1 governs the apical localization of moesin and ezrin, as the loss of TMIGD1 in mice altered apical localization of moesin and ezrin in epithelial cells. In cell culture, TMIGD1 inhibited moesin-induced filopodia-like protrusions and cell migration. More importantly, TMIGD1 stimulated the Lysine (K40) acetylation of α-tubulin and promoted mitotic spindle organization and CRISPR/Cas9-mediated knockout of moesin impaired the TMIGD1-mediated acetylation of α-tubulin and filamentous (F)-actin organization.ConclusionsTMIGD1 binds to moesin and ezrin, and regulates their cellular localization. Moesin plays critical roles in TMIGD1-dependent acetylation of α-tubulin, mitotic spindle organization and cell migration. Our findings offer a molecular framework for understanding the complex functional interplay between TMIGD1 and the ERM family proteins in the regulation of cell adhesion and mitotic spindle assembly, and have wide-ranging implications in physiological and pathological processes such as cancer progression.
Vaccine safety surveillance using routinely collected healthcare data – An empirical evaluation of epidemiological designs
Authors: Schuemie Martijn J. , Arshad Faaizah , Pratt Nicole , Nyberg Fredrik , Alshammari Thamir M , Hripcsak George , Ryan Patrick , Prieto-Alhambra Daniel , Lai Lana YH , Li Xintong , Stephen Fortin , Minty Evan , Suchard Marc A. 
Published: August 2021

AbstractBackgroundRoutinely collected healthcare data such as administrative claims and electronic health records (EHR) can complement clinical trials and spontaneous reports when ensuring the safety of vaccines, but uncertainty remains about what epidemiological design to use.MethodsUsing 3 claims and 1 EHR database, we evaluate several variants of the case-control, comparative cohort, historical comparator, and self-controlled designs against historical vaccinations with real negative control outcomes (outcomes with no evidence to suggest that they could be caused by the vaccines) and simulated positive controls.ResultsMost methods show large type 1 error, often identifying false positive signals. The cohort method appears either positively or negatively biased, depending on the choice of comparator index date. Empirical calibration using effect-size estimates for negative control outcomes can restore type 1 error to close to nominal, often at the cost of increasing type 2 error. After calibration, the self-controlled case series (SCCS) design shows the shortest time to detection for small true effect sizes, while the historical comparator performs well for strong effects.ConclusionsWhen applying any method for vaccine safety surveillance we recommend considering the potential for systematic error, especially due to confounding, which for many designs appears to be substantial. Adjusting for age and sex alone is likely not sufficient to address the differences between vaccinated and unvaccinated, and for the cohort method the choice of index date plays an important role in the comparability of the groups Inclusion of negative control outcomes allows both quantification of the systematic error and, if so desired, subsequent empirical calibration to restore type 1 error to its nominal value. In order to detect weaker signals, one may have to accept a higher type 1 error.HighlightsMost methods used in vaccine safety surveillance show large type 1 error, which could lead to many false safety signals.Empirical calibration using effect-size estimates for negative control outcomes can restore type 1 error to close to nominal, often at the cost of marginal increases in type 2 error.After calibration, the self-controlled case series (SCCS) design shows the shortest time to detection for small true effect sizes, while the historical comparator appears best for large true effect sizes.Implementing negative control outcomes in a safety surveillance system is recommended to identify vulnerability to systematic error.
What is the future of lab-on-a-chip diagnostic devices? Assessing changes in experts’ expectations over time
Authors: Mota Fabio , Braga Luiza Amara Maciel , Cabral Bernardo Pereira Pereira , Conte Filho Carlos Gilbert 
Published: August 2021

Purpose
Lab on-a-chip (LOC) may lead to low-cost point-of-care devices for the diagnosis of human diseases, possibly making laboratories dispensable. However, as it is still an emerging technology, very little is known about its future impact on the diagnosis of human diseases, and on the laboratory industry. Hence, the purpose of this study is to foresee possible developments of this technology through a consultation with researchers in the field in two distinct time periods.

Design/methodology/approach
Based on Technology Foresight, this study addresses this gap by assessing the opinions of over five hundred LOC researchers and tracking changes in their views on the future of LOC diagnostic devices. These researchers participated in a two-wave global survey with an interval of two and a half years

Findings
Although second-wave (2020) respondents are less optimistic than those of the first wave (2017), the results of both surveys show that LOC diagnostic devices are expected to: move from proof-of-concept demonstrations to industrial development, becoming commercially feasible worldwide; integrate all laboratory processes, delivering cheaper, faster and more reliable diagnoses than laboratories; and provide low-cost point-of-care solutions, improving access to healthcare.

Research limitations/implications
Although it would be desirable to collect and explore the views of different sets of stakeholders, the method of generating lists of survey respondents shows a bias toward academic/scientific circles because the respondents are authors of scientific publications. These publications may as well be authored by stakeholders from other fields but it is reasonable to assume that most of them are researchers affiliated with universities and research and development organizations. Therefore, this study lacks in providing an image of the future based on a more diverse set of respondents.

Social implications
The results show that these devices are expected to radically change the diagnostic testing market and the way laboratories are organized, perhaps moving to a non-laboratory-based model. In conclusion, in the coming decades, these devices may promote substantial changes in the way human diseases are diagnosed.

Originality/value
Only a few studies have attempted to foresee the future of LOC devices, and most are based on literature reviews. Thus, this study goes beyond the existing research by providing a broad understanding of what the future will look like from the views of researchers who are contributing to the advancement of knowledge in the field. The researchers invited to take part in this study are authors of LOC-related scientific publications indexed in the Web of Science Core Collection.