bluuebunny/crossref_metadata_2025 huggingface dataset:
Causal feature selection using a knowledge graph combining structured knowledge from the biomedical literature and ontologies: a use case studying depression as a risk factor for Alzheimer's disease
Authors: Malec Scott Alexander , Taneja Sanya B , Albert Steven M , Shaaban C. Elizabeth , Karim Helmet T , Levine Art S , Munro Paul Wesley , Callahan Tiffany J , Boyce Richard David
Published: July 2022

Background: Causal feature selection is essential for estimating effects from observational data. Identifying confounders is a crucial step in this process. Traditionally, researchers employ content-matter expertise and literature review to identify confounders. Uncontrolled confounding from unidentified confounders threatens validity, conditioning on intermediate variables (mediators) weakens estimates, and conditioning on common effects (colliders) induces bias. Additionally, without special treatment, erroneous conditioning on variables combining roles introduces bias. However, the vast literature is growing exponentially, making it infeasible to assimilate this knowledge. To address these challenges, we introduce a novel knowledge graph (KG) application enabling causal feature selection by combining computable literature-derived knowledge with biomedical ontologies. We present a use case of our approach specifying a causal model for estimating the total causal effect of depression on the risk of developing Alzheimer's disease (AD) from observational data. Methods: We extracted computable knowledge from a literature corpus using three machine reading systems and inferred missing knowledge using logical closure operations. Using a KG framework, we mapped the output to target terminologies and combined it with ontology-grounded resources. We translated epidemiological definitions of confounder, collider, and mediator into queries for searching the KG and summarized the roles played by the identified variables. Finally, we compared the results with output from a complementary method and published observational studies and examined a selection of confounding and combined role variables in-depth. Results: Our search identified 128 confounders, including 58 phenotypes, 47 drugs, 35 genes, 23 collider, and 16 mediator phenotypes. However, only 31 of the 58 confounder phenotypes were found to behave exclusively as confounders, while the remaining 27 phenotypes played other roles. Obstructive sleep apnea emerged as a potential novel confounder for depression and AD. Anemia exemplified a variable playing combined roles. Conclusion: Our findings suggest combining machine reading and KG could augment human expertise for causal feature selection. However, the complexity of causal feature selection for depression with AD highlights the need for standardized field-specific databases of causal variables. Further work is needed to optimize KG search and transform the output for human consumption.
Community evenness and sample size affect estimates of predation intensity and prey selection: A model-based validation
Authors: Bhattacherjee Madhura , Chattopadhyay Devapriya
Published: July 2022

Predation estimates inferred from the preserved records of predation traces are essential in evaluating the evolutionary effect of ecological interactions. It is, however, crucial to establish how sampling intensity and community composition of an assemblage influence the reliability of these measures.

Using a resampling technique, we evaluated the effect of sampling intensity and a community’s evenness on the inferred predation estimates. We theoretically simulated model communities representing different levels of evenness, predation intensity, and predatory behavior (selective, non-selective). We calculated the total predation intensity and the number of prey species for each community. We then resampled each community without replacement and noted variations in the inferred measure from the accurate estimate as the sampling intensity increased. Our results demonstrate that the evenness of a community does not influence the inferred predation intensity for non-selective predation. However, communities with highly selective predation are sensitive to evenness and sampling intensity; inferred predation intensity of these assemblages can substantially differ from the actual value. The inferred number of prey species is also influenced by the community’s original evenness, predation selectivity, and predation intensity. When predation is selective, sampling intensity heavily influences communities with low evenness and low predation intensity; inferred predation intensity is underrepresented in smaller sample sizes. For communities of low evenness and predation intensity where rare species are attacked preferentially, the inferred prey richness differs significantly at a small sample size.

We proposed a post-facto standardization method for comparing predation estimates of discrete communities that differ in the sample size. We validated its utility using the published predation data of the Plio-Pleistocene molluscan fossil assemblage. The present approach attempts to provide critical insight into the reliability of predation estimates and may help in comparing predation patterns across time and space. Several factors, including preservation bias, might impact the final predation signature of an assemblage. It warrants a future research direction to develop a comprehensive framework of post-hoc standardization of assemblages with differing predation styles and preservation history.
Is there a placental microbiota? A critical review and re-analysis of published placental microbiota datasets
Authors: Panzer Jonathan , Romero Roberto , Greenberg Jonathan M. , Winters Andrew D. , Galaz Jose , Gomez-Lopez Nardhy , Theis Kevin R.
Published: July 2022

The existence of a placental microbiota is under debate. The human placenta has historically been considered sterile and microbial colonization has been associated with adverse pregnancy outcomes. Yet, recent investigations using DNA sequencing reported a microbiota in human placentas from typical term pregnancies. However, this detected microbiota could represent background DNA contamination. Using fifteen publicly available 16S rRNA gene datasets, existing data were uniformly re-analyzed. 16S rRNA gene Amplicon Sequence Variants (ASVs) identified as Lactobacillus were highly abundant in eight of fifteen studies. However, the prevalence of Lactobacillus, a typical vaginal bacterium, was clearly driven by bacterial contamination from vaginal delivery and background DNA. After removal of likely DNA contaminants, Lactobacillus ASVs were highly abundant in only one of five studies for which data analysis could be restricted to placentas from term cesarean deliveries. A six study sub-analysis targeting the 16S rRNA gene V4 hypervariable region demonstrated that bacterial profiles of placental samples and technical controls share principal bacterial ASVs and that placental samples clustered primarily by study origin and mode of delivery. Across studies, placentas from typical term pregnancies did not share a consistent bacterial taxonomic signal. Contemporary DNA- based evidence does not support the existence of a placental microbiota.

IMPORTANCE

Early-gestational microbial influences on human development are unclear. By applying DNA sequencing technologies to placental tissue, bacterial DNA signals were observed, leading some to conclude that a live bacterial placental microbiome exists in typical term pregnancy. However, the low-biomass nature of the proposed microbiome and high sensitivity of current DNA sequencing technologies indicate that the signal may alternatively derive from environmental or delivery-associated bacterial DNA contamination. Here we address these alternatives with a re- analysis of 16S rRNA gene sequencing data from 15 publicly available placental datasets. After identical DADA2 pipeline processing of the raw data, subanalyses were performed to control for mode of delivery and environmental DNA contamination. Both environment and mode of delivery profoundly influenced the bacterial DNA signal from term-delivered placentas. Aside from these contamination-associated signals, consistency was lacking across studies. Thus, placentas delivered at term are unlikely to be the original source of observed bacterial DNA signals.
Walking the line between assessment, improvement, and learning: an exploratory study on opportunities and risks of peer discussion of audit and feedback
Authors: van der Winden Dorien , van Dijk Nynke , Visser Mechteld , Bont Jettie
Published: July 2022

Introduction

There is a broad call for change in existing quality systems within health care. One of the anticipated reforms, is transferring ownership back to care deliverers. A promising way to establish this in general practice care, is to combine audit and feedback with peer group discussion. However, it is unknown what different stakeholder groups think of giving prominence to this type of quality improvement. In this study we explore ideas and opinions of different stakeholder groups in general practice on the opportunities and risks that could arise.

Methods

We conducted an exploratory qualitative study, combining interviews with focus discussion groups. Included stakeholder groups were general practitioners, patients, professional organizations and insurance companies. Within a constructivist paradigm, two researchers coded the data in three rounds, using thematic analysis. After continuously comparing and discussing codes with a third researcher, a final code tree emerged, presenting us with the main themes.

Results

In eight interviews and two focus discussion groups, 22 participants reflected upon opportunities and risks. We identified three main opportunities: deeper levels of reflection upon data, adding context to numbers and more ownership, and three main risks: handling of unwilling colleagues, lacking a safe group and the necessity of patient involvement. An additional theme concerned disagreement on the amount of transparency that should be offered: insurance companies and patients advocated for complete transparency on data and improvement of outcomes, while GPs and professional organizations urged to restrict transparency to giving insight into the process.

Conclusion

Peer discussion of audit and feedback could be part of a change movement, towards a quality system based on learning and trust, that is powered from within the profession. Creating a safe learning environment is key herein. Caution is needed when complete transparency is asked, since it can jeopardize practitioners’ reflection and learning in safety.

Strengths and limitations of this study

Exploratory study of a gap in the knowledge towards implementation of a promising intervention.

Participants included the four main stakeholder groups that are involved in implementation, in order to study agreement and disagreement between different stakeholders.

Additional stakeholders, such as governmental agencies, were not included. They may have offered other perspectives.

This exploratory qualitative study offers insight into opportunities and risks. In order to get a broad overview of how these findings are supported by GPs in general, additional quantitative research is necessary.
Battle for the histones: a secreted bacterial sirtuin from Campylobacter jejuni activates neutrophils and induces inflammation during infection
Authors: Callahan Sean M. , Hancock Trevor J. , Doster Ryan S. , Parker Caroline B. , Wakim Mary E. , Gaddy Jennifer A. , Johnson Jeremiah G.
Published: July 2022

Histone modifications alter numerous cornerstone processes in eukaryotes, including metabolism, physiology, and immunity. Numerous bacterial pathogens can alter expression of host-derived sirtuins to deacetylate histones in order to promote infection, yet, a bacterial-derived sirtuin has yet to be investigated to deacetylate host histones. Using Campylobacter jejuni, the leading cause of bacterial-derived gastroenteritis, we found a secreted sirtuin, SliP, which binds to and deacetylates neutrophil histones. We found neutrophil activation and extrusion of neutrophil extracellular traps was SliP dependent, whereby sliP mutants are unable to activate neutrophils or promote NETosis. Leveraging the mouse model of campylobacteriosis, we further demonstrate the sliP mutant can efficiently infect IL-10-/- mice, but induction of proinflammatory cytokine production and gastrointestinal pathology is SliP-dependent. In conclusion, we investigate a unique bacterial effector which targets host histones and is responsible for the inflammatory response and tissue pathology observed during campylobacteriosis.

Highlights

C. jejuni encodes a secreted effector, SliP, which functions as a canonical sirtuin

SliP binds to and deacetylates neutrophil histone H3 during bacterial infection

C. jejuni-induced neutrophil activation and NETosis are SliP-dependent

Inflammation and tissue pathology during C. jejuni infection is SliP-dependent
Antigen binding kinetics are quite different for B-cell receptors and free antibodies
Authors: García-Sánchez Miguel , Castro Mario , Faro José
Published: July 2022

Since the pioneering works of Berg and Purcell, discriminating between diffusion followed by binding has played a central role in understanding cell signaling. B-cell receptors (BCR) and antibodies (Ab) challenge that simplified view as binding to antigen follows after a chain of diffusion and rotations, including whole molecule rotation, and independent tilts and twists of their Fab arms due to their Y-shaped structure and flexibility. In this paper, we combine analytical calculations with Brownian simulations to derive the first-passage times due to these three rotations positioning the Fab paratopes at a proper distance and orientation required for antigen binding. Applying these estimations and those for 2-dimensional (2D) and 3D translational diffusion of, respectively, BCRs and Abs, we evidence that measuring Ab-Ag effective kinetic binding rates using experimental methods in which the analyte is in solution gives values proportional to the intrinsic binding rates,k+andk−, only for values ofk+up to 109s−1, beyond which a plateau of the effective 3D on rate between 108M−1s−1and 109M−1s−1is attained. Moreover, for BCR-Ag interactions, the effective 2D on and off binding rates can be inferred from the corresponding effective 3D on and off rates only for values of effective 3D on rates lower than 106M−1s−1. This is highly relevant when one seeks to relate BCR-antigen binding strength and B cell response, particularly during germinal center reactions. Thus, there is an urgent need to revisit our current understanding of the BCR-antigen kinetic rates in germinal centers using state-of-the-art experimental assays for BCR-Ag interactions.

Significance Statement

In germinal centers, binding between BCRs and antigen (Ag) tethered on the membrane of follicular dendritic cells occurs via two-dimensional (2D) membrane-to-membrane interactions. In contrast, inin vitroassays antibody (Ab)-antigen interactions occur with one component in solution. Structurally, there are large qualitative and quantitative differences between BCR-Ag 2D and Ab-Ag 3D translational and rotational diffusion processes, with the 2D translational diffusion being about 1000-fold lower than the 3D one. Moreover, the effective binding kinetics of both BCR-Ag and Ab-Ag interactions strongly deviate from the intrinsic molecular on and off rates. Here we expose this mismatch and, performing numerical and analytical calculations, quantify the ranges for which the experimental in-vitro data is informative on the BCR-Ag binding strength.
Tecovirimat is highly efficient on the Monkeypox virus lineage responsible for the international 2022 outbreak
Authors: Frenois-Veyrat Gaëlle , Gallardo Franck , Gorgé Olivier , Marcheteau Elie , Ferraris Olivier , Baidaliuk Artem , Favier Anne-Laure , Enfroy Cécile , Holy Xavier , Lourenco Jérémy , Khoury Rhéa , Nolent Flora , Grosenbach Douglas W. , Hruby Dennis , Ferrier Audrey , Iseni Frédéric , Simon-Loriere Etienne , Tournier Jean-Nicolas
Published: July 2022

The ongoing monkeypox virus (MPXV) outbreak is the largest ever recorded outside of Africa. Genomic analysis revealed a divergent phylogenetic lineage within clade 3, and atypical clinical presentations have been noted. We report the sequencing and isolation of the virus from the first clinical case diagnosed in France in May 2022. We tested thein vitroeffect of tecovirimat (ST-246), a FDA approved drug, against this novel strain, showing efficacy at the nanomolar range. In comparison, cidofovir showed activity at micromolar concentrations. These results and the safety profile of tecovirimat strongly support its use in clinical care of severe forms for the 2022 MPXV outbreak.
Deep generative modeling and clustering of single cell Hi-C data
Authors: Liu Qiao , Zeng Wanwen , Zhang Wei , Wang Sicheng , Chen Hongyang , Jiang Rui , Zhou Mu , Zhang Shaoting
Published: July 2022

Deciphering 3D genome conformation is important for understanding gene regulation and cellular function at a spatial level. The recent advances of single cell Hi-C technologies have enabled the profiling of the 3D architecture of DNA within individual cell, which allows us to study the cell-to-cell variability of 3D chromatin organization. Computational approaches are in urgent need to comprehensively analyze the sparse and heterogeneous single cell Hi-C data. Here, we proposed scDEC-Hi-C, a new framework for single cell Hi-C analysis with deep generative neural networks. scDEC-Hi-C outperforms existing methods in terms of single cell Hi-C data clustering and imputation. Moreover, the generative power of scDEC-Hi-C could help unveil the heterogeneity of chromatin architecture across different cell types. We expect that scDEC-Hi-C could shed light on deepening our understanding of the complex mechanism underlying the formation of chromatin contacts. scDEC-Hi-C is freely available at https://github.com/kimmo1019/scDEC-Hi-C.

Key points

scDEC-Hi-C provides an end-to-end framework based on autoencoder and deep generative model to comprehensively analyze single cell Hi-C data, including low-dimensional embedding and clustering.

Through a series of experiments including single cell Hi-C data clustering and structural difference identification, scDEC-Hi-C demonstrates suprioir performance over existing methods.

In the downstream analysis of chromatin loops from single cell Hi-C data, scDEC-Hi-C is capable of significantly enhancing the ability for identifying single cell chromatin loops by data imputation.
Intergenerational effects from spatial and genetic environment predict early-life social network structure
Authors: Franks Victoria R. , Thorogood Rose , Brekke Patricia
Published: July 2022

Early independence is a crucial stage in the ontogeny of social environments, but it is often challenging to study in the wild. Genetics may structure groups if young animals associate with familiar kin, but association opportunities also develop as a by-product of environmental processes such as spatial resource distribution. The contribution of these alternate factors in initial opportunities for bonding outside direct relatives is difficult to pick apart, despite its importance in shaping later life. However, species where genetics and spatial structure are less closely coupled (for example, via extra-pair mating) provide a natural opportunity to disentangle these effects. We addressed this gap by investigating the contribution of relatedness versus spatiotemporal synchrony (natal nest-box location and fledge timing) to early-life social structure in newly-independent young hihi (Notiomystis cincta). We also investigated the contribution of inbreeding in both juveniles and their parents, to individual-level sociality, as this genetic factor has had limited focus in studies of social structure. Using a long-term genetic pedigree, detailed breeding records, and social network data collected across three cohorts, we found that juvenile social associations were predicted by natal nest-box location, irrespective of relatedness between juveniles. Therefore, the physical environment can create initial opportunities for associations to develop once young animals disperse from natal sites. Furthermore, juvenile sociability was predicted by their father’s (but not mother’s) inbreeding, highlighting how genetics may have indirect and intergenerational effects on social behaviour. Overall, social structure in wild animals can emerge early in life if the natal environment determines association opportunities. These patterns may even be pre-determined across generations if breeding and settlement decisions made by parents affect the physical and social environments experienced by their offspring. Ultimately, our study highlights how influences on early life social structure may have important consequences for population dynamics and evolutionary potential.
First molecular phylogeny of the freshwater planarian genus Girardia (Platyelminthes, Tricladida) unveils hidden taxonomic diversity and initiates resolution of its historical biogeography
Authors: Benítez-Álvarez Lisandra , Sluys Ronald , Leal Zanchet Ana María , Leria Laia , Riutort Marta
Published: July 2022

The genus Girardia (Platyhelminthes: Tricladida) comprises several species of which some have spread from their original areas of distribution in the Americas to other parts of the globe. Due to great anatomical similarities between species, morphology-based phylogenetic analyses struggled to resolve the affinities between species and species-groups. This problem is exacerbated by the fact that populations of Girardia may show only asexual reproduction by fissiparity and, thus, do not exhibit a copulatory apparatus, which hampers taxonomic identification and extraction of phylogenetic characters. In the present work this problem has been resolved by constructing a molecular phylogeny of the genus. Although our samples do not include representatives of all known species, they cover a large part of the original distributional range of the genus Girardia. Our phylogenetic results suggest the presence of two main clades, which are genetically and karyologically highly differentiated. North and South American nominal G. tigrina actually constitute two sibling species that are not even closely related. The South American form is here described as a new species. The phylogenetic tree brings to light that Girardia arose on the South American portion of Gondwanaland, from which it, subsequently, dispersed to the Nearctic Region, probably more than once.
Molecular evolution and characterization of domestic duck (Anas platyrynchos) and Goose (Anser indicus) with reference to its wild relatives through whole mitochondrial genome sequencing
Authors: Pal Aruna , Debnath Manti , Chakraborty Argha , Banerjee Samiddha , Pal Abantika
Published: July 2022

It is important to study the evolution and domestication of the domesticated duck (Anas platyrynchos) population from the wide range of wild relatives of Anas spp. Whole mitochondrial genome sequencing was attempted for Anas platyrynchos (Bengal duck) and Anser indicus (goose) from same geographical region. The study deals with the Molecular evolution of domestic duck based on mitochondrial gene due to its sequence variability, and to find out the phylogenetic relationships amongAnas platyrynchosand its wild relatives. In this study we have used 45 wild species of Anas spp to study the mitochondrial genes and phylogenomics. Our result signifies that duck species were effectively discriminated with respect to mitochondrial genes, which could then be used for an appropriate genetic conservation program for the wild duck and domestic duck breeds. The DNA sequences from any unknown sample of the mitochondrial gene may be determined and can compare with those on a DNA database and can do blast for phylogenetic analysis of unknown wild duck, which gives its future scope. In silico analysis for 3D structure forAnas platyrynchoswith the closest relative asAnas poecilorhyncha(Indian spot-billed duck) was attempted.Anas platyrynchoswas also compared withAnser indicus. Therefore, this experiment was conducted to investigate the genetic diversity of West Bengal wild ducks with reference to its wild relatives based on mitochondrial gene.
Low amplitude transcutaneous auricular vagus nerve stimulation modulates performance but not pupil size during non-native speech category learning
Authors: McHaney Jacie R. , Schuerman William L. , Leonard Matthew K. , Chandrasekaran Bharath
Published: July 2022

Sub-threshold transcutaneous auricular vagus nerve stimulation (taVNS) synchronized with behavioral training can selectively enhance non-native speech category learning in adults. Prior work has demonstrated behavioral performance increases when taVNS is paired with easier-to-learn Mandarin tone categories in native English listeners, relative to when taVNS is paired with harder-to-learn Mandarin tone categories or without taVNS. Mechanistically, this temporally-precise plasticity has been attributed to noradrenergic modulation. However, prior work did not specifically utilize methodologies that indexed noradrenergic modulation and, therefore, were unable to explicitly test this hypothesis. Our goals for the current study were to use pupillometry to gain mechanistic insights into taVNS behavioral effects. Participants learned to categorize Mandarin tones while pupillometry was recorded. In a double-blind design, participants were divided into two taVNS groups that, as in the prior study, differed according to whether taVNS was paired with easier-to-learn tones or harder-to-learn tones. We found that taVNS led to faster rates of learning on trials paired with stimulation. Lower amplitude taVNS also led to faster rates of learning compared to higher amplitude taVNS. However, these effects were not group specific, and we did not find evidence of a taVNS correlate in the pupillary response. The results suggest that stimulation amplitude may be a critical determinant of learning outcomes and pupillary modulation. Future studies on subthreshold taVNS need to systematically evaluate the effect of stimulation intensity on behavioral plasticity and potential taVNS biomarkers.
Analysis of codon usage and allele frequencies reveal the double-edged nature of cross-kingdom RNAi
Authors: Werner Bernhard T. , Kopp-Schneider Annette , Kogel Karl-Heinz
Published: July 2022

Background

In recent years, a new class of small 21- to 24-nt-(s)RNAs has been discovered from microbial pathogens that interfere with their host’s gene expression during infection, reducing the host’s defence in a process called cross-kingdom RNA interference (ckRNAi). According to this model, microbial sRNAs should exert selection pressure on plants so that gene sequences that reduce complementarity to sRNAs are preferred. In this paper, we test this consequence of the ckRNA model by analyzing changes to target sequences considering codon usage and allele frequencies in the model system Arabidopsis thaliana (At) – Hyaloperonospora arabidopsidis (Ha) and Hordeum vulgare (Hv) – Fusarium graminearum (Fg). In both pathosystems, some selected sRNA and their corresponding target have been described and experimentally validated, while the lengthy methodology prevents the analysis of all discovered sRNAs. To expand the understanding of ckRNAi, we apply a new in silico approach that integrates the majority of sRNAs.

Results

We calculated the probability (PCHS) that synonymous host plant codons in a predicted sRNA target region would show the same or stronger complementarity as actually observed and compared this probability to sets of virtual analogous sRNAs. For the sets of Ha and Fg sRNAs, there was a significant difference in codon usage in their plant gene target regions (for Ha: PCHS 24.9% lower than in the virtual sets; for Fg: PCHS 19.3% lower than in the virtual sets), but unexpectedly for both sets of microbial sRNA we found a tendency towards codons with an unexpectedly high complementarity. To distinguish between complementarity caused by balancing sRNA-gene coevolution and directional selection we estimated Wright’s F-statistic (FST), a measurement of population structure, in which positive deviations from the background indicate directional and negative deviations balancing selection at the respective loci. We found a negative correlation between PCHS and FST (p=0.03) in the At-Ha system indicating deviations from codon usage favoring complementarity are generally directionally selected.

Conclusion

The directional selection of complementary codons in host plants suggests an evolutionary pressure to facilitate silencing by exogenous microbial sRNAs, which is not consistent with the anticipated biological role of pathogen sRNAs as exclusively effectors in cross-kingdom RNAi. To resolve this conflict, we propose an extended model in which microbial sRNAs are perceived by plants via RNA interference and, via coevolution, primarily help to fine-tune plant gene expression.
Operationalizing climate risk in a global warming hotspot
Authors: Boyce Daniel G. , Tittensor Derek P. , Fuller Susanna , Henson Stephanie , Kaschner Kristen , Reygondeau Gabriel , Schleit Kathryn E. , Saba Vincent , Shackell Nancy , Stanley Ryan , Worm Boris
Published: July 2022

There has been a proliferation of climate change vulnerability assessments of species, yet possibly due to their limited reproducibility, scalability, and interpretability, their operational use in applied decision-making remains paradoxically low. We use a newly developed Climate Risk Index for Biodiversity to evaluate the climate vulnerability and risk for ∼2,000 species across three ecosystems and 90 fish stocks in the northwest Atlantic Ocean, a documented global warming hotspot. We found that harvested and commercially valuable species were at significantly greater risk of exposure to hazardous climate conditions than non-harvested species, and emissions mitigation disproportionately reduced their projected exposure risk and cumulative climate risk. Of the 90 fish stocks we evaluated, 41% were at high climate risk, but this proportion dropped to 25% under emissions mitigation. Our structured framework demonstrates how climate risk can be operationalized to support short- and long-term fisheries objectives to enhance marine fisheries’ climate readiness and resilience.
Single cell transcriptomic landscapes of human liver organoids stratify models of non-alcoholic fatty liver disease
Authors: Hess Anja , Gentile Stefan D. , Saad Amel Ben , Rahman Raza-Ur , Habboub Tim , Mullen Alan C.
Published: July 2022

Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of morbidity with few treatment options available. Thus, accuratein vitrosystems to test new therapies are indispensable. Recently, human liver organoid (HLO) NAFLD models have emerged. However, a systematic evaluation of their translational potential is currently missing. Here, we develop a structured approach to evaluate NAFLD-HLO models, testing oleic acid (OA) and palmitic acid (PA) in comparison to TGF-β1 for disease induction. Through analysis of ∼100K single-cell transcriptomes of the HLO injury landscape, we find all three models induce inflammatory signatures. However, only TGF-β1 promotes collagen production, fibrosis, and hepatic stellate cell (HSC) expansion. In striking contrast, OA ameliorates fibrotic signatures and reduces the HSC population. Integrating data from each model with that of NAFLD patients across disease progression further demonstrates PA and TGF-β1 more robustly model inflammation and fibrosis. Our findings highlight the importance to stratify NAFLD-HLO models by clinical disease progression, provide a single-cell reference to benchmark future organoid injury models, and allow us to study evolving steatohepatitis, fibrosis, and HSC susceptibility to injury in a dynamic, multi-lineage humanin vitrosystem.
Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY
Authors: Kim Colin Y. , Mitchell Andrew J. , Kastner David W. , Albright Claire E. , Gutierrez Michael , Glinkerman Christopher M. , Kulik Heather J. , Weng Jing-Ke
Published: July 2022

Plants contain rapidly evolving specialized metabolic enzymes to support the synthesis of a myriad of functionally diverse natural products. In the case of coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered in Arabidopsis that catalyzes coumarin formation fromo-hydroxylatedtrans-hydroxycinnamoyl-CoA substrates. COSY is the first and only BAHD enzyme known to date that catalyzes an intramolecular acyl transfer reaction. Here we combine structural, biochemical, and computational approaches to investigate the mechanistic basis for the unique coumarin synthase activity of COSY. Comparative analyses of crystal structures ofArabidopsis thalianaCOSY relative to other BAHD proteins reveal that COSY possesses an unconventional active-site configuration adapted to its specialized activity. Through deuterium exchange experiments, we discover a unique proton exchange mechanism at the α-carbon of theo-hydroxylatedtrans-hydroxycinnamoyl-CoA substrates during the catalytic cycle of COSY. Mutagenesis studies and quantum mechanical cluster modeling further support that this mechanism is key to COSY’s ability to lower the activation energy of thetrans-to-cisisomerization of the hydroxycinnamoyl-CoA substrates, a critical rate-limiting step leading to coumarin production. This study unveils the emergence of an unconventional catalytic mechanism mediated by a BAHD-family enzyme, and sheds light on the potential evolutionary origin of COSY and its recruitment to the evolutionarily new coumarin biosynthetic pathway in eudicots.
Quantifying shared and unique gene content across 17 microbial ecosystems
Authors: Zimmerman Samuel , Tierney Braden T , Patel Chirag J , Kostic Aleksandar D
Published: July 2022

Measuring microbial diversity is traditionally based on microbe taxonomy. Here, in contrast, we aimed to quantify heterogeneity in microbial gene content across 14,183 metagenomic samples spanning 17 ecologies including -- 6 human-associated, 7 non-human-host-associated, and 4 in other non-human host environments. In total, we identified 117,629,181 non-redundant genes. The vast majority of genes (66%) occurred in only one sample (i.e. “singletons”). By contrast, we found 1,864 sequences present in every metagenome, but not necessarily every bacterial genome. Additionally, we report datasets of other ecology-associated genes (e.g. abundant in only gut ecosystems) and simultaneously demonstrated that prior microbiome gene catalogs are both incomplete and inaccurately cluster microbial genetic life (e.g. at gene-sequence identifies that are too restrictive). We provide our results and the sets of environmentally-differentiating genes described above at http://www.microbial-genes.bio.

Importance

The amount of shared genetic elements has not been quantified between the human microbiome and other host and non-host associated microbiomes. Here we made a gene catalog of 17 different microbial ecosystems and compared them. We show that most species shared between environment and human gut microbiomes are pathogens and that prior gene catalogs described as “near-complete” are far from it. Additionally, over two-thirds of all genes only appear in a single sample and only 1,864 genes (0.001%) are found in all types of metagenomes. These results highlight the large diversity between metagenomes and reveal a new, rare class of genes, those found in every type of metagenome, but not every microbial genome.
Clostridioides difficile bile salt hydrolase activity has substrate specificity and affects biofilm formation
Authors: Aguirre Andrea Martinez , Sorg Joseph A.
Published: July 2022

The Clostridioides difficile pathogen is responsible for nosocomial infections. Germination is an essential step for the establishment of C. difficile infection (CDI) because toxins that are secreted by vegetative cells are responsible for the symptoms of CDI. Germination can be stimulated by the combinatorial actions of certain amino acids and either conjugated or deconjugated cholic acid-derived bile salts. During synthesis in the liver, cholic acid- and chenodeoxycholic acid-class bile salts are conjugated with either taurine or glycine at the C24 carboxyl. During GI transit, these conjugated bile salts are deconjugated by microbes that express bile salt hydrolases (BSHs). Here, we surprisingly find that several C. difficile strains have BSH activity. We observed this activity in both C. difficile vegetative cells and in spores and that the observed BSH activity was specific to taurine-derived bile salts. Additionally, we find that this BSH activity can produce cholate for metabolic conversion to deoxycholate by C. scindens. The C. scindens-produced deoxycholate signals to C. difficile to initiate biofilm formation. Our results show that C. difficile BSH activity has the potential to influence the interactions between microbes and this could extend to the GI setting.

Importance

Both primary and secondary bile salts are well-established to impact C. difficile spore germination and vegetative growth. Here, we find that C. difficile vegetative cells, and spores, have bile salt hydrolase activity that is specific to taurine-derived bile salts. When grown in co-culture with the secondary bile salt-producing bacterium, C. scindens, we find that C. difficile-mediated deconjugation of taurocholate, ‘feeds’ C. scindens cholate. C. scindens 7α-dehydroxylates cholate to deoxycholate. The C. scindens-produced deoxycholate then stimulates biofilm formation by C. difficile cells. Thus, this suggests that the bile salt hydrolase activity expressed by several C. difficile strains could be responsible for modulating in vivo biofilm formation and maintenance in a host.
Enriching Representation Learning Using 53 Million Patient Notes through Human Phenotype Ontology Embedding
Authors: Daniali Maryam , Galer Peter D. , Lewis-Smith David , Parthasarathy Shridhar , Kim Edward , Salvucci Dario D. , Miller Jeffrey M. , Haag Scott , Helbig Ingo
Published: July 2022

The Human Phenotype Ontology (HPO) is a dictionary of more than 15,000 clinical phenotypic terms with defined semantic relationships, developed to standardize their representation for phenotypic analysis. Over the last decade, the HPO has been used to accelerate the implementation of precision medicine into clinical practice. In addition, recent research in representation learning, specifically in graph embedding, has led to notable progress in automated prediction via learned features. Here, we present a novel approach to phenotype representation by incorporating phenotypic frequencies based on 53 million full-text health care notes from more than 1.5 million individuals. We demonstrate the efficacy of our proposed phenotype embedding technique by comparing our work to existing phenotypic similarity-measuring methods. Using phenotype frequencies in our embedding technique, we are able to identify phenotypic similarities that surpass the current computational models. In addition, we show that our embedding technique aligns with domain experts’ judgment at a level that exceeds their agreement. We show that our proposed technique efficiently represents complex and multidimensional phenotypes in HPO format, which can then be used as input for various downstream tasks that require deep phenotyping, including patient similarity analyses and disease trajectory prediction.
Integrative multi-omics analysis of genomic, epigenomic, and metabolomics data leads to new insights for Attention-Deficit/Hyperactivity Disorder
Authors: Hubers Nikki , Hagenbeek Fiona A. , Pool René , Déjean Sébastien , Harms Amy C. , Roetman Peter J. , van Beijsterveldt Catharina E. M. , Fanos Vassilios , Ehli Erik A. , Vermeiren Robert R. J. M. , Bartels Meike , Hottenga Jouke Jan , Hankemeier Thomas , Dongen Jenny van , Boomsma Dorret I.
Published: July 2022

The evolving field of multi-omics combines data and provides methods for simultaneous analysis across several omics levels. Here, we integrated genomics (transmitted and non-transmitted polygenic scores (PGS)), epigenomics and metabolomics data in a multi-omics framework to identify biomarkers for ADHD and investigated the connections among the three omics levels. We first trained single- and next multi-omics models to differentiate between cases and controls in 596 twins (cases=14.8%) from the Netherlands Twin Register (NTR) demonstrating reasonable in-sample prediction through cross-validation. The multi-omics model selected 30 PGSs, 143 CpGs, and 90 metabolites. We confirmed previous associations of ADHD with glucocorticoid exposure and the transmembrane protein familyTMEM, show that the DNA methylation of theMAD1L1gene associated with ADHD has a relation with parental smoking behavior, and present novel findings including associations between indirect genetic effects and CpGs of theSTAP2gene. Out-of-sample prediction in NTR participants (N=258, cases=14.3%) and in a clinical sample (N=145, cases=51%) did not perform well (range misclassification was [0.40, 0.57]). The results highlighted connections between omics levels, with the strongest connections between non-transmitted PGS, CpGs, and amino acid levels and show that multi-omics designs considering interrelated omics levels can help unravel the complex biology underlying ADHD.
Identifying cell state–associated alternative splicing events and their coregulation
Authors: Buen Abad Najar Carlos F. , Burra Prakruthi , Yosef Nir , Lareau Liana F.
Published: July 2022

Alternative splicing shapes the transcriptome and contributes to each cell's unique identity, but single-cell RNA sequencing (scRNA-seq) has struggled to capture the impact of alternative splicing. We previously showed that low recovery of mRNAs from single cells led to erroneous conclusions about the cell-to-cell variability of alternative splicing. Here, we present a method, Psix, to confidently identify splicing that changes across a landscape of single cells, using a probabilistic model that is robust against the data limitations of scRNA-seq. Its autocorrelation-inspired approach finds patterns of alternative splicing that correspond to patterns of cell identity, such as cell type or developmental stage, without the need for explicit cell clustering, labeling, or trajectory inference. Applying Psix to data that follow the trajectory of mouse brain development, we identify exons whose alternative splicing patterns cluster into modules of coregulation. We show that the exons in these modules are enriched for binding by distinct neuronal splicing factors and that their changes in splicing correspond to changes in expression of these splicing factors. Thus, Psix reveals cell type–dependent splicing patterns and the wiring of the splicing regulatory networks that control them. Our new method will enable scRNA-seq analysis to go beyond transcription to understand the roles of post-transcriptional regulation in determining cell identity.
How the introduction of new regulatory forms shapes firm self-regulation in the US automobile industry
Authors: Cavazos David
Published: July 2022

Purpose

The current research aims to explore how the implementation of new regulatory forms contributes to firm self-regulation.

Design/methodology/approach

Longitudinal analysis of firm-initiated product recalls for 15 manufacturers in the US automobile industry from 1966–2012.

Findings

Examining firm-initiated product recalls for 15 manufacturers in the US automobile industry from 1966–2012 has several important findings regarding how the introduction of specific regulatory forms contributes to firm-initiated vehicle recalls. Firms are not likely to self-regulate in response to surveillance or standards-based regulation while information-based regulation results in a greater likelihood of firm self-regulation.

Originality/value

This result suggests that even at the product level; firms become increasingly motivated to self-regulate as regulators introduce information-based regulations.
PMBOK, IPMA and fuzzy-AHP based novel framework for leadership competencies development in megaprojects
Authors: Faisal Mohd. Nishat , Al Subaie Abdulla Abdulaziz , Sabir Lamay Bin , Sharif Khurram Jahangir
Published: July 2022

Purpose

Effective leaders have emerged as the cornerstone of project success. The major purpose of this paper is to propose a framework to categorize and prioritize leadership competencies for project managers in megaprojects.

Design/methodology/approach

In the first stage, this study utilizes PMBOK 6th Edition, IPMA ICB 4.0 frameworks to develop a hierarchy-based four clusters of leadership competencies. In the second stage, a Fuzzy-AHP (Analytic Hierarchy Process) approach was employed to prioritize the leadership competencies for an organization dealing in megaprojects. Finally, using ordinal priority approach (OPA), the results of Fuzzy-AHP method are validated.

Findings

Based on PMBOK, IPMA and literature, the proposed framework deduced twenty-four leadership competencies and grouped them in four clusters. The Fuzzy-AHP results indicate that among clusters, people competencies cluster is ranked most important, followed by perspective, practice, and innovation competencies. Considering the sub-categories and global weights, culture/values, governance, interpersonal skills, and development and growth emerged as the most important leadership competencies. The results from OPA corroborate the findings of Fuzzy-AHP method.

Practical implications

Megaprojects are characterized by massive investments and extensive economic and social impact. The proposed framework would be an important aid for policymakers to develop suitable strategies and programs to inculcate leadership competencies that would lead to successful project managers and improved project performance.

Originality/value

The need for this research stems from the need to integrate popular project management frameworks in leadership competencies development in project based organizations. The proposed integrated framework, based on PMBOK 6th Edition and IPMA ICB 4.0 competency frameworks, is an original contribution to understand and prioritize leadership competencies for megaproject success.
How public client’s control systems affect contractors’ innovation possibilities
Authors: Järvenpää Anna-Therése , Larsson Johan , Eriksson Per Erik
Published: July 2022

Purpose

This paper aims to identify how a public client’s use of control systems (process, output and social control) affect innovation possibilities in construction projects.

Design/methodology/approach

Semi-structured interviews about six infrastructure projects were conducted to identify respondents’ views on innovation possibilities. These possibilities were then analyzed from an organizational control perspective within principal–agent relationships between the Swedish Transport Administration (STA) and their contractors.

Findings

How the client uses control systems affects innovation possibilities. Relying on process control could negatively affect innovation opportunities, whereas output control could have a positive influence. In addition, social control seems to have a weak effect, as the STA appears not to use social control to facilitate joint innovation. Public clients must comply with the Public Procurement Act and, therefore, retain the requirements specified in the tendering documents. Much of the steering of the execution is connected to the ex ante phase (before signing the contract), which affects innovation possibilities in the design and execution phases for the contractor.

Research limitations/implications

This study was conducted with only one client, thus limiting its generalizability. However, the findings provide an important stepping stone to further investigation into balancing control systems and creating innovation possibilities in a principal–agent relationship.

Originality/value

Although public procurement has increasingly been emphasized as a major potential source of innovation, studying how a public client’s use of organizational control systems affects innovation possibilities in the construction sector has received scant attention.