bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of methods for mechanistic inference of the gut microbiome in disease
Authors: Santangelo Brook , Hunter Lawrence , Lozupone Catherine
Published: December 2023

Motivation

Knowledge graphs have found broad biomedical applications, providing useful representations of complex knowledge. Although plentiful evidence exists linking the gut microbiome to disease, mechanistic understanding of those relationships remains generally elusive. A structured analysis of existing resources is necessary to characterize the resources and methodologies needed to facilitate mechanistic inference.

Results

Here we demonstrate the potential of knowledge graphs to hypothesize plausible mechanistic accounts of host-microbe interactions in disease and define the need for semantic constraint in doing so. We constructed a knowledge graph of linked microbes, genes and metabolites called MGMLink, and one of microbial traits, environments, and human pheno-types called KG-microbe-phenio. Using a shortest path search and a pattern based semantically constrained path search through the graphs, we highlight the need for a microbiome-disease resource and semantically informed search methods to enable mechanistic inference.

Availability

The software to create MGMLink is openly available athttps://github.com/bsantan/MGMLink, and KG-microbe is available athttps://github.com/Knowledge-Graph-Hub/kg-microbeand KG-phenio is available athttps://github.com/Knowledge-Graph-Hub/kg-phenio.

Contact

brook.santangelo@cuanschutz.edu
Strain-specific evolution and host-specific regulation of transposable elements in the model plant symbiontRhizophagus irregularis
Authors: Oliveira Jordana Inácio Nascimento , Corradi Nicolas
Published: December 2023

Transposable elements (TE) are repetitive DNA that can create variability in genome structure and regulation. The genome ofRhizophagus irregularis, a widely studied arbuscular mycorrhizal fungus (AMF), comprises approximately 50% repetitive sequences that include transposable elements (TE). Despite their abundance, two-thirds of TE remain unclassified, and their regulation among AMF life-stages remains unknown. Here, we aimed to improve our understanding of TE diversity and regulation in this model species by curating repeat datasets obtained from chromosome-level assemblies and by investigating their expression across multiple conditions. Our analyses uncovered new TE superfamilies and families in this model symbiont and revealed significant differences in how these sequences evolve both within and betweenR. irregularisgenomes. With this curated TE annotation, we detected that the number of upregulated TE families in colonized roots is four times higher than extraradical mycelium, and their overall expression differs depending on their host. This work provides a fine-scale view of TE diversity and evolution in model plant symbionts and highlights their transcriptional dynamism and specificity during host-microbe interactions. We also provide Hidden Markov Model profiles of TE domains are now available for future manual curation of uncharacterized sequences (https://github.com/jordana-olive/TE-manual-curation/tree/main).
UBE2N is essential for maintenance of skin homeostasis and suppression of inflammation
Authors: Lee Min Jin , Ben Hammouda Manel , Miao Wanying , Okafor Arinze , Jin Yingai , Sun Huiying , Jain Vaibhav , Markovtsov Vadim , Diao Yarui , Gregory Simon G. , Zhang Jennifer Y.
Published: December 2023

UBE2N, a Lys63-ubiquitin conjugating enzyme, plays critical roles in embryogenesis and immune system development and function. However, its roles in adult epithelial tissue homeostasis and pathogenesis are unclear. We generated conditional mouse models that deletedUbe2nin skin cells in a temporally and spatially controlled manner. We found thatUbe2n-knockout (KO) in the adult skin keratinocytes induced a range of inflammatory skin defects characteristic of psoriatic and actinic keratosis. These included eczematous inflammation, epidermal and dermal thickening, parakeratosis, and increased immune cell infiltration, as well as signs of edema and blistering. Single cell transcriptomic analyses and RT-qPCR showed thatUbe2nKO keratinocytes expressed elevated myeloid cell chemo-attractants such asCxcl1andCxcl2and decreased the homeostatic T lymphocyte chemo-attractant,Ccl27a. Consistently, the infiltrating immune cells ofUbe2n-KO skin were predominantly myeloid-derived cells including neutrophils and M1-like macrophages that were highly inflammatory, as indicated by expression ofIl1βandIl24.Pharmacological blockade of the IL-1 receptor associated kinases (IRAK1/4) alleviated eczema, epidermal and dermal thickening, and immune infiltration of theUbe2nmutant skin. Together, these findings highlight a key role of keratinocyte-UBE2N in maintenance of epidermal homeostasis and skin immunity and identify IRAK1/4 as potential therapeutic target for inflammatory skin disorders.
Power-law growth models explain incidences and sizes of pancreatic cancer precursor lesions and confirm spatial genomic findings
Authors: Kiemen Ashley L. , Wu Pei-Hsun , Braxton Alicia M. , Cornish Toby C. , Hruban Ralph H. , Wood Laura , Wirtz Denis , Zwicker David
Published: December 2023

Pancreatic ductal adenocarcinoma is a rare but lethal cancer. Recent evidence reveals that pancreatic intraepithelial neoplasms (PanINs), the microscopic precursor lesions in the pancreatic ducts that can give rise to invasive pancreatic cancer, are significantly larger and more prevalent than previously believed. Better understanding of the growth law dynamics of PanINs may improve our ability to understand how a miniscule fraction of these lesions makes the transition to invasive cancer. Here, using artificial intelligence (AI)-based three-dimensional (3D) tissue mapping method, we measured the volumes of >1,000 PanIN and found that lesion size is distributed according to a power law with a fitted exponent of -1.7 over > 3 orders of magnitude. Our data also suggest that PanIN growth is not very sensitive to the pancreatic microenvironment or an individual’s age, family history, and lifestyle, and is rather shaped by general growth behavior. We analyze several models of PanIN growth and fit the predicted size distributions to the observed data. The best fitting models suggest that both intraductal spread of PanIN lesions and fusing of multiple lesions into large, highly branched structures drive PanIN growth patterns. This work lays the groundwork for future mathematical modeling efforts integrating PanIN incidence, morphology, genomic, and transcriptomic features to understand pancreas tumorigenesis, and demonstrates the utility of combining experimental measurement of human tissues with dynamic modeling for understanding cancer tumorigenesis.
Memory B cells dominate the early antibody-secreting cell response to SARS-CoV-2 mRNA vaccination in naïve individuals independently of their antibody affinity
Authors: Li Zhe , Obraztsova Anna , Shang Fuwei , Oludada Opeyemi Ernest , Malapit Joshua , Busch Katrin , van Straaten Monique , Stebbins Erec , Murugan Rajagopal , Wardemann Hedda
Published: December 2023

Memory B cells (MBCs) formed over the individual’s lifetime constitute nearly half of the adult peripheral blood B cell repertoire in humans. To assess their response to novel antigens, we tracked the origin and followed the differentiation paths of MBCs in the early anti-S response to mRNA vaccination in SARS-CoV-2-naïve individuals on single-cell and monoclonal antibody level. Newly generated and pre-existing MBCs differed in their differentiation paths despite similar levels of SARS-CoV-2 and common corona virus S-reactivity. Pre-existing highly mutated MBCs showed no signs of germinal center re-entry and rapidly developed into mature antibody secreting cells (ASCs). In contrast, newly generated MBCs derived from naïve precursors showed strong signs of antibody affinity maturation before differentiating into ASCs. Thus, although pre-existing human MBCs have an intrinsic propensity to differentiate into ASCs, the quality of the anti-S antibody and MBC response improved through the clonal selection and affinity maturation of naïve precursors.

Highlights

mRNA vaccination of SARS-CoV-2 naïve individuals recruits naïve and pre-existing MBCs with similar levels of S-reactivity into the response

S-reactive naïve but not pre-existing MBCs undergo affinity maturation

S-reactive pre-existing MBCs dominate the early ASC response independent of their antigen affinity

High-affinity S-reactive MBCs and ASCs develop over time and originate from affinity matured naïve precursors
Environmental and ecological signals predict periods of nutritional stress for Eastern Australian flying fox populations
Authors: Lagergren John , Ruiz-Aravena Manuel , Becker Daniel J. , Madden Wyatt , Ruytenberg Lib , Hoegh Andrew , Han Barbara , Peel Alison J. , Eby Peggy , Jacobson Daniel , Plowright Raina K.
Published: December 2023

Food availability determines where animals use space across a landscape and therefore affects the risk of encounters that lead to zoonotic spillover. This relationship is evident in Australian flying foxes (Pteropusspp; fruit bats), where acute food shortages precede clusters of Hendra virus spillovers. Using explainable artificial intelligence, we predicted months of food shortages from climatological and ecological covariates (1996-2022) in eastern Australia. Overall accuracy in predicting months of low food availability on a test set from 2018 up to 2022 reached 93.33% and 92.59% based on climatological and bat-level features, respectively. Seasonality and Oceanic El Niño Index were the most important environmental features, while the number of bats in rescue centers and their body weights were the most important bat-level features. These models support predictive signals up to nine months in advance, facilitating action to mitigate spillover risk.
Examining the role of oxygen-binding proteins on the early evolution of multicellularity
Authors: Wong Whitney , Bravo Pablo , Yunker Peter J. , Ratcliff William C. , Burnetti Anthony J.
Published: December 2023

Oxygen availability is a key factor in the evolution of multicellularity, as larger and more sophisticated organisms often require mechanisms allowing efficient oxygen delivery to their tissues. One such mechanism is the presence of oxygen-binding proteins, such as globins and hemerythrins, which arose in the ancestor of bilaterian animals. Despite their importance, the precise mechanisms by which oxygen-binding proteins influenced the early stages of multicellular evolution under varying environmental oxygen levels are not yet clear. We addressed this knowledge gap by heterologously expressing the oxygen binding proteins myoglobin and myohemerythrin in snowflake yeast, a model system of simple, undifferentiated multicellularity. These proteins increased the depth and rate of oxygen diffusion, increasing the fitness of snowflake yeast growing aerobically. Experiments show that, paradoxically, oxygen-binding proteins confer a greater fitness benefit for larger organisms under high, not low, O2conditions. We show via biophysical modeling that this is because facilitated diffusion is more efficient when oxygen is abundant, transporting a greater quantity of O2which can be used for metabolism. By alleviating anatomical diffusion limitations to oxygen consumption, the evolution of O2-binding proteins in the oxygen-rich Neoproterozoic may have been a key breakthrough enabling the evolution of increasingly large, complex multicellular metazoan lineages.
Proteomic and Physiological Signatures of Altitude Adaptation in aMyrsine coriaceaPopulation under Common Garden Conditions
Authors: Paschoa Roberta Pena da , Pinto Vitor Batista , Pereira Jéssica Priscilla , Cavatte Paulo Cezar , Garbin Mário Luís , Godinho Tiago de Oliveira , Xavier Lucas Rodrigues , Carrijo Tatiana Tavares , Silveira Vanildo
Published: December 2023

Plants exhibit phenotypic plasticity in response to environmental variations, which can lead to stable genetic and physiological adaptations if exposure to specific conditions is prolonged.Myrsine coriaceademonstrates this through its ability to thrive in diverse environments. The objective of the article is to investigate the adaptive responses ofM. coriaceaby cultivating plants from seeds collected at four different altitudes in a common garden experiment. Through integrated physiological and proteomic analyses, we identified 170 differentially accumulated proteins and observed significant physiological differences among the populations. The high-altitude population (POP1) exhibited a unique proteomic profile with significant down-regulation of proteins involved in carbon fixation and energy metabolism, suggesting a potential reduction in photosynthetic efficiency. Physiological analyses showed lower leaf nitrogen content, net CO2assimilation rate, specific leaf area, and relative growth rate in stem height for POP1, alongside higher leaf carbon isotopic composition (δ13C) and leaf carbon (C) content. These findings provide insight into the complex interplay between proteomic and physiological adaptations inM. coriacea and underscore the importance of local adaptations. This study enhances our understanding of how altitude-specific selection pressures can shape plant molecular biology and physiology, offering valuable perspectives for predicting plant responses to global environmental changes.

Highlight

This study unveils proteomic and physiological adaptations in a high-altitudeM. coriaceapopulation with reduced carbon fixation and energy metabolism.
Design of SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model
Authors: Tan Bin , Zhang Xiaoming , Ansari Ahmadullah , Jadhav Prakash , Tan Haozhou , Li Kan , Chopra Ashima , Ford Alexandra , Chi Xiang , Ruiz Francesc Xavier , Arnold Eddy , Deng Xufang , Wang Jun
Published: December 2023

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. In this study, we designed and synthesized 85 noncovalent PLproinhibitors that bind to the newly discovered Val70Ubsite and the known BL2 groove pocket. Potent compounds inhibited PLprowith inhibitory constant Kivalues from 13.2 to 88.2 nM. The co-crystal structures of PLprowith eight leads revealed their interaction modes. Thein vivoleadJun12682inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50from 0.44 to 2.02 µM. Oral treatment withJun12682significantly improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting PLproinhibitors are promising oral SARS-CoV-2 antiviral candidates.

One-Sentence Summary

Structure-guided design of SARS-CoV-2 PLproinhibitors within vivoantiviral efficacy in a mouse model.
Image-based force inference by biomechanical simulation
Authors: Vanslambrouck Michiel , Thiels Wim , Vangheel Jef , van Bavel Casper , Smeets Bart , Jelier Rob
Published: December 2023

During morphogenesis, cells precisely generate forces that drive cell shape changes and cellular motion. These forces predominantly arise from contractility of the actomyosin cortex, allowing for cortical tension, protrusion formation, and cell division. Image-based force inference can derive such forces from microscopy images, without complicated and time-consuming experimental set-ups. However, current methods do not account for common effects, such as physical confinement and local force generation. Here we propose a force-inference method based on a biophysical model of cell shape, and assess relative cellular surface tension, adhesive tension between cells, as well as cytokinesis and protrusion formation. We applied our method on fluorescent microscopy images of the earlyC. elegansembryo. Predictions for cell surface tension at the 7-cell stage were validated by measurements using cortical laser ablation. Our non-invasive method facilitates the accurate tracking of force generation, and offers many new perspectives for studying morphogenesis.

Author summary

An important challenge in understanding morphogenesis is to determine where forces are generated. Force generation, such as differential cortical tension, plays a key role in cellular self-organization. However, measuring these forces experimentally is a big challenge that typically requires complicated experiments and direct access to the cells being investigated. A non-invasive method, such as force inference based on cell shapes, would have important advantages. Unfortunately, current methods can only be applied in certain cases. Here, we describe a more flexible 3D force inference method, FIDES, that can account for physical confinement, cell divisions and protrusions. We applied the method to infer forces throughout earlyC. elegansembryogenesis. By using cortical laser ablations, we confirmed that FIDES correctly inferred cell surface tensions in a dynamic stage of the nematode’s embryogenesis. Our approach offers a route to routinely infer force generation in complex movements during morphogenesis, with microscopy images of cell shapes as the sole experimental input.
SLCO1B1functional variants and statin-induced myopathy in people with recent genealogical ancestors from Africa: a population-based real-world study
Authors: Yee Sook Wah , Haldar Tanushree , Kvale Mark , Yang Jia , Douglas Michael P , Oni-Orisan Akinyemi
Published: December 2023

Background

Clinical pharmacogenetic implementation guidelines for statin therapy are derived from evidence of primarily Eurocentric study populations. FunctionalSLCO1B1variants that are rare in these study populations have not been investigated as a determinant of statin myotoxicity and are thus missing from guideline inclusion.

Objective

Determine the relationship between candidate functionalSLCO1B1variants and statin-induced myopathy in people with recent genealogical ancestors from Africa.

Design

Population-based pharmacogenetic study using real-world evidence from electronic health record-linked biobanks

Setting

Various health care settings

Participants

Self-identified white and Black statin users with genome-wide genotyping data available.

Measurements

Primarily, the odds of statin-induced myopathy + rhabdomyolysis. Secondarily, total bilirubin levels. Thirdly, cell-based functional assay results.

Results

Meta-analyses results demonstrated an increased risk of statin-induced myopathy + rhabdomyolysis with c.481+1G>T (odds ratio [OR] = 3.27, 95% confidence interval [CI] 1.43-7.46,P=.005) and c.1463G>C (OR = 2.45, 95% CI 1.04-5.78,P=.04) for Black participants. For White participants, c.521T>C was also significantly associated with increased risk of statin-induced myopathy + rhabdomyolysis (OR = 1.41, 95% CI 1.20-1.67,P=5.4x10−5). This effect size for c.521T>C was similar in the Black participants, but did not meet the level of statistical significance (OR = 1.47, 95% CI 0.58-3.73,P=0.41). Supporting evidence using total bilirubin as an endogenous biomarker ofSLCO1B1function as well as from cell-based functional studies corroborated these findings.

Limitations

Data limited to severe statin myotoxicity events.

Conclusion

Our findings implicate AfrocentricSLCO1B1variants on preemptive pharmacogenetic testing panels, which could have an instant impact on reducing the risk of statin-associated myotoxicity in historically excluded groups.

Primary Funding Source

National Institutes of Health, Office of the Director - All of Us (OD-AoURP)
In field use of water samples for genomic surveillance of ISKNV infecting tilapia fish in Lake Volta, Ghana
Authors: Alathari Shayma , Joseph Andrew , Bolaños Luis M. , Studholme David , Jeffries Aaron , Appenteng Patrick , Duodu Kwaku , Sawyerr Eric , Paley Richard , Tyler Charles R. , Temperton Ben
Published: December 2023

Viral outbreaks are a constant threat to aquaculture, limiting production for better global food security. A lack of diagnostic testing and monitoring in resource-limited areas hinders the capacity to respond rapidly to disease outbreaks and to prevent viral pathogens becoming endemic in fisheries productive waters. Recent developments in diagnostic testing for emerging viruses, however, offers a solution for rapidin situmonitoring of viral outbreaks. Genomic epidemiology has furthermore proven highly effective in detecting viral mutations involved in pathogenesis and assisting in resolving chains of transmission.

Here, we demonstrate the application of an in-field epidemiological tool kit to track viral outbreaks in aquaculture on farms with reduced access to diagnostic labs, and with non-destructive sampling. Inspired by the “lab in a suitcase” approach used for genomic surveillance of human viral pathogens and wastewater monitoring of COVID19, we evaluated the feasibility of real-time genome sequencing surveillance of the fish pathogen, Infectious spleen and kidney necrosis virus (ISKNV) in Lake Volta. Viral fractions from water samples collected from cages holding Nile tilapia (Oreochromis niloticus) with suspected ongoing ISKNV infections were concentrated and used as a template for whole genome sequencing, using a previously developed tiled PCR method for ISKNV. Mutations in ISKNV in samples collected from the water surrounding the cages matched those collected from infected caged fish, illustrating that water samples can be used for detecting predominant ISKNV variants in an ongoing outbreak. This approach allows for the detection of ISKNV and tracking of the dynamics of variant frequencies, and may thus assist in guiding control measures for the rapid isolation and quarantine of infected farms and facilities.
Xanthomonas euvesicatoriaeffectorXeAvrRxo1 triggers a Rxo1-mediated defense response inNicotiana benthamianaand its chaperone Xe4429 functions as an antitoxin, an expression repressor, and an enhancer ofXeAvrRxo1 secretion
Authors: Wang Zhibo , Zhou Changhe , Roach Tiffany G. , Li Qi , Wang Kunru , Miao Jiamin , Toro Carlos , Wu Shuchi , Tang Yu , Han Qian , Sun Furong , Capelluto Daniel G. S. , Li Jianyong , Zhao Bingyu
Published: December 2023

Xanthomonas euvesicatoria(X. euvesicatoria) is the causal agent of bacterial spot disease that threatens pepper and tomato production around the globe.X. euvesicatoriageneXe4428encodes a type III effector (T3E) that shares 89.67% amino acid identity withXanthomonas oryzaepv.oryzicola(Xoc) T3E AvrRxo1. Deletion ofXe4428in the genome ofX. euvesicatoria(strain Xcv85-10) compromised its virulence to infect pepper andNicotiana benthamianaplants. Transient co-expression of Xe4428 andRxo1on pepper andN. benthamianaplant leaves results in a robust hypersensitive reaction. Thus, Xe4428, renamed asXeAvrRxo1, is a bona fide orthologue ofXocAvrRxo1 that possesses both virulence and avirulence functions. Expression ofXeAvrRxo1 inE. coliandX. euvesicatoriais toxic to both bacterial cells. AnotherX. euvesicatoriageneXe4429, encodes a putative chaperone ofXeAvrRxo1, which can interact with XeAvrRxo1 to suppress its toxicity inX. euvesicatoriaandE. colibacterial cells. Xe4429 also binds to the promoter region ofXeavrRxo1and represses its transcription/translation inX. euvesicatoriabacterial cells. In addition, expression of Xe4429 can enhance the secretion and translocation ofXeAvrRxo1 into plant cells. Therefore, Xe4429 functions as an antitoxin, a transcription repressor, and a type III chaperone that is capable of enhancing the secretion and translocation ofXeAvrRxo1 during pathogenesis.
Cortical Network Disruption is Minimal in Early Stages of Psychosis
Authors: Van Dyken Peter C. , MacKinley Michael , Khan Ali R. , Palaniyappan Lena
Published: December 2023

1

Background and Hypothesis

Chronic schizophrenia is associated with white matter disruption and topological reorganization of cortical connectivity but the trajectory of these changes over the disease course are poorly understood. Current white matter studies in first-episode psychosis (FEP) patients using diffusion magnetic resonance imaging (dMRI) suggest such disruption may be detectable at the onset of psychosis, but specific results vary widely and few reports have contextualized their findings with direct comparison to chronic patients. Here, we test the hypothesis that structural changes are not a significant feature of early psychosis.

Study Design

Diffusion and T1-weighted 7T MR scans were obtained from N=113 (61 FEP patients, 37 controls, 15 chronic patients) recruited from an established cohort in London, Ontario. Voxel- and network-based analyses were used to detect changes in diffusion microstructural parameters. Graph theory metrics were used to probe changes in the cortical network hierarchy and to assess the vulnerability of hub regions to disruption. Experiments were replicated with N=167 (111 patients, 56 controls) from the Human Connectome Project - Early Psychosis (HCP-EP) dataset.

Study Results

Widespread microstructural changes were found in chronic patients, but changes in FEP patients were minimal. Unlike chronic patients, no appreciable topological changes in the cortical network were observed in FEP patients. These results were replicated in the early psychosis patients of the HCP-EP datasets, which were indistinguishable from controls on nearly all metrics.

Conclusions

The white matter structural changes observed in chronic schizophrenia are not a prominent feature in the early stages of this illness.
Developing clinician-centred design principles for Genomic Test Reports in Pakistan
Authors: Agha Momal , Khan Faisal F
Published: December 2023

Despite rapid technological progress being made in genomics, a growing disparity is emerging between healthcare in developed and developing countries. Thisgenomic dividecan be partly explained by the scarcity of available genomics workforce and in some parts by limited genomic literacy of healthcare professionals that reportedly deters them from proposing genomic testing in a clinical setting. This study aims to study this gap in a local context and learn how we can reduce thisgenomic divideby developing a user-centred design of genomic test reports in Pakistan. The user being the clinician in this study.

We selected two commonly used genomic reports which varied in language, content, and layout. Report A was a one-page genomic report from the Laboratory for Molecular Medicine at Partner’s Healthcare. Report B was a report with multiple pages of information from FoundationOneCDx. We employed a qualitative descriptive study design, including a survey of trainees, non-specialists, and specialists. The parameters recorded were: subjective comprehension, overall visual impression, level of difficulty of the language, and communication efficacy depending on the reports’ graphical representation, along with actionability and degree of reliability.

A total of 49 medical professionals across 11 institutes in Pakistan participated in the survey. Based on the answers and suggestions provided by the participants, we extracted 11 recommendations and broadly grouped them into four categories, i.e. language, content, layout and reliability.

Our findings highlights key areas that need to be taken into consideration when designing impactful genomic reports for clinicians in Pakistan. This incudes accessible and appropriate language, adequate content and a non-overwhelming and friendly layout as well as an emphasis on establishing reliability and actionability of what the clinician finds in the report. This can be instrumental in helping us improve the adoption of genomic testing in clinics around Pakistan, and potentially in other similar contexts.
Effect of mRNA vaccination on pulmonary sequelae after mild COVID-19
Authors: Gagiannis D , Hackenbroch C , Zech F , Kirchhoff F , Bloch W , Junghans K , Steinestel K
Published: December 2023

Background

Previous studies indicate a protective role for SARS-CoV-2 vaccination against development of pulmonary post-acute sequelae of COVID (PASC). We compared clinical, imaging, histopathology and ultrastructural features of pulmonary PASC with and without prior vaccination in a consecutive cohort of 54 unvaccinated, 17 partially vaccinated and 28 fully vaccinated patients who presented with dyspnea on exertion after mild COVID-19 (without hospitalization).

Methods

Patients underwent full clinical evaluation including autoantibody (ANA/ENA) serology, high-resolution computed tomography (HRCT), bronchioloalveolar lavage fluid (BAL) analysis and transbronchial biopsy followed by histopathological and ultrastructural analysis and SARS-CoV-2 immunohistochemistry.

Results

While vaccinated patients were younger (p=0.0056), included more active smokers (p=0.0135) and a longer interval since infection (35 vs. 17 weeks, p=0.0002), dyspnea on exertion and impaired lung function were not different between vaccinated and unvaccinated patients. Ground glass opacities in HRCT and centrilobular fibrosis were more frequent in unvaccinated patients (p=0.0154 and p=0.0353), but presence of autoantibodies, BAL lymphocytosis and bronchiolitis were common findings in all groups. While vaccination against SARS-CoV-2 is associated with a longer time span between infection and consultation along with a reduced frequency of ground glass opacities and centrilobular fibrosis, impaired lung function, bronchiolitis and presence of autoantibodies are comparable between vaccinated and unvaccinated patients. Residual virus was not detected in lung tissue in all but 1 patient.

Conclusion

While differences between the investigated groups with regard to age, smoking status and SARS-CoV-2 variants have to be taken into account, a proposed protective role of SARS-CoV-2 vaccination against pulmonary PASC is so far not fully explained by clinical and histopathology findings.

KEY MESSAGES

The role of SARS-CoV-2 vaccination in the protection against pulmonary post-acute sequelae of COVID-19 (PASC) is unclear. Using a multidimensional approach integrating clinical, serological, imaging and histopathology data as well as ultrastructural analyses, we show here that previous vaccination has no impact on lung function, bronchiolitis or the detection of autoantibodies or residual virus in a previously healthy cohort of 99 PASC patients after mild COVID-19. While a higher frequency of ground glass opacities in unvaccinated patients might be due to the longer interval between infection and consultation, the observed fibrotic remodeling should prompt further investigation of a possible pro-fibrotic role of SARS-CoV-2 infection in the lung.
Interconversion of tripartite and bipartite systems for site-specificO-sialylation of flagellin in Gram-negative and Gram-positive bacteria
Authors: Unay Jovelyn , Kint Nicolas , Viollier Patrick
Published: December 2023

Many bacteria decorate flagellin with sialic acid-like sugars such as pseudaminic acid (Pse) by O-glycosylation on serine or threonine residues. Evidence for sufficiency of sialylation by a conserved flagellin glycosyltransferase (fGT) system is lacking, presumably because of (a) missing component(s). Here, we reconstituted two Maf-type fGTs from the Gram-negative bacteriumShewanella oneidensisMR-1 in a heterologous host producing a Pse donor sugar. While Maf-1 is sufficient for flagellin glycosylation, Maf-2 reconstitution requires a newly identified,cis-encoded and conserved specificity factor GlfM, predicted to form a four-helix bundle. While GlfM binds Maf-2 to form a ternary complex with flagellin, the C-terminal tetratricopeptide repeat (TPR) domain of Maf-1 confers flagellin acceptor and O-glycosylation specificity at preferred serine residues. GlfM from Gram-negative and Gram-positive bacteria are functional, providing evidence for convergent evolution of specialized flagellin modification systems with acceptor serine selectivity, while also shaping the interconversion of bacterial tripartite and bipartite O-glycosylation systems.
Spatial and Temporal Resolution of Cyanobacterial Bloom Chemistry Reveals an Open-OceanTrichodesmium thiebautiias a Talented Producer of Specialized Metabolites
Authors: Via Christopher W. , Grauso Laura , McManus Kelly M. , Kirk Riley D. , Kim Andrew M. , Webb Eric A. , Held Noelle A. , Saito Mak A. , Scarpato Silvia , Zimba Paul. V. , Moeller Peter. D. R. , Mangoni Alfonso , Bertin Matthew J.
Published: December 2023

While the ecological role thatTrichodesmiumsp. play in nitrogen fixation has been widely studied, little information is available on potential specialized metabolites that are associated with blooms and standing stockTrichodesmiumcolonies. While a collection of biological material from aT. thiebautiibloom event from North Padre Island, TX in 2014 indicated that this species was a prolific producer of chlorinated specialized metabolites, additional spatial and temporal resolution was needed. We have completed these metabolite comparison studies, detailed in the current report, utilizing LC-MS/MS-based molecular networking to visualize and annotate the specialized metabolite composition of theseTrichodesmiumblooms and colonies in the Gulf of Mexico (GoM) and other waters. Our results showed thatT. thiebautiiblooms and colonies found in the GoM have a remarkably consistent specialized metabolome. Additionally, we isolated and characterized one new macrocyclic compound fromT. thiebautii, trichothilone A (1), which was also detected in three independent cultures ofT. erythraeum. Genome mining identified genes predicted to synthesize certain functional groups in theT. thiebautiimetabolites. These results provoke intriguing questions of how these specialized metabolites affectTrichodesmiumecophysiology, symbioses with marine invertebrates, and niche development in the global oligotrophic ocean.
ConvexML: Scalable and accurate inference of single-cell chronograms from CRISPR/Cas9 lineage tracing data
Authors: Prillo Sebastian , Ravoor Akshay , Yosef Nir , Song Yun S.
Published: December 2023

CRISPR/Cas9 gene editing technology has enabled lineage tracing for thousands of cellsin vivo. However, most of the analysis of CRISPR/Cas9 lineage tracing data has so far been limited to the reconstruction of single-cell treetopologies, which depict lineage relationships between cells, but not the amount of time that has passed between ancestral cell states and the present. Time-resolved trees, known aschronograms, would allow one to study the evolutionary dynamics of cell populations at an unprecedented level of resolution. Indeed, time-resolved trees would reveal the timing of events on the tree, the relative fitness of subclones, and the dynamics underlying phenotypic changes in the cell population – among other important applications. In this work, we introduce the first scalable and accurate method to refine any given single-cell tree topology into a single-cell chronogram by estimating its branch lengths. To do this, we leverage a statistical model of CRISPR/Cas9 cutting with missing data, paired with a conservative version of maximum parsimony that reconstructs only the ancestral states that we are confident about. As part of our method, we propose a novel approach to represent and handle missing data – specifically, double-resection events – which greatly simplifies and speeds up branch length estimation without compromising quality. All this leads to a convex maximum likelihood estimation (MLE) problem that can be readily solved in seconds with off-the-shelf convex optimization solvers. To stabilize estimates in low-information regimes, we propose a simple penalized version of MLE using a minimum branch length and pseudocounts. We benchmark our method using simulations and show that it performs well on several tasks, outperforming more naive baselines. Our method, which we name ‘ConvexML’, is available through the cassiopeia open source Python package.
High yield, low magnesium flexizyme reactions in a water-ice eutectic phase
Authors: Davisson Joshua A. , Alejo Jose L. , Blank Mace , Kalb Evan M. , Prasad Angelin , Knudson Isaac J. , Schepartz Alanna , Engelhart Aaron E. , Adamala Katarzyna P.
Published: December 2023

Flexizymes enable the stoichiometric acylation of tRNAs with a variety of compounds, enabling thein vitrotranslation of peptides with both non-natural backbones and side chains. However, flexizyme reactions have several drawbacks, including single-turnover kinetics, high Mg(II) carryover inhibitingin vitrotranslation, and rapid product hydrolysis. Here we present flexizyme reactions utilizing an ice-eutectic phase, with high yields, 30X lower Mg(II), and long-term product stability. The eutectic flexizyme reactions increase the ease of use and flexibility of flexizyme aminoacylation, and increase thein vitroprotein production.
Aberrant expression prediction across human tissues
Authors: Hölzlwimmer Florian R. , Lindner Jonas , Wagner Nils , Casale Francesco Paolo , Yépez Vicente A. , Gagneur Julien
Published: December 2023

Despite the frequent implication of aberrant gene expression in diseases, algorithms predicting aberrantly expressed genes of an individual are lacking. To address this need, we compiled an aberrant expression prediction benchmark covering 8.2 million rare variants from 633 individuals across 48 tissues. While not geared toward aberrant expression, the deleteriousness score CADD and the loss-of-function predictor LOFTEE showed mild predictive ability (1-1.5% average precision). Leveraging these and further variant annotations, we next trained AbExp, a model that yielded 10% average precision by combining in a tissue-specific fashion expression variability with variant effects on isoforms and on aberrant splicing. Integrating expression measurements from clinically accessible tissues led to another two-fold improvement. Furthermore, we show on UK Biobank blood traits that performing rare variant association testing using the continuous and tissue-specific AbExp variant scores instead of LOFTEE variant burden increases gene discovery sensitivity and enables improved phenotype predictions.
High-speed Auto-Polarization Synchronization Modulation Three-dimensional Structured Illumination Microscopy
Authors: Li Yaning , Cao Ruijie , Ren Wei , Fu Yunzhe , Hou Yiwei , Zhong Suyi , Zhanghao Karl , Li Meiqi , Xi Peng
Published: December 2023

In recent years, notable progress has been achieved in both the hardware and algorithms of structured illumination microscopy (SIM). Nevertheless, the advancement of 3DSIM has been impeded by challenges arising from the speed and intricacy of polarization modulation. In this study, we introduce a high-speed modulation 3DSIM system, leveraging the polarization maintaining and modulation capabilities of a digital micro-mirror device (DMD) in conjunction with an electro-optic modulator. The DMD-3DSIM system yields a 2-fold enhancement in both lateral (133 nm) and axial (300 nm) resolution compared to wide-field imaging, and can acquire a data set comprising 29 sections of 1024×1024 pixels, with 15 ms exposure time and 6.75 s per volume. The versatility of the DMD-3DSIM approach was exemplified through the imaging of various specimens, including fluorescent beads, nuclear pores, microtubules, actin filaments, and mitochondria within cells, as well as plant and animal tissues. Notably, polarized 3DSIM elucidated the orientation of actin filaments. Furthermore, the implementation of diverse deconvolution algorithms further enhances three-dimensional resolution. The DMD-based 3DSIM system presents a rapid and reliable methodology for investigating biomedical phenomena, boasting capabilities encompassing 3D superresolution, fast temporal resolution, and polarization imaging.
IL-1β disrupts blood-brain barrier development by inhibiting endothelial Wnt/β-catenin signaling
Authors: Fetsko Audrey R. , Sebo Dylan J. , Budzynski Lilyana B. , Scharbarth Alli , Taylor Michael R.
Published: December 2023

During neuroinflammation, the proinflammatory cytokine Interleukin-1β (IL-1β) impacts blood-brain barrier (BBB) function by disrupting brain endothelial tight junctions, promoting vascular permeability, and increasing transmigration of immune cells. Here, we examined the effects of Il-1β on thein vivodevelopment of the BBB. We generated a doxycycline-inducible transgenic zebrafish model that drives secretion of Il-1β in the CNS. To validate the utility of our model, we showed Il-1β dose-dependent mortality, recruitment of neutrophils, and expansion of microglia. Using live imaging, we discovered that Il-1β causes a significant reduction in CNS angiogenesis and barriergenesis. To demonstrate specificity, we rescued the Il-1β induced phenotypes by targeting the zebrafishil1r1gene using CRISPR/Cas9. Mechanistically, we determined that Il-1β disrupts BBB development by decreasing Wnt/β-catenin transcriptional activation in brain endothelial cells. Given that several neurodevelopmental disorders are associated with inflammation, our findings support further investigation into the connections between proinflammatory cytokines, neuroinflammation, and neurovascular development.
ZO-1 regulates Hippo-independent YAP activity and cell proliferation via a GEF-H1- and TBK1-regulated mechanosensitive signalling network
Authors: Haas Alexis J. , Karakus Mert , Zihni Ceniz , Balda Maria S. , Matter Karl
Published: December 2023

Tight junctions are a barrier-forming cell-cell adhesion complex and have been proposed to regulate cell proliferation. However, the underlying mechanisms are not well understood. Here, we used cells deficient in the junction scaffold ZO-1 alone or together with its paralog ZO-2, which disrupts the junctional barrier. We found that ZO-1 knockout increased cell proliferation, loss of cell density-dependent proliferation control, and promoted cell death. These phenotypes were enhanced by double ZO-1/ZO-2 knockout. Increased proliferation was dependent on YAP and ZONAB, two transcriptional regulators. ZO-1 knockout stimulated YAP nuclear translocation and activity without changes in Hippo-dependent phosphorylation. Knockout promoted TANK-binding Kinase 1 (TBK1) activation and increased expression of the RhoA activator GEF-H1. Knockdown of ZO-3, another paralog interacting with ZO1, was sufficient to induce GEF-H1 expression and YAP activity. GEF-H1, TBK1, and mechanotransduction at focal adhesions were required for YAP/TEAD activation in ZO-1-deficient cells. Thus, ZO-1 controls cell proliferation and Hippo-independent YAP activity by activating a GEF-H1- and TBK1-regulated mechanosensitive signalling network.
Internet of Things adoption: unpacking the role of perceived brand credibility
Authors: Dutta Abhisek , Kovid Raj K. , Drave Vinayak A. , Bhatia Manjot Singh
Published: December 2023

Purpose

This study aims to examine how perceived brand credibility (PBC) moderates the adoption of the Internet of Things (IoT) and identifies the influencing variables that consumers consider while adopting IoT products and services. The study uses the technology acceptance model (TAM) and extends its constructs by investigating the role of PBC to measure the intention to use IoT.

Design/methodology/approach

To test the proposed relationships, data was gathered using the survey method, from respondents in India, an emerging market. The data was analyzed using partial least square based structural equation modeling (PLS-SEM). Moreover, the study measured the moderating effect of PBC and evaluated the effect of control variables – gender and degree of exposure to IoT.

Findings

The study found that perceived usefulness (PU) and perceived ease of use (PEOU) have a significant influence on customers’ attitudes towards using IoT devices and services. Further, PBC moderates the relationship between attitude and behavioral intention to utilize IoT devices and services. Both components of PBC – brand trustworthiness and trust – have significant moderating effect on the adoption of IoT-based services and devices.

Originality/value

The study tests TAM empirically in a new setting and extends it further. Introducing PBC as a moderating variable improves the understanding of the way consumers adopt IoT technology and hence strengthens the predictive power of TAM. Thus, the study provides rich insights for businesses to effectively position their IoT devices and services among their target users.
Effects of enclosure shape on MHD nanofluid flow and irreversibility in different shaped systems under fluid volume constraint
Authors: Manna Nirmal K. , Saha Abhinav , Biswas Nirmalendu , Ghosh Koushik
Published: December 2023

Purpose

The purpose of this study is to investigate the influence of enclosure shape on magnetohydrodynamic (MHD) nanofluidic flow, heat transfer and irreversibility in square, trapezoidal and triangular thermal systems under fluid volume constraints, with the aim of optimizing thermal behavior in diverse applications.

Design/methodology/approach

The study uses numerical simulations based on a finite element-based technique to analyze the effects of the Rayleigh number (Ra), Hartmann number (Ha), magnetic field orientation (γ) and nanoparticle concentration (ζ) on heat transfer characteristics and thermodynamic entropy production.

Findings

The key findings reveal that the geometrical design significantly influences fluid velocity, heat transfer and irreversibility. Trapezoidal thermal systems outperform square systems, while triangular systems achieve optimal enhancement. Nanoparticle concentration enhances heat transfer and flow strength at higher Rayleigh numbers. The magnetic field intensity has a significant impact on fluid flow and heat transport in natural convection, with higher Hartmann numbers resulting in reduced flow strength and heat transfer. The study also highlights the influence of various parameters on thermodynamic entropy production.

Research limitations/implications

Further research can explore additional geometries, parameters and boundary conditions to expand the understanding of enclosure shape effects on MHD nanofluidic flow and heat transfer. Experimental validation can complement the numerical simulations presented in this study.

Originality/value

This study provides valuable insights into the impact of enclosure shape on heat transfer performance in MHD nanofluid flow systems. The findings contribute to the optimization of thermal behavior in applications such as electronics cooling and energy systems. The comparison of different enclosure shapes and the analysis of thermodynamic entropy production add novelty to the study.
Anti-corruption disclosure and corporate governance mechanisms: insights from FTSE 100
Authors: Ghazwani Musa , Alamir Ibrahim , Salem Rami Ibrahim A. , Sawan Nedal
Published: December 2023

Purpose

This study aims to examine the impact of corporate governance (CG) on anti-corruption disclosure (A-CD), paying particular attention to the FTSE 100. Notably, it examines how board and audit committees’ characteristics affect the quantity and quality of anti-corruption disclosure.

Design/methodology/approach

Data from FTSE 100 firms, spanning the period from 2014 to 2020, were analysed using the regression of the Poisson fixed effect and GEE analyses.

Findings

The findings show that gender diversity, audit committee expertise and the independence of the audit committee are positively associated with both quantity and quality of anti-corruption disclosure. Notably, no statistically significant relationships were identified between anti-corruption disclosure and factors such as board size, role duality or board meetings.

Research limitations/implications

The findings provide valuable insights for decision-makers and regulatory bodies, shedding light on the elements that compel UK companies to enhance their anti-corruption disclosure and governance protocols to alleviate corruption and propel efforts towards ethical behaviour.

Originality/value

This study makes a notable contribution to the sparse body of evidence by examining the influence of board and audit committee attributes on anti-corruption disclosure subsequent to the implementation of the UK Bribery Act in 2010. Specifically, to the best of the authors’ knowledge, this study assesses for the first time the impact of board and audit committee mechanisms on both the quantity and quality of anti-corruption disclosure.