bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuron Enriched Exosomal MicroRNA Expression Profiles as a Marker of Early Life Alcohol Consumption
Authors: Yakovlev Vasily , Lapato Dana M. , Rana Pratip , Ghosh Preetam , Frye Rebekah , Roberson-Nay Roxann
Published: June 2023

Background

Alcohol consumption may impact and shape brain development through perturbed biological pathways and impaired molecular functions. We investigated the relationship between alcohol consumption rates and neuron-enriched exosomal microRNA (miRNA) expression to better understand the impact of alcohol use on early life brain biology.

Methods

Neuron-enriched exosomal miRNA expression was measured from plasma samples collected from young people using a commercially available microarray platform while alcohol consumption was measured using the Alcohol Use Disorders Identification Test. Linear regression and network analyses were used to identify significantly differentially expressed miRNAs and to characterize the implicated biological pathways, respectively.

Results

Compared to alcohol naïve controls, young people reporting high alcohol consumption exhibited significantly higher expression of four neuron-enriched exosomal miRNAs including miR-30a-5p, miR-194-5p, and miR-339-3p, although only miR-30a-5p and miR-194-5p survived multiple test correction. The miRNA-miRNA interaction network inferred by a network inference algorithm did not detect any differentially expressed miRNAs with a high cutoff on edge scores. However, when the cutoff of the algorithm was reduced, five miRNAs were identified as interacting with miR-194-5p and miR-30a-5p. These seven miRNAs were associated with 25 biological functions; miR-194-5p was the most highly connected node and was highly correlated with the other miRNAs in this cluster.

Conclusions

Our observed association between neuron-enriched exosomal miRNAs and alcohol consumption concurs with results from experimental animal models of alcohol use and suggests that high rates of alcohol consumption during the adolescent/young adult years may impact brain functioning and development by modulating miRNA expression.
Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules
Authors: Ma Bowen , Khan Khadija Shahed , Xu Tongyang , Amada Josefina Xeque , Guo Zhihao , Yan Yu , Cheng Alfred Sze-Lok , Ng Billy Wai-Lung
Published: June 2023

Protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of O-GlcNAcylation homeostasis has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- and site-specific O-GlcNAc modification, rendering the precise study of O-GlcNAcylation challenging. To address this, we have developed first-in-class heterobifunctional small molecules, named O-GlcNAcylation targeting chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2in celluloby recruiting O-GlcNAc transferase (OGT), with temporal and magnitude control. Mass spectrometry data revealed that OGTACs induced site-selective O-GlcNAcylation of BRD4. Overall, OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.
Cell-free chromatin particles activate immune checkpoints in human T cells: Implications for cancer therapy
Authors: Shabrish Snehal , Pal Kavita , Khare Naveen Kumar , Satsangi Dharana , Pilankar Aishwarya , Jadhav Vishalkumar , Shinde Sushma , Raphael Nimisha , Sriram Gaurav , Lopes Relestina , Raghuram Gorantla V. , Tandel Harshali , Mittra Indraneel
Published: June 2023

Immune checkpoint blockade is an exciting breakthrough in cancer therapy, but how immune checkpoints are activated is unknown. We have earlier reported that cell-free chromatin particles (cfChPs) that circulate in the blood, or those that are released locally from dying cells, are readily internalized by healthy cells with biological consequences. Here we show that treatment of human lymphocytes with cfChPs isolated from sera of cancer patients led to marked activation of immune checkpoints viz. PD-1, CTLA-4, LAG-3, NKG2A, and TIM-3. Concurrently activated were stress-related markers cJun, cFos, JunB, FosB, NFКB, and EGR1. The above immune checkpoints were also activated when lymphocytes were treated with cfChPs released from dying HeLa cells; the latter could be abrogated by three cfChPs deactivating agents. These results suggest that immune checkpoints are activated by lymphocytes as stress response to cfChPs. Simultaneous downregulation of multiple immune checkpoints may herald a new approach to immunotherapy of cancer.

Statement of Significance

We show that cell-free chromatin particles (cfChPs) that circulate in the blood of cancer patients, or those released from dying cancer cells, simultaneously activate five immune checkpoints as a stress response by human lymphocytes. Activation of checkpoints was abrogated by cfChPs deactivating agents suggesting a novel approach to cancer treatment.
An atlas of protein homo-oligomerization across domains of life
Authors: Schweke Hugo , Levin Tal , Pacesa Martin , Goverde Casper A. , Kumar Prasun , Duhoo Yoan , Dornfeld Lars J. , Dubreuil Benjamin , Georgeon Sandrine , Ovchinnikov Sergey , Woolfson Derek N. , Correia Bruno E. , Dey Sucharita , Levy Emmanuel D.
Published: June 2023

Protein structures are essential to understand cellular processes in molecular detail. While advances in AI revealed the tertiary structure of proteins at scale, their quaternary structure remains mostly unknown. Here, we describe a scalable strategy based on AlphaFold2 to predict homo-oligomeric assemblies across four proteomes spanning the tree of life. We find that 50% of archaeal, 45% of bacterial, and 20% of eukaryotic proteomes form homomers. Our predictions accurately capture protein homo-oligomerization, recapitulate megadalton complexes, and unveil hundreds of novel homo-oligomer types. Analyzing these datasets reveals coiled-coil regions as major enablers of quaternary structure evolution in Eukaryotes. Integrating these structures with omics data shows that a majority of known protein complexes are symmetric. Finally, these datasets provide a structural context for interpreting disease mutations, which we find enriched at interfaces. Our strategy is applicable to any organism and provides a comprehensive view of homo-oligomerization in proteomes, protein networks, and disease.

Abstract Figure
Comparative analysis of gonadal transcriptomes between turtle and alligator identifies common molecular cues activated during the temperature-sensitive period for sex determination
Authors: Toyota Kenji , Akashi Hiroshi , Ishikawa Momoka , Yamaguchi Katsushi , Shigenobu Shuji , Sato Tomomi , Lange Anke , Tyler Charles R. , Iguchi Taisen , Miyagawa Shinichi
Published: June 2023

The mode of sex determination in vertebrates can be categorized as genotypic or environmental. In the case of genotypic sex determination (GSD), the sexual fate of an organism is determined by the chromosome composition with some having dominant genes, named sex-determining genes, that drive the sex phenotypes. By contrast, many reptiles exhibit environmental sex determination (ESD), whereby environmental stimuli drive sex determination, and most notably temperature. To date, temperature-dependent sex determination (TSD) has been found in most turtles, some lizards, and all crocodilians, but commonalities in the controlling processes are not well established. Recent innovative sequencing technology has enabled investigations into gonadal transcriptomic profiles during temperature-sensitive periods (TSP) in various TSD species which can help elucidate the controlling mechanisms. In this study, we conducted a time-course analysis of the gonadal transcriptome during the male-producing temperature (26L) of the Reeve’s turtle (Chinese three-keeled pond turtle)Mauremys reevesii. We then compared the transcriptome profiles for this turtle species during the TSP with that for the American alligatorAlligator mississippiensisto identify conserved reptilian TSD-related genes. Our transcriptome-based findings provide an opportunity to retrieve the candidate molecular cues that are activated during TSP and compare these target responses between TSD and GSD turtle species, and between TSD species.

Highlights

- A time-course gonadal RNA-seq was conducted usingMauremys reevesii.

- Sexual differentiation genes in males were activated at an earlier stage than the ones in females.

- Turtle-alligator comparative analysis revealed novel candidate TSD genes.
Physicochemical, functional, and evolutionary characteristics of protein loop regions in human andEscherichia coliproteomes
Authors: Zhang Lin , Nishi Hafumi
Published: June 2023

Protein loops often play crucial roles in the formation of binding and enzyme active sites. However, the general structural and biological characteristics of these loops remain unclear. In this study, we investigated protein loop regions on a large scale from structural and evolutionary perspectives. After removing redundancy at the protein chain level, 555,516, 102,901, and 24,818 loops were extracted from the entire PDB, Homo sapiens, andEscherichia coliproteins, respectively. Regardless of whether they were isolated from humans orE. coli, numerous loop sequences tended to be unique among proteins or protein chains. However, loop properties exhibited high similarity or conservation, including length, distance, and stretch. The CATH classification analysis suggested that most loops connected the same superfamily, while the heterogeneity of superfamily context repertoires was not explained at the topology or homologous level. In contrast, the functions of conserved loops between human andE. coliproteins were not consistently conserved, with sequences exhibiting considerable divergence in enrichment. The amino acid composition profiles showed that loops from humans exhibited a preference for serine, whereasE. coliloops had biases for glycine and alanine. Although the amino acid composition was primarily determined by the species, the composition of certain special types of loops clustered separately from other classes, suggesting the existence of conserved loops with complex functions. Collectively, this study provides a detailed overview of protein loops from the structural, functional, and evolutionary perspectives and a vast natural loop repertoire for mining additional information.
Functional diversity reduces the risk of hydraulic failure in tree mixtures through hydraulic disconnection
Authors: Moreno Myriam , Simioni Guillaume , Cochard Hervé , Doussan Claude , Guillemot Joannès , Decarsin Renaud , Fernandez Pilar , Dupuy Jean-Luc , Trueba Santiago , Pimont François , Ruffault Julien , Martin-StPaul Nicolas K.
Published: June 2023

Forest ecosystems are increasingly threatened by anthropogenic pressures, especially by the increase in drought frequency and intensity. Tree species mixtures could improve resilience to diverse global anthropogenic pressures. However, there is still little consensus on how tree diversity affects water stress. Although some studies suggest that mixing species with different drought response strategies could be beneficial, the underlying mechanisms have seldom been identified. By combining a greenhouse experiment and a soil-plant-atmosphere hydraulic model, we explored whether mixing a drought avoidant (Pinus halepensis) and a drought tolerant (Quercus ilex) tree species could reduce plant water stress (defined as the risk of hydraulic failure) during extreme drought, compared to their respective monocultures. Our experiment showed that mixing species with divergent drought response strategies had a neutral effect on the drought-avoidant species and a positive effect on the drought-tolerant species. The model simulations further suggested that the beneficial effect of mixture on plant water stress during extreme drought was related to changes in the hydraulic connection of the plant from both the soil and the atmosphere. The ability of the drought-avoidant species to disconnect from the soil and the atmosphere limits its exposure to water stress, whereas the ability of the drought-tolerant species to increase its hydraulic connection to the soil lowers its hydraulic risk. This study brings a new insight on the mechanisms and traits combinations improving drought resistance in diversified forests and plantations, with important implications for forest management under climate change.
Assessing the Accuracy of a Smart Collar for Dogs: Predictive Performance for Heart and Breathing Rates on a Large Scale Dataset
Authors: Jarkoff Hugo , Lorre Guillaume , Humbert Eric
Published: June 2023

We present an evaluation of a smart collar for dogs that measures resting heart and breathing rates. The study involved 40 dogs of various breeds, ages, and sizes. The collar’s accuracy in estimating heart rates, breathing rates and detecting heart pulses was evaluated by comparing the measurements from the collar with those from a portable ECG device, completed by labels annotated by trained humans. The results show that the collar provides accurate and reliable measurements of heart and breathing rates, with a (symmetric) mean absolute percentage error of 0.38% and 1.42% respectively, and a F1 score of 98.04% for the detection of heart beats at 50ms precision.

Our study demonstrates the potential of Invoxia’sSmart Dog Collaras a medical-grade tool for continuous, noninvasive, remote monitoring of vital signs in dogs, helping to improve the quality of life for dogs, detect early signs of illness, and strengthen the bond between dogs and their owners.
Alternative splicing of a potato disease resistance gene maintains homeostasis between development and immunity
Authors: Sun Biying , Huang Jie , Kong Liang , Gao Chuyun , Zhao Fei , Shen Jiayong , Wang Tian , Li Kangping , Wang Luyao , Wang Yuanchao , Halterman Dennis A. , Dong Suomeng
Published: June 2023

Plants possess a robust and sophisticated innate immune system against pathogens. The intracellular receptors with nucleotide-binding, leucine-rich repeat (NLR) motifs recognize pathogen-derived effector proteins to trigger the immune response. To balance plant growth and rapid pathogen detection, NLR expression is precisely controlled in multifaceted ways. The alternative splicing (AS) of introns in response to infection is recurrently observed but poorly understood. Here we report that the potato NLR geneRBundergoes AS of its intron, resulting in two transcriptional isoforms, which coordinately regulate plant immunity and growth homeostasis. During normal growth,RBpredominantly exists as intron-retained isoformRB_IR, encoding a truncated protein containing only the N-terminus of the NLR. Upon late blight infection, the pathogen induces intron splicing ofRB, increasing the abundance ofRB_CDS, which encodes a full-length and active R protein. By deploying theRBsplicing isoforms fused with aluciferasereporter system, we identified IPI-O1 (also known as Avrblb1), the RB cognate effector, as a facilitator ofRBAS. IPI-O1 directly interacts with potato splicing factor StCWC15, resulting in altered localization of StCWC15 from the nucleoplasm to the nucleolus and nuclear speckles. Mutations in IPI-O1 that eliminate StCWC15 binding also disrupt StCWC15 re-localization andRBintron splicing. Thus, our study reveals that StCWC15 serves as a surveillance facilitator sensing the pathogen-secreted effector, and regulates the trade-off betweenRB-mediated plant immunity and growth, expanding our understanding of molecular plant-microbe interactions.

One-sentence summary

Potato resistance geneRBbalances plant growth and immunity through AS (alternative splicing), while pathogen-secreted effector IPI-O1 mediates AS ofRBby targeting the conserved splicing factor StCWC15, further increasing theRB_CDSexpression level to activate immunity.
In Vitro Culture Alters Cell Lineage Composition and Cellular Metabolism of Bovine Blastocyst
Authors: Ming Hao , Zhang Mingxiang , Rajput Sandeep , Logsdon Deirdre , Zhu Linkai , Schoolcraft William B , Krisher Rebecca , Jiang Zongliang , Yuan Ye
Published: June 2023

Profiling transcriptome at single cell level of bovine blastocysts derived in vivo (IVV), in vitro from conventional culture medium (IVC), and reduced nutrient culture medium (IVR) has enabled us to reveal cell lineage segregation, during which forming inner cell mass (ICM), trophectoderm (TE), and an undefined population of transitional cells. Only IVV embryos had well-defined ICM, indicating in vitro culture may delay the first cell fate commitment to ICM. Differences between IVV, IVC and IVR embryos were mainly contributed by ICM and transitional cells. Pathway analysis by using the differentially expressed genes of these non-TE cells between groups pointed to highly active metabolic and biosynthetic processes, with reduced cellular signaling and membrane transport in IVC embryos, which may lead to reduced developmental potential. IVR embryos had lower activities in metabolic and biosynthetic processes, but increased cellular signaling and membrane transport, suggesting these cellular mechanisms may contribute to the improved blastocyst development compared to IVC embryos. However, the IVR embryos had compromised development when compared to IVV embryos with notably over-active membrane transport activities that led to impaired ion homeostasis.

Summary Statement

Single-cell transcriptomic analysis of bovine blastocysts produced in vivo, and in vitro in conventional and reduced nutrient conditions reveals the effect of culture environments on embryo developmental potential.
Single-cell RNA sequencing identifies response of renal lymphatic endothelial cells to acute kidney injury
Authors: Creed Heidi A. , Kannan Saranya , Tate Brittany L. , Banerjee Priyanka , Mitchell Brett M. , Chakraborty Sanjukta , Rutkowski Joseph M.
Published: June 2023

The inflammatory response to acute kidney injury (AKI) likely dictates future renal health. Lymphatic vessels are responsible for maintaining tissue homeostasis through transport and immunomodulatory roles. Due to the relative sparsity of lymphatic endothelial cells (LECs) in the kidney, past sequencing efforts have not characterized these cells and their response to AKI. Here we characterized murine renal LEC subpopulations by single-cell RNA sequencing and investigated their changes in cisplatin AKI. We validated our findings by qPCR in LECs isolated from both cisplatin-injured and ischemia reperfusion injury, by immunofluorescence, and confirmation inin vitrohuman LECs. We have identified renal LECs and their lymphatic vascular roles that have yet to be characterized in previous studies. We report unique gene changes mapped across control and cisplatin injured conditions. Following AKI, renal LECs alter genes involved endothelial cell apoptosis and vasculogenic processes as well as immunoregulatory signaling and metabolism. Differences between injury models are also identified with renal LECs further demonstrating changed gene expression between cisplatin and ischemia reperfusion injury models, indicating the renal LEC response is both specific to where they lie in the lymphatic vasculature and the renal injury type. How LECs respond to AKI may therefore be key in regulating future kidney disease progression.
Detecting haplotype-specific transcript variation in long reads with FLAIR2
Authors: Tang Alison D. , Hrabeta-Robinson Eva , Volden Roger , Vollmers Christopher , Brooks Angela N.
Published: June 2023

Background

RNA-Seq has brought forth significant discoveries regarding aberrations in RNA processing, implicating these RNA variants in a variety of diseases. Aberrant splicing and single nucleotide variants in RNA have been demonstrated to alter transcript stability, localization, and function. In particular, the upregulation of ADAR, an enzyme which mediates adenosine-to-inosine editing, has been previously linked to an increase in the invasiveness of lung ADC cells and associated with splicing regulation. Despite the functional importance of studying splicing and SNVs, short read RNA-Seq has limited the community’s ability to interrogate both forms of RNA variation simultaneously.

Results

We employed long-read technology to obtain full-length transcript sequences, elucidating cis-effects of variants on splicing changes at a single molecule level. We have developed a computational workflow that augments FLAIR, a tool that calls isoform models expressed in long-read data, to integrate RNA variant calls with the associated isoforms that bear them. We generated nanopore data with high sequence accuracy of H1975 lung adenocarcinoma cells with and without knockdown ofADAR. We applied our workflow to identify key inosine-isoform associations to help clarify the prominence of ADAR in tumorigenesis.

Conclusions

Ultimately, we find that a long-read approach provides valuable insight toward characterizing the relationship between RNA variants and splicing patterns.

Highlights

FLAIR2 has improved transcript isoform detection and incorporates sequence variants for haplotype-specific transcript detection.

In addition to haplotype-specific variant detection, it identifies transcript-specific RNA editing

Able to identify haplotype-specific transcript isoform bias in expression

Long-read sequencing identifies hyperedited transcripts that are missed from short-read sequencing methods for a more comprehensive identification of ADAR targets
13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8+T cells
Authors: Ma Eric H. , Dahabieh Michael S. , DeCamp Lisa M. , Kaymak Irem , Kitchen-Goosen Susan M. , Roy Dominic G. , Verway Mark J. , Johnson Radia M. , Samborska Bozena , Scullion Catherine A. , Steadman Mya , Vos Matthew , Roddy Thomas P. , Krawczyk Connie M. , Williams Kelsey S. , Sheldon Ryan D. , Jones Russell G.
Published: June 2023

Infusion of 13C-labeled metabolites provides a gold-standard for understanding the metabolic processes used by T cells during immune responsesin vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, acetate) inListeria monocytogenes(Lm)-infected mice, we demonstrate that CD8+ T effector (Teff) cells utilize metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cellsin vivoshunt glucose primarily towards nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support ATP andde novopyrimidine synthesis. Additionally, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)—which regulatesde novoaspartate synthesis—for effector cell expansionin vivo. Importantly, Teff cells change fuel preference over the course of infection, switching from glutamine-to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with Teff cell functionin vivo.

Teaser

Interrogating dynamics of fuel utilization by CD8+T cellsin vivoreveals new metabolic checkpoints for immune functionin vivo.
Soil chemical and microbial gradients determine accumulation of root exuded secondary metabolites and plant-soil feedbacks in the field
Authors: Gfeller Valentin , Cadot Selma , Waelchli Jan , Gulliver Sophie , Terrettaz Céline , Thönen Lisa , Mateo Pierre , Robert Christelle A.M. , Mascher Fabio , Steinger Thomas , Bigalke Moritz , Erb Matthias , Schlaeppi Klaus
Published: June 2023

Introduction

Harnessing positive plant-soil feedbacks via crop rotations is a promising strategy for sustainable agriculture. Plants can influence soil properties including microbes by exuding specialized metabolites. However, the effects are often context dependent and variable. If and how local soil heterogeneity may explain this variation is unknown. Benzoxazinoids are specialized metabolites that are released in high quantities by cereals such as wheat and maize. Benzoxazinoids can alter rhizosphere microbiota and the performance of plants subsequently growing in the exposed soils and are thus an excellent model to study agriculturally relevant plant-soil feedbacks in the field, and to assess how soil factors affect their outcome.

Materials & methods

To understand the importance of local variation in soil properties on benzoxazinoid-mediated plant-soil feedbacks, we conditioned plots with wild-type maize and benzoxazinoid-deficientbx1mutant plants in a grid pattern across an arable field. We then grew winter wheat across the entire field in the following season. We determined accumulation of benzoxazinoids, root-associated microbial communities, abiotic soil properties and wheat performance in each plot. We also determined benzoxazinoid conversion dynamics in a labelling experiment under controlled conditions, and then assessed associations between soil chemical variation and benzoxazinoid-mediated plant-soil feedbacks.

Results

Across the field, we detected a marked gradient in soil chemical and microbial community composition. This gradient resulted in significant differences in benzoxazinoid accumulation. These differences were explained by differential benzoxazinoid degradation rather than exudation. Benzoxazinoid exudation modulated alpha diversity of root and rhizosphere bacteria and fungi during maize growth, but not during subsequent wheat growth, while the chemical fingerprint of benzoxazinoid accumulation persisted. Averaged across the field, we detected no significant feedback effects of benzoxazinoid conditioning on wheat performance and defence, apart from a transient decrease in biomass during vegetative growth. Closer analysis however, revealed pronounced feedback effects along the chemical and microbial gradient of the field, with effects gradually changing from negative to positive along the gradient.

Conclusion

Overall, this study revealed that plant-soil feedbacks differ in strength and direction within a field, and that this variation can be explained by standing chemical and microbial gradients, which strongly affect benzoxazinoid accumulation in the soil. Understanding within-field soil heterogeneity is crucial for the future exploitation of plant-soil feedbacks in sustainable precision agriculture.
Increased cardiovascular mortality in patients with mechanically expandable transcatheter aortic valve and without permanent pacemaker
Authors: Hájek Petr , Adlová Radka , Horváth Martin , Hansvenclová Eva , Pecková Monika , Veselka Josef
Published: June 2023

Introduction

Use of the mechanically expandable transcatheter aortic valve (MEV) has been recently linked to increased risks of valve dysfunction and cardiovascular mortality. The risk of developing conduction disturbance with the MEV valve is well-known, and the negative prognostic impact of permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) is another consideration.

Aim

This study aimed to compare the mid-term survival of patients with MEV and self-expandable valves (SEV), and to examine survival of both groups according to the presence or absence of PPI.

Methods

This single-center, retrospective, observational study examined data from MEV and SEV groups comprising 92 and 373 patients, respectively. The mean clinical follow-up was 2.5 ± 1.7 years. Mortality information was obtained from the National Institutes of Health Information and Statistics.

Results

Baseline characteristics were comparable between the groups. The log-rank test showed higher cardiovascular mortality in the MEV group [p=0.042; RR: 1.594 (95%CI: 1.013-2.508)]. The Cox proportional hazards model identified MEV implantation as an independent predictor of cardiovascular mortality. The rate of PPI was twice as high in the MEV versus SEV group (33.7% vs. 16.1%;p<0.001). We compared the survival of both groups according to the presence or absence of PPI and found higher mortality in the MEV group without PPI versus the SEV group without PPI (p=0.007; RR: 2.156 [95%CI: 1.213-3.831]). Survival did not differ in the groups with PPI.

Conclusions

A higher mid-term cardiovascular mortality rate was observed with MEV versus SEV implants. Comparing both groups according to the presence or absence of PPI, we observed a higher mortality risk in patients with MEV without PPI than in SEV without PPI. In contrast, mortality did not differ between the groups when PPI was implanted.

What is already known on this topic

Use of the mechanically expandable transcatheter aortic valve (MEV) has been recently linked to increased risks of valve dysfunction and cardiovascular mortality. The risk of developing conduction disturbance with the MEV valve is well-known, and the negative prognostic impact of permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation is another consideration.

What this study adds

Our study suggested that higher cardiovascular mortality was independently associated with the use of MEV versus self-expandable valves (SEV) implants. Comparing both groups according to the presence or absence of PPI, we observed a higher mortality risk in patients with MEV without PPI than in those with SEV without PPI.

How this study might affect research, practice or policy

Although MEV were recalled in 2020, thousands of patients have been treated with them. Therefore, patients with MEV without PPI deserve increased attention during long-term follow-up.
Subtyping strokes using blood-based biomarkers: A proteomics approach
Authors: Misra Shubham , Singh Praveen , Sengupta Shantanu , Kushwaha Manoj , Rahman Zuhaibur , Bhalla Divya , Talwar Pumanshi , Nath Manabesh , Chakraborty Rahul , Kumar Pradeep , Kumar Amit , Aggarwal Praveen , Srivastava Achal K , Pandit Awadh K , Mohania Dheeraj , Prasad Kameshwar , Vibha Deepti
Published: June 2023

Background and Objectives:Rapid diagnosis of stroke and its subtypes is critical in early stages. We aimed to discover and validate blood-based protein biomarkers to differentiate ischemic stroke (IS) from intracerebral hemorrhage (ICH) within 24 hours using high-throughput proteomics.

Methods:We collected serum samples within 24 hours from acute stroke (IS & ICH) and mimics patients. In the discovery phase, SWATH-MS proteomics identified differentially expressed proteins (fold change: 1.5, p<0.05, and confirmed/tentative selection using Boruta random forest) between IS and ICH which were validated using Multiple Reaction Monitoring (MRM) proteomics in the validation phase. Protein-protein interactions and pathway analysis were conducted using STRING version 11 and Cytoscape 3.9.0. Cut-off points were determined using Youden Index. Prediction models were developed using backward stepwise multivariable logistic regression analysis. Hanley-McNeil test, Integrated discrimination improvement index, and likelihood ratio test determined the improved discrimination ability of biomarkers added to clinical models.

Results:Discovery phase included 20 IS and 20 ICH while validation phase included 150 IS, 150 ICH, and 6 stroke mimics. We quantified 365 proteins in the discovery phase. Between IS and ICH, we identified 20 differentially expressed proteins. In the validation phase, combined prediction model including three biomarkers: GFAP (OR 0.04; 95%CI 0.02-0.11), MMP9 (OR 0.09; 95%CI 0.03-0.28), APO-C1 (OR 5.76; 95%CI 2.66-12.47) and clinical variables independently differentiated IS from ICH (accuracy: 92%, sensitivity: 96%, specificity: 69%). Addition of biomarkers to clinical variables improved the discrimination capacity by 26% (p<0.001). Subgroup analysis within 6 hours identified that GFAP and MMP9 differentiated IS from ICH with a sensitivity> 90%.

Conclusions:Our study identified that GFAP, MMP, and APO-C1 biomarkers independently differentiated IS from ICH within 24 hours and significantly improved the discrimination ability to predict IS. Temporal profiling of these biomarkers in the acute phase of stroke is urgently warranted.
Evolution of chromosome arm aberrations in breast cancer through genetic network rewiring
Authors: Kuzmin Elena , Baker Toby M. , Lesluyes Tom , Monlong Jean , Abe Kento T. , Coelho Paula P. , Schwartz Michael , Zou Dongmei , Morin Genevieve , Pacis Alain , Yang Yang , Martinez Constanza , Barber Jarrett , Kuasne Hellen , Li Rui , Bourgey Mathieu , Fortier Anne-Marie , Davison Peter G. , Omeroglu Atilla , Guiot Marie-Christine , Morris Quaid , Kleinman Claudia L. , Huang Sidong , Gingras Anne-Claude , Ragoussis Jiannis , Bourque Guillaume , Van Loo Peter , Park Morag
Published: June 2023

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize the evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. TCGA data analysis showed recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a unique panel of 23 primary tumor/patient-derived xenograft basal breast cancers revealed early evolution of chr4p deletion. Mechanistically we show that Chr4p loss is associated with enhanced proliferation. Gene function studies identified an unknown gene,C4orf19,within chr4p, which suppressed proliferation when overexpressed and is a novel member of a PDCD10-GCKIII kinase module, we name asPGCA1. Genome-wide pooled overexpression screens using a barcoded library of human open reading frames, identified chromosomal regions, including chr4p, that suppress proliferation when overexpressed in a context-dependent manner implicating network interactions. Together this sheds light on the early emergence of complex aneuploid karyotypes involving chr4p and adaptive landscapes shaping breast cancer genomes.
Decoded EEG Neurofeedback-Guided Cognitive Reappraisal Training for Emotion Regulation
Authors: Li Linling , Gui Xueying , Huang Gan , Zhang Li , Han Xue , Liang Zhen , Zhang Zhiguo
Published: June 2023

Neurofeedback is an innovative self-training that adjusts and enhances brain function. One of the more studied application scenarios with neurofeedback training is emotion regulation. Compared with regional brain activity-informed neurofeedback techniques, neurofeedback protocols using the decoded brain states as feedback signals could make the setting of regulation targets more specific and objective. In the present study, we constructed an EEG neurofeedback-guided cognitive reappraisal training protocol for emotion regulation. Forty-two healthy participants (20 females; 22.4±2.2 years old) were recruited and were randomly assigned to either the neurofeedback group or the control group. During the training process, we calculate the real-time self-regulation performance on the evoked emotion based on the decoded emotional states and fed it back to the subjects as the feedback signal. According to our results, real-time feedback of the regulation effect helps subjects improve emotion regulation performance for emotional stimuli with low positive valence. Further analysis of selected EEG features for emotion classification revealed the neural correlates with neurofeedback training. This newly proposed neurofeedback training protocol is a promising treatment for emotion-related mental disorders, with the potential to be a low-cost and high-portability brain-based, non-invasive, neural modulation technique.
A subtle structural modification of a synthetic cannabinoid receptor agonist drastically increases its efficacy at the CB1 receptor
Authors: Yano Hideaki , Chitsazi Rezvan , Lucaj Christopher , Tran Phuong , Hoffman Alexander F. , Baumann Michael H. , Lupica Carl R. , Shi Lei
Published: June 2023

The emergence of synthetic cannabinoid receptor agonists (SCRAs) as illicit psychoactive substances has posed considerable public health risks that include fatalities. Many SCRAs exhibit much higher efficacy and potency, compared with the phytocannabinoid Δ9-tetrahydrocannabinol (THC), at the cannabinoid receptor 1 (CB1R), a G protein-coupled receptor involved in modulating neurotransmitter release. In this study, we investigated structure activity relationships (SAR) of aminoalkylindole SCRAs at CB1Rs, focusing on 5F-pentylindoles containing an amide linker attached to different head moieties. Usingin vitrobioluminescence resonance energy transfer (BRET) assays, we identified a few of SCRAs exhibiting significantly higher efficacy in engaging the Gi protein and recruiting β-arrestin than the reference CB1R full agonist CP55940. Importantly, adding a methyl group at the head moiety of 5F-MMB-PICA yielded 5F-MDMB-PICA, an agonist exhibiting a large increase in efficacy and potency at the CB1R. This pharmacological observation was supported by a functional assay of the effects of these SCRAs on glutamate field potentials recorded in hippocampal slices. Molecular modeling and simulations of the CB1R bound with either of the SCRAs revealed critical structural determinants contributing to the higher efficacy of 5F-MDMB-PICA, and how these subtle differences propagated to the receptor-G protein interface. Thus, we find that apparently minor structural changes in the head moiety of SCRAs can cause major changes in efficacy. Our results highlight the need for close monitoring of structural modifications of newly emerging SCRAs and their potential for toxic drug responses in humans.
Impaired motor-to-sensory transformation mediates auditory hallucinations
Authors: Yang Fuyin , Zhu Hao , Cao Xinyi , Li Hui , Fang Xinyu , Yu Lingfang , Li Siqi , Wu Zenan , Li Chunbo , Zhang Chen , Tian Xing
Published: June 2023

Distinguishing reality from hallucinations requires efficient monitoring of agency. It has been hypothesized that a copy of motor signals, termedefference copy (EC) or corollary discharge (CD), suppresses sensory responses to yield a sense of agency; impairment of the inhibitory function leads to hallucinations. However, how can the sole absence of inhibition yield positive symptoms of hallucinations? We hypothesize that selective impairments in functionally distinct signals ofCDandECduring motor-to-sensory transformation cause the positive symptoms of hallucinations. In an electroencephalography (EEG) experiment with a delayed articulation paradigm in schizophrenic patients with (AVHs) and without auditory verbal hallucinations (non-AVHs), we found that preparing to speak without knowing the contents (general preparation) did not suppress auditory responses in both patient groups, suggesting the absent of inhibitory function ofCD. Whereas, preparing to speak a syllable (specific preparation) enhanced the auditory responses to the prepared syllable in non-AVHs, whereas AVHs showed enhancement in responses to unprepared syllables, opposite to the observations in the normal population, suggesting that the enhancement function ofECis not precise in AVHs. A computational model with a virtual lesion of an inhibitory inter-neuron and disproportional sensitization of auditory cortices fitted the empirical data and further quantified the distinct impairments in motor-to-sensory transformation in AVHs. These results suggest that ‘broken’CDplus ‘noisy’ECcauses erroneous monitoring on the imprecise generation of internal auditory representation and yields auditory hallucinations. Specific impairments in functional granularity of motor-to-sensory transformation mediate positivity symptoms of agency abnormality in mental disorders.
Spatiotemporal Transcriptomes of Pig Hearts Reveal Midkine-Mediated Vascularization in a Chronic Myocardial Infarcted Model
Authors: Adusumalli Swarnaseetha , Lim Samantha , Ren Vincent , Chong Li Yen , Tham Roy , Lei Ye , Wang Yibin , Petretto Enrico , Tryggvason Karl , Yap Lynn
Published: June 2023

Ischemic heart disease is the most prevalent cause of death globally. Regenerative cardiology using stem cell-based therapy is a potential approach to replace infarcted myocardial (MI) heart tissue. We used cardiovascular progenitors (CVPs) derived from human pluripotent embryonic stem cells differentiated to cardiomyocyte progenitors on a laminin 521+221 matrix and transplanted them into acute and chronic MI pig hearts (AMI and CMI). We performed time-series spatial transcriptomics to characterize these human cells at AMI 1- and 2- and at CMI 1-, 4- and 12 weeks post-transplantation. Both models showed high transcriptional reproducibility in the replicates. Furthermore, the human grafts engrafted well, matured, and expressed metabolic, ribosomal, T-tubule, and channel-related genes in the human graft over time. Cell-cell communication analysis revealed Midkine (MDK) signaling as a key pathway that may lead to increased angiogenesis of collaterals in the human graft.
cTBS Over the Left Supplementary Motor Area (lSMA) Does Not Modulate Rhythmic Bimanual Coordination in the Presence and Absence of Visual Cues
Authors: Kaur Jaskanwaljeet , Balasubramaniam Ramesh
Published: June 2023

Bimanual coordination modes, namely in-phase and anti-phase, represent two distinct movement patterns characterized by simultaneous & symmetrical movements of both hands and alternating complementary actions, respectively. These coordination modes are integral in various activities, such as playing musical instruments, typing, and participating in sports that demand precise hand-eye coordination. The objective of the present experiment was to investigate the impact of continuous theta burst stimulation (cTBS) targeting the left supplementary motor area (lSMA) on bimanual coordination during in/anti-phase coordination modes. To explore this, we utilized a steady-state system of coordination dynamics and evaluated the continuous relative phase (ϕ) and variability of relative phase (SDϕ) during cued and non-cued trials in both pre- and post-transcranial magnetic stimulation (TMS) conditions. The results revealed that visual cues (cued trials) significantly enhanced bimanual coordination performance in both in/anti-phase coordination modes. However, contrary to expectations, the downregulation of lSMA through cTBS did not lead to significant disruptions in movement during in/anti-phase bimanual coordination in pre- and post-TMS stimulation. Potential factors for the lack of observed effects include methodological limitations, individual differences, and functional redundancy within the motor system. Further research is needed to optimize stimulation parameters, increase sample sizes, and explore the interactions between the lSMA, and other brain regions involved in motor control to gain a comprehensive understanding of the contributions of the lSMA in bimanual coordination.
The motor anomalies seen in isolated REM sleep behavior disorder
Authors: Simonet Cristina , Pérez-Carbonell Laura , Huxford Brook FR , Chohan Harneek , Gill Aneet , Leschziner Guy , Lees Andrew J , Schrag Anette , Noyce Alastair J
Published: June 2023

Background

Isolated REM sleep behavior disorder (iRBD) is known to be an early feature in some PD patients. Quantitative tools are needed to detect early motor anomalies in iRBD.

Methods

A motor battery was used to compare iRBD patients with controls. This included two online keyboard-based tests, the BRadykineisa Akinesia INcoordination (BRAIN) test and the Distal Finger Tapping (DFT) test, a timed handwriting task and two motor assessments (10-meter walking and finger tapping) carried out both alone and during a mental task. This battery was compared with the motor section of the MDS-MDS-UPDRS-III. ROC analyses were used to measure diagnostic accuracy.

Results

We included 33 patients with video-PSG-confirmed iRBD and 29 age and sex matched controls. The iRBD group performed the BRAIN test and DFT test more slowly (p<0.001, p=0.020 respectively) and erratically (p<0.001, p=0.009 respectively) than controls. Handwriting speed was 10 seconds slower in iRBDs than controls (p=0.004). Unlike controls, under a mental task the iRBD group decreased their walking pace (p<0.001) and had a smaller amplitude (p=0.001) and slower (p=0.007) finger tapping than tasks in isolation. The combination of BRAIN & DFT tests with the effect of mental tasks on walking and finger tapping showed 90.3% sensitivity for 89.3% specificity (AUC 0.94, 95% CI 0.88-0.99), which was higher than the MDS-UPDRS-III (minus action tremor) (69.7% sensitivity, 72.4% specificity; AUC 0.81, 95% CI 0.71-0.91) for detecting motor abnormalities.

Conclusion

This study suggests that speed, incoordination, and dual task motor deterioration might be accurate indicators of incipient PD in iRBD.
Combined near infrared photoacoustic imaging and ultrasound detects vulnerable atherosclerotic plaque
Authors: Schneider Martin Karl , Wang James , Kare Aris , Adkar Shaunak S. , Salmi Darren , Bell Caitlin F. , Alsaigh Tom , Wagh Dhananjay , Coller John , Mayer Aaron , Snyder Sarah J. , Borowsky Alexander D. , Long Steven R. , Lansberg Maarten G. , Steinberg Gary K. , Heit Jeremy J. , Leeper Nicholas J. , Ferrara Katherine W.
Published: June 2023

Atherosclerosis is an inflammatory process resulting in the deposition of cholesterol and cellular debris, narrowing of the vessel lumen and clot formation. Characterization of the morphology and vulnerability of the lesion is essential for effective clinical management. Photoacoustic imaging has sufficient penetration and sensitivity to map and characterize human atherosclerotic plaque. Here, near infrared photoacoustic imaging is shown to detect plaque components and, when combined with ultrasound imaging, to differentiate stable and vulnerable plaque. In anex vivostudy of photoacoustic imaging of excised plaque from 25 patients, 88.2% sensitivity and 71.4% specificity were achieved using a clinically-relevant protocol. In order to determine the origin of the near-infrared auto-photoacoustic (NIRAPA) signal, immunohistochemistry, spatial transcriptomics and proteomics were applied to adjacent sections of the plaque. The highest NIRAPA signal was spatially correlated with bilirubin and associated blood-based residue and inflammatory macrophages bearing CD74, HLA-DR, CD14 and CD163 markers. In summary, we establish the potential to apply the NIRAPA-ultrasound imaging combination to detect vulnerable carotid plaque.

Graphical Abstract
Quality of Refractive Error Care in Cambodia: An Unannounced Standardised Patient Study
Authors: Burnett Anthea , Meng Ngy , Seiha Do , Kong Neath , Chea Seila , Dean Malis , Horm Piseth , Meas Kim San , Varga Beatrice , Ho Suit May , McGuinness Myra , Lee Ling
Published: June 2023

Purpose

Quality-of-care in refractive error services is essential, as it directly affects vision outcomes, wellbeing, educational attainment, and workforce participation. In Cambodia, uncorrected refractive error is a leading cause of mild and moderate vision impairment in adults. We evaluated the quality of refractive error care in Cambodia by estimating the proportion of prescribed and dispensed spectacles appropriate for people’s refractive error needs and factors associated with spectacle quality.

Methods

A cross-sectional protocol was employed with 18 Khmer-speaking adult participants observing testing procedures in 156 optical services across six provinces in 2022. A total of 496 dispensed spectacles were assessed against spectacle quality indicators.

Results

The analysis revealed that 35.1% of dispensed spectacles were of optimal quality. The most common error observed in sub-optimal spectacles was the presence of horizontal prism outside of tolerance limits. The study also found that 44.0% of emmetrope visits involved unnecessary prescription spectacle recommendations, and 18.3% of written prescriptions did not correspond with dispensed spectacles. Sex differences were observed, with men predominantly providing refractive error care and women more likely to be unnecessarily recommended prescription spectacles.

Conclusion

The findings highlight the importance of prioritizing quality-of-care in refractive error services. A key recommendation is to consider regulatory mechanisms to ensure optical services employ appropriately qualified staff. Additionally, efforts should be made to eliminate unnecessary prescriptions –– especially for emmetropes and females –– standardize written prescriptions, ensure consistent pupil distance measurements, reduce reliance on autorefraction, and address the gender imbalance in the refractive error workforce.