bluuebunny/crossref_metadata_2025 huggingface dataset:
Inferring the location and orientation of cell divisions on time-lapse image sequences
Authors: Karnat Marc , Saadaoui Mehdi , Tlili Sham , Karpinski Romain , Rupprecht Jean-François
Published: February 2024

We propose a two-stage method to characterize cell divisions. In a first stage, the division detection problem is recast into a semantic segmentation task on image sequences. In a second stage, a local regression on individual divisions yields the orientation and distance between daughter cells. We apply our formalism to confocal image sequences of neural tube formation in chicken embryos, where divisions occur within a well-defined plane. We show that our two-stage method can be implemented using simple networks, e.g. a U-Net for the segmentation and a 4-layer CNN for the regression. Optimization of the networks was achieved through a systematic exploration of hyperparameters. In particular, we show that considering several frames as inputs significantly improves the segmentation performance. We reach a performance of 96% in the F1 measure for the detection and errors for the angle, which are within the bounds of the uncertainty of the ground-truth annotation dataset.
Evaluating the likelihood for areas important for conservation to be recognized as Other Effective area-based Conservation Measures
Authors: Cook Carly N , Rao Madhu , Clyne Peter J , Rathbone Vanessa , Barrientos Christian , Boveda Antonio , Diment Alex , Parra Jorge , Falabella Valeria , Linkie Matthew , Kujirakwinja Deo , Ostrowski Stephane , Olson Kirk , Patankar Vardhan , Rasolofomanan Lovy , Grantham Hedley S
Published: February 2024

Other effective area-based conservation measures (OECMs) have expanded area-based conservation to recognize sites that deliver effective biodiversity outcomes even if not managed for conservation. Yet our ability to identify sites likely to qualify as OECMs remains limited. To address this gap, we established and tested a set of indicators to judge whether sites meet the essential criteria to be considered OECMs, evaluating a large, global sample of 173 important conservation areas: 81 potential OECMs and 92 nearby protected areas. We found that most potential OECMs were largely in good condition with the potential to achieve conservation outcomes, but none currently met all the OECM criteria. Formally designated protected areas in our dataset performed better but the majority also failed the criteria. With so many important conservation areas unable to deliver effective conservation outcomes, our findings raise important questions about how to ensure area-based conservation promotes positive and sustained outcomes for biodiversity.
Quantifying the seed sensitivity of cancer subclonal reconstruction algorithms
Authors: Steinberg Philippa L. , Liu Lydia Y. , Neiman-Golden Anna , Patel Yash , Boutros Paul C.
Published: February 2024

Background

Intra-tumoural heterogeneity complicates cancer prognosis and impairs treatment success. One of the ways subclonal reconstruction (SRC) quantifies intra-tumoural heterogeneity is by estimating the number of subclones present in bulk DNA sequencing data. SRC algorithms are probabilistic and need to be initialized by a random seed. However, the seeds used in bioinformatics algorithms are rarely reported in the literature. Thus, the impact of the initializing seed on SRC solutions has not been studied. To address this gap, we generated a set of ten random seeds to systematically benchmark the seed sensitivity of three probabilistic SRC algorithms: PyClone-VI, DPClust, and PhyloWGS.

Results

We characterized the seed sensitivity of three algorithms across fourteen whole-genome sequences of head and neck squamous cell carcinoma and nine SRC pipelines, each composed of a single nucleotide variant caller, a copy number aberration caller and an SRC algorithm. This led to a total of 1470 subclonal reconstructions, including 1260 single-region and 210 multi-region reconstructions. The number of subclones estimated per patient vary across SRC pipelines, but all three SRC algorithms show substantial seed sensitivity: subclone estimates vary across different seeds for the same set of input using the same SRC algorithm. No seed consistently estimated the mode number of subclones across all patients for any SRC algorithm.

Conclusions

These findings highlight the variability in quantifying intra-tumoural heterogeneity introduced by the seed sensitivity of probabilistic SRC algorithms. We recommend that authors, reviewers and editors adopt guidelines to both report and randomize seed choices. It may also be valuable to consider seed-sensitivity in the benchmarking of newly developed SRC algorithms. These findings may be of interest in other areas of bioinformatics where seeded probabilistic algorithms are used and suggest consideration of formal seed reporting standards to enhance reproducibility.
Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids
Authors: Miao Yifei , Tan Cheng , Pek Nicole M. , Yu Zhiyun , Iwasawa Kentaro , Kechele Daniel O. , Sundaram Nambirajan , Pastrana-Gomez Victor , Kishimoto Keishi , Yang Min-Chi , Jiang Cheng , Tchieu Jason , Whitsett Jeffrey A. , McCracken Kyle W. , Rottier Robbert J. , Kotton Darrell N. , Helmrath Michael A. , Wells James M. , Takebe Takanori , Zorn Aaron M. , Chen Ya-Wen , Guo Minzhe , Gu Mingxia
Published: February 2024

To investigate the co-development of vasculature, mesenchyme, and epithelium crucial for organogenesis and the acquisition of organ-specific characteristics, we constructed a human pluripotent stem cell-derived organoid system comprising lung or intestinal epithelium surrounded by organotypic mesenchyme and vasculature. We demonstrated the pivotal role of co-differentiating mesoderm and endoderm via precise BMP regulation in generating multilineage organoids and gut tube patterning. Single-cell RNA-seq analysis revealed organ specificity in endothelium and mesenchyme, and uncovered key ligands driving endothelial specification in the lung (e.g., WNT2B and Semaphorins) or intestine (e.g., GDF15). Upon transplantation under the kidney capsule in mice, these organoids further matured and developed perfusable human-specific sub-epithelial capillaries. Additionally, our model recapitulated the abnormal endothelial-epithelial crosstalk in patients withFOXF1deletion or mutations. Multilineage organoids provide a unique platform to study developmental cues guiding endothelial and mesenchymal cell fate determination, and investigate intricate cell-cell communications in human organogenesis and disease.

Highlights

BMP signaling fine-tunes the co-differentiation of mesoderm and endoderm.

The cellular composition in multilineage organoids resembles that of human fetal organs.

Mesenchyme and endothelium co-developed within the organoids adopt organ-specific characteristics.

Multilineage organoids recapitulate abnormal endothelial-epithelial crosstalk in FOXF1-associated disorders.
Explaining Conformational Diversity in Protein Families through Molecular Motions
Authors: Lombard Valentin , Grudinin Sergei , Laine Elodie
Published: February 2024

Proteins play a central role in biological processes, and understanding their conformational variability is crucial for unraveling their functional mechanisms. Recent advancements in high-throughput technologies have enhanced our knowledge of protein structures, yet predicting their multiple conformational states and motions remains challenging. This study introduces Dimensionality Analysis for protein Conformational Exploration (DANCE) for a systematic and comprehensive description of protein families conformational variability. DANCE accommodates both experimental and predicted structures. It is suitable for analysing anything from single proteins to superfamilies. Employing it, we clustered all experimentally resolved protein structures available in the Protein Data Bank into conformational collections and characterized them as sets of linear motions. The resource facilitates access and exploitation of the multiple states adopted by a protein and its homologs. Beyond descriptive analysis, we assessed classical dimensionality reduction techniques for sampling unseen states on a representative benchmark. This work improves our understanding of how proteins deform to perform their functions and opens ways to a standardised evaluation of methods designed to sample and generate protein conformations.
Personalized Molecular Signatures of Insulin Resistance and Type 2 Diabetes
Authors: Larsen Jeppe Kjærgaard , Stocks Ben , Henderson John , Andersson Daniel , Bäckdahl Jesper , Eriksson-Hogling Daniel , Stidsen Jacob V. , Sakamoto Kei , Højlund Kurt , Rydén Mikael , Zierath Juleen R. , Krook Anna , Deshmukh Atul S.
Published: February 2024

Highlights

Advanced proteomics analysis reveals personalized signatures of insulin resistance

Fasting muscle proteome and phosphoproteome predicts whole-body insulin sensitivity

Insulin-stimulated phosphoproteome reveals selective insulin resistance signatures

Phosphoproteome and proteome atlas explains sex-specific muscle metabolism

Graphical Abstract

Insulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of skeletal muscle from >120 men and women with normal glucose tolerance or type 2 diabetes, with varying degrees of insulin sensitivity. Leveraging deepin vivophenotyping, we reveal that fasting proteome and phosphoproteome signatures strongly predict insulin sensitivity. Furthermore, the insulin-stimulated phosphoproteome revealed both dysregulated and preserved signaling nodes - even in individuals with severe insulin resistance. While substantial sex-specific differences in the proteome and phosphoproteome were identified, molecular signatures of insulin resistance remained largely similar between men and women. These findings underscore the need for precision medicine approaches in type 2 diabetes care, acknowledging disease heterogeneity.
A Cautionary Note on Using STRUCTURE to Detect Hybridization in a Phylogenetic Context
Authors: Pang Xiao-Xu , Zhang Da-Yong
Published: February 2024

Population genetic clustering methods are widely used to detect hybridization events between closely related populations within species, as well as between deeply diverged lineages across phylogenetic time-scales, although their strengths and limitations in the latter cases remain poorly explored. This study presents the first systematic evaluation of the performance of the most popular population clustering method, STRUCTURE, under a variety of cross-species hybridization scenarios, including hybrid speciation, as well as introgression involving ghost (i.e., extinct or unsampled) lineages or otherwise. Our simulations demonstrate that STRUCTURE performs well in identifying hybrids and their parental donors only when admixture happens very recently between sampled extant lineages. However, STRUCTURE generally fails to detect signals of admixture when hybridization occurs in deep time or when gene flow stems from ghost lineages. We find that symmetrical parental contribution in cases of hybrid speciation will often be revealed as extremely asymmetrical in STRUCTURE, especially when the admixture event occurred more than some time ago. Our results suggest that population-genetic clustering methods may be very inefficient for detecting either ancient or ghost admixtures, partly explaining why ghost introgression has escaped the attention of evolutionary biologists until recently.
Bacterial ecology and evolution converge on seasonal and decadal scales
Authors: Rohwer Robin R , Kirkpatrick Mark , Garcia Sarahi L , Kellom Matthew , McMahon Katherine D , Baker Brett J.
Published: February 2024

Ecology and evolution are often viewed as distinct processes, which interact on contemporary time scales in microbiomes. To observe these processes in a natural system, we collected a two-decade, 471-sample freshwater lake time series, creating the longest metagenome dataset to date. Among 2,855 species-representative genomes, diverse species and strains followed cyclical seasonal patterns, and one in five species experienced decadal shifts in strain composition. The most globally abundant freshwater bacterium had constant species-level abundance, but environmental extremes appeared to trigger a shift in strain composition and positive selection of amino acid and nucleic acid metabolism genes. These genes identify organic nitrogen compounds as potential drivers of freshwater responses to global change. Seasonal and long-term strain dynamics could be regarded as ecological processes or equivalently as evolutionary change. Rather than as distinct processes that interact, we propose a conceptualization where ecology and evolution converge along a continuum to better describe change in diverse microbial communities.
GSK3 inhibition ameliorates the abnormal contractility of Newfoundland ACM patient iPSC-cardiomyocytes
Authors: Noort Rebecca J , Salman Wesam , Fuchs Camila , Braun Ursula , Pace David , Hodgkinson Kathleen , Esseltine Jessica L
Published: February 2024

Arrhythmogenic Cardiomyopathy (ACM) is clinically characterized by ventricular arrhythmias causing sudden cardiac death and fibrofatty replacement of the myocardium leading to heart failure. One form of ACM is highly prevalent in the Canadian Province of Newfoundland and Labrador (NL) and has earned the moniker, The Newfoundland Curse. This ACM in NL patients is often caused by a fully penetrant heterozygous missense pathogenic variant in the TMEM43 gene (TMEM43 c.1073C>T; TMEM43 p.S358L). Although the causative variant has been identified, little is known about the function of the TMEM43 protein in cardiomyocytes, how the TMEM43 p.S358L mutation contributes to the development of arrhythmias, or why the disease is more severe in males than females. To explore the role of TMEM43 in cardiomyocyte function, we generated induced pluripotent stem cells (iPSCs) from 2 severely affected male Newfoundland ACM (TMEM43 p.S358L) patients. CRISPR-Cas9 was used to genetically repair the heterozygous TMEM43 variant in ACM patient iPSCs or for TMEM43 gene knockout. ACM patient iPSC-cardiomyocytes with the TMEM43 p.S358L variant display pro-arrhythmogenic phenotypes in vitro with significantly elevated contraction rates and altered calcium handling, although no obvious gross abnormalities were observed across several major intracellular organelles. GSK3 inhibition significantly increased protein expression of b-catenin as well as Lamin A/C and ameliorated the pro-arrhythmic tendencies of ACM patient iPSC-CMs.
miR-203 controls developmental timing and early fate restriction during preimplantation embryogenesis
Authors: González-Martínez José , Sánchez-Belmonte Agustín , Ayala Estefanía , García Alejandro , Nogueira Enrique , Muñoz Jaime , Melati Anna , Giménez Daniel , Losada Ana , Ortega Sagrario , Malumbres Marcos
Published: February 2024

Commonly expressed at developmental transitions, microRNAs operate as fine tuners of gene expression to facilitate cell fate acquisition and lineage segregation. Nevertheless, how they might regulate the earliest developmental transitions in early mammalian embryogenesis remains obscure. Here, in a strictly in vivo approach based on novel genetically-engineered mouse models and single-cell RNA sequencing, we identify miR-203 as a critical regulator of timing and cell fate restriction within the totipotency to pluripotency transition in mouse embryos. Genetically engineered mouse models show that loss of miR-203 slows down developmental timing during preimplantation leading to the accumulation of embryos with high expression of totipotency-associated markers, including MERVL endogenous retroviral elements. A new embryonic reporter (eE-Reporter) transgenic mouse carrying MERVL-Tomato and Sox2-GFP transgenes showed that lack of miR-203 leads to sustained expression of MERVL and reduced Sox2 expression in preimplantation developmental stages. A combination of single-cell transcriptional studies and epigenetic analyses identified the central coactivator and histone acetyltransferase P300 as a major miR-203 target at the totipotency to pluripotency transition in vivo. By fine tuning P300 levels, miR-203 carves the epigenetic rewiring process needed for this developmental transition, allowing a timely and correctly paced development.
Dispensable regulation of brain development and myelination by the immune-related protein Serpina3n
Authors: Zhu Meina , Wang Yan , Park Joohyun , Titus Annlin , Guo Fuzheng
Published: February 2024

Serine protease inhibitor clade A member 3n (Serpina3n) or its human orthologue SERPINA3 is a secretory immune-related molecule produced primarily in the liver and brain under homeostatic conditions and upregulated in response to system inflammation. Yet it remains elusive regarding its cellular identity and physiological significance in the development of the postnatal brain. Here, we reported that oligodendroglial lineage cells are the major cell population expressing Serpina3n protein in the postnatal murine CNS. Using loss-of-function genetic tools, we found that Serpina3n conditional knockout (cKO) from Olig2-expressing cells does not significantly affect cognitive and motor functions in mice. Serpina3n depletion does not appear to interfere with oligodendrocyte differentiation and developmental myelination nor affects the population of other glial cells and neuronsin vivo. Together, these data suggest that the immune-related molecule Serpina3n plays a minor role, if any, in regulating neural cell development in the postnatal brain under homeostatic conditions. We found that Serpina3n is significantly upregulated in response to oxidative stress, and it potentiates oxidative injury and cell senescence of oligodendrocytes. Our data raise the interest in pursuing its functional significance in the CNS under disease/injury conditions.
A reassessment of Hardy-Weinberg equilibrium filtering in large sample Genomic studies
Authors: Greer Phil J , Sedlakova Anastazie , Ellison Mitchell , Oranburg Talia DeFrancesco , Maiers Martin , David C Whitcomb , Busby Ben
Published: February 2024

Hardy Weinberg Equilibrium (HWE) is a fundamental principle of population genetics. Adherence to HWE, using a p-value filter, is used as a quality control measure to remove potential genotyping errors prior to certain analyses. Larger sample sizes increase power to differentiate smaller effect sizes, but will also affect methods of quality control. Here, we test the effects of current methods of HWE QC filtering on varying sample sizes up to 486,178 subjects for imputed and Whole Exome Sequencing (WES) genotypes using data from the UK Biobank and propose potential alternative filtering methods.

METHODS

Simulations were performed on imputed genotype data using chromosome 1. WES GWAS (Genome Wide Association Study) was performed using PLINK2.

RESULTS

Our simulations on the imputed data from Chromosome 1 show a progressive increase in the number of SNPs eliminated from analysis as sample sizes increase. As the HWE p-value filter remains constant at p<1e-15, the number of SNPs removed increases from 1.66% at n=10,000 to 18.86% at n=486,178 in a multi-ancestry cohort and from 0.002% at n=10,000 to 0.334% at n=300,000 in a European ancestry cohort. Greater reductions are shown in WES analysis with a 11.91% reduction in analyzed SNPs in a European ancestry cohort n=362,192, and a 32.70% reduction in SNPs in a multi-ancestry dataset n=463,605. Using a sample size specific HWE p-value cutoff removes ∼ 2.25% of SNPs in the all ancestry cohort across all sample sizes, but does not currently scale beyond 300,000 samples. A hard cutoff of +/- 20% deviation from HWE produces the most consistent results and scales across all sample sizes but requires additional user steps.

CONCLUSION

Testing for deviance from HWE may still be an important quality control step in GWAS studies, however we demonstrate here that using an HWE p-value threshold that is acceptable for smaller sample sizes will be inappropriate for large sample studies due to an unnecessarily high number of variants removed prior to analysis. Rather than exclude variants that fail HWE prior to analysis it may be better to include all variants in the analysis and examine their deviation from HWE afterward. We believe that adjusting the cutoffs will be even more important for large whole genome sequencing results and more diverse population studies.

KEY TAKEAWAYS

Current thresholds for assessing HWE are impractical for large sample sizes.

Filtering imputed datasets for HWE regardless of sample size is unnecessary and in fact detrimental if you have a diverse, mixed, or unknown ancestry cohort.

WES data shows more distributed deviation from HWE for all Minor Allele Frequencies (MAF).

We present an alternative p-value filter for HWE for large sample sizes.

We recommend that all genotype data (imputed, WES or WGS) should be analyzed, HWE computed, results combined, and then filtered post-hoc.
Heterogeneity of Diagnosis and Documentation of Post-COVID Conditions in Primary Care: A Machine Learning Analysis
Authors: Hendrix Nathaniel , Parikh Rishi V. , Taskier Madeline , Walter Grace , Rochlin Ilia , Saydah Sharon , Koumans Emilia H. , Rincón-Guevara Oscar , Rehkopf David H. , Phillips Robert L.
Published: February 2024

Background

Post-COVID conditions (PCC) present clinicians with significant challenges due to their variable presentation.

Objective

To characterize patterns of PCC diagnosis in generalist primary care settings.

Design

Retrospective observational study

Setting

519 primary care clinics around the United States who were in the American Family Cohort registry between October 1, 2021 and November 1, 2023.

Patients

6,116 with diagnostic code for PCC; 5,020 with PCC and COVID-19

Measurements

Time between COVID-19 and PCC (U09.9) diagnostic codes; count of patients with PCC diagnostic codes per clinician; patient-specific probability of PCC diagnostic code estimated by a tree-based machine learning model trained on clinician and specific practice visited, patient demographics, and other diagnoses; performance of a natural language classifier trained on notes from 5,000 patients annotated by two physicians to indicate probable PCC.

Results

Of patients with diagnostic codes for PCC and COVID-19, 43.0% were diagnosed with PCC less than 4 weeks after initial recorded COVID-19 diagnostic code. Six clinicians (out of 3,845 total) made 15.4% of all PCC diagnoses. The high-performing (F1: 0.98) tree-based model showed that patient demographics, practice visited, clinician visited, and calendar date of visit were more predictive of PCC diagnostic code than any symptom. Inter-rater agreement on PCC diagnosis was moderate (Cohen’s kappa: 0.60), and performance of the natural language classifiers was poor (best F1: 0.54).

Limitations

Cannot validate date of COVID-19 diagnosis, as it may not reflect when disease began and could have been coded retrospectively. Few options for medically focused language models.

Conclusion

We identified multiple sources of heterogeneity in the documentation of PCC diagnostic codes in primary care practices after introduction of ICD-10 codes for PCC, which has created challenges for public health surveillance.

Funding Source

US CDC
Estimation of mean pulmonary artery pressure by cardiovascular magnetic resonance four-dimensional flow and compressed sensing
Authors: Abdula Goran , Bergqvist Pernilla , Castaings Jenny , Fyrdahl Alexander , Giese Daniel , Jin Ning , Testud Frederik , Sörensson Peder , Sigfridsson Andreas , Ugander Martin , Marlevi David
Published: February 2024

Background

Four-dimensional (4D) phase-contrast cardiovascular magnetic resonance (CMR) allows for precise non-invasive estimation of mean pulmonary artery pressure (mPAP) by estimating the duration of pathological vortex persistence in the main pulmonary artery. This has previously been achieved with compressed sensing acceleration of a multiple two-dimensional (CS-M2D) flow sequence, but acquisition using a true time-resolved 3D excitation (CS-4D) offers theoretical advantages including spatiotemporal coherence. This study aimed to validate a state-of-the-art CS-4D sequence with a previously utilized CS-M2D sequence for estimating mPAP, and compare both to right heart catheterization (RHC).

Methods

The study included patients clinically referred for CMR (n=45), of which a subgroup (n=20) had prior mPAP of >16 mmHg confirmed by RHC. CMR was performed at 1.5T using CS-M2D and CS-4D sequences covering the main pulmonary artery. mPAP was estimated using a previously published linear relationship between vortex duration and mPAP. Agreement between CS-M2D and CS-4D estimates was quantified, including analysis of intra- and interobserver variabilities. The diagnostic performance of CS-M2D and CS-4D in predicting mPAP was further compared to gold-standard RHC.

Results

CS-M2D and CS-4D both had average scan durations under 3 minutes (175±36 and 135±34 seconds, respectively). Estimated mPAP by CS-4D and CS-M2D were strongly correlated (R2=0.93, p<0.001), with negligible mean±SD bias (0.0±2.7 mmHg) and good reproducibility. There was excellent agreement with RHC for both CS-M2D (R2=0.92, p<0.001, bias 0.6±3.1 mmHg) and CS-4D (R2=0.86, p<0.001, bias 1.1±4.5 mmHg).

Conclusions

CS-4D and CS-M2D sequences effectively yield interchangeable non-invasive estimations of mPAP, with excellent agreement compared to invasive RHC. They can both be acquired in a scan time applicable to clinical workflow, offering a promising tool for non-invasive mPAP estimation in clinical practice.
High Initial Heart Rate Score is an Independent Predictor of New Atrial High-Rate Episodes in Pacemaker Patients with Sinus Node Dysfunction
Authors: Hayashi Katsuhide , Abe Haruhiko , Olshansky Brian , Sharma Arjun D. , Jones Paul W. , Wold Nicholas , Perschbacher David , Kohno Ritsuko , Lip Gregory Y. H. , Wilkoff Bruce L.
Published: February 2024

Background

Heart Rate Score (HRSc), the percent of atrial beats in the largest paced/sensed 10-bpm histogram bin recorded in cardiac devices, is a metric of chronotropic incompetence. It remains uncertain if HRSc independently predicts atrial high-rate episodes (AHREs) in patients with sinus node dysfunction (SND) undergoing pacemaker (PM) implantation.

Objective

To determine the relationship between initial HRSc post-PM implant and new-onset AHREs in patients with SND.

Methods

The cohort included patients with Boston Scientific PMs implanted for SND from 2012-2021 at Cleveland Clinic, University of Occupational and Environmental Health, Japan, Kyushu Rosai Hospital, and JCHO Kyushu Hospital. Patients were excluded if they had atrial fibrillation before PM implant or AHREs in the initial 3-months post-implant. Subsequent AHREs post-implant (>1% of atrial beats>170 bpm) were evaluated.

Results

Over 48.9 (IQR 25.8-50.4) months, 136 consecutive PM patients (age 75±10 years, 42% male) were followed. The median initial HRSc was 73(55-86)%. AHREs developed in 28/136 (21%). Although %RA pacing and HRSc correlated, rate-responsive pacing was associated with a HRSc only in the patients with high %RA pacing. Patients with HRSc≥80% had higher occurrence of AHREs than those with HRSc<80% (p=0.01, log-rank test). After adjusting for age, race, comorbidities, left ventricular ejection fraction, left atrial diameter, %RA/RV pacing, and rate-response programming, HRSc (HR:2.84, 95% CI:1.17-6.92; P=0.02) and male sex (HR:2.55, 95% CI:1.15-6.19; P=0.04) were independent predictors of AHREs.

Conclusion

HRSc≥80% independently predicted new-onset, device-determined AHREs for patients undergoing PM implant for SND. HRSc may have prognostic and therapeutic implications.
Arktos: a simple tool for the design of polyhedral DNA nanostructures
Authors: Balaji Harshitha , Samprathi Anish Hemanth , Kolipakala Rakshita Sukruth , Pradeep Pushya , Nagarajan Deepesh
Published: February 2024

DNA nanostructures are a class of self-assembling nanomaterials with a wide range of potential applications in biomedicine and nanotechnology. The history of DNA nanotechnology can be traced back to the 1980s with the development of simple DNA polyhedra using either human intuition or simple algorithms. Today the field is dominated by DNA origami constructs to such an extent that the original algorithms used to design non-origami nanostructures have been lost. In this work we describe Arktos: an algorithm developed to design simple DNA polyhedra without the use of DNA origami. Arktos designs sequences predicted to fold into a desired structure using simulated annealing optimization. As a proof-of-concept, we used Arktos to design a simple DNA tetrahedron. The generated oligonucleotide sequences were synthesized and experimentally validated via polyacrylamide gel electrophoresis, indicating that they fold into the desired structure. These results demonstrate that Arktos can be used to design custom DNA polyhedra as per the needs of the research community.
Generation of surrogate brain maps preserving spatial autocorrelation through random rotation of geometric eigenmodes
Authors: Koussis Nikitas C , Pang James C , Jeganathan Jayson , Paton Bryan , Fornito Alex , Robinson P A , Misic Bratislav , Breakspear Michael
Published: February 2024

The brain expresses activity in complex spatiotemporal patterns, reflected in the influence of spatially distributed cytoarchitectural, biochemical, and genetic properties. The correspondence between these multimodal "brain maps" may reflect underlying causal pathways and is hence a topic of substantial interest. However, these maps possess intrinsic smoothness (spatial autocorrelation, SA) which can inflate spurious cross-correlations, leading to false positive associations. Identifying true associations requires knowledge about the distribution of correlations that arise by chance in the presence of SA. This null distribution can be generated from an ensemble of surrogate brain maps that preserve internal SA but break correlations between maps. The present work introduces "eigenstrapping", using a spectral decomposition of cortical and subcortical surfaces in terms of geometric eigenmodes, and then randomly rotating these modes to produce SA-preserving surrogate brain maps. It is shown that these surrogates appropriately represent the null distribution of chance pairwise correlations, with similar or superior false positive control to current state-of-the-art procedures. Eigenstrapping is fast, eschews the need for parametric assumptions about the nature of the SA, and works with maps defined on smooth surfaces with or without a boundary. It generalizes to broader classes of null models than existing techniques, offering a unified approach for inference on cortical and subcortical maps, spatiotemporal processes, and complex patterns possessing higher-order correlations.
Bidirectional emotional regulation through prefrontal innervation of the locus coeruleus
Authors: Watanabe Mayumi , Uematsu Akira , Johansen Joshua P.
Published: February 2024

Traumatic experiences produce powerful emotional memories which can subsequently be enhanced or reduced through cognitive control mechanisms. Noradrenaline from the brainstem locus coeruleus (LC) is activated during aversive emotion-inducing experiences and upregulated in individuals suffering from anxiety and trauma related disorders. The medial prefrontal cortex (mPFC) participates in cognitive and emotional control processes such as production of learned defensive responses and suppression of aversive memories through extinction. However, it is unclear whether or how distinct mPFC regions influence the LC to regulate learned emotional responding. Using viral based anatomical tracing techniques, we found that the LC receives topographically organized projections from the prelimbic (PL) and infralimbic (IL) subregions of mPFC. Furthermore, optogenetic approaches revealed that PL and IL inputs to LC are required to inhibit or facilitate, respectively, the extinction of aversive memories. Moreover, LC-projecting neurons in PL and IL exhibited distinct activity patterns during extinction learning, with IL-to-LC neurons displaying sustained, sensory cue-evoked activation, while activity in PL-to-LC inputs is elevated during periods of externally and internally generated aversive emotional responding. Together, these results demonstrate that mPFC subregions bidirectionally regulate extinction of emotional memories through differential modulation of the LC-noradrenaline system.
Loop-mediated Isothermal Amplification (LAMP) assay for reliable detection ofXanthomonas axonopodispv.vasculorum
Authors: Marabella Mitchell , Howard Julia , Bhandari Santosh , Do Sally , Montoya-Pimolwatana Maya , Dou Yichen , Dobhal Shefali , Arizala Dario , Montesinos Stefania , Andreason Sharon A. , Ochoa-Corona Francisco , Bingham Jon-Paul , Odani Jenee , Jenkins Daniel , Ma Li Maria , Fletcher Jacqueline , Stack James P. , Arif Mohammad
Published: February 2024

Xanthomonas axonopodispv.vasculorum(Xav), the causative agent of sugarcane gumming disease, represents a significant threat to global sugarcane production due to its systemic and destructive nature. Despite the economic implications, a field-deployable, Xav-specific diagnostic tool has not been developed. This resulted in a loop-mediated isothermal amplification (LAMP) assay targeting thepelLgene, unique to Xav strains, as a rapid and precise diagnostic assay. The selection of thepelLgene was informed by comprehensivein silicoanalyses of Xav genomes and relatedXanthomonasspecies and other close relatives. Validation against the NCBI GenBank database and internally sequenced genomes confirmed the gene’s exclusivity to Xav. Subsequent primers for both endpoint PCR and LAMP assays were designed using thepelLgene region. The LAMP assay underwent extensive testing against inclusivity and exclusivity panels. Use of exclusivity panel, comprising 81 strains from related species, other bacterial genera, and host genomes, demonstrated the assay’s specificity with no false positives. The assay exhibited a detection limit of 1 pg, and its effectiveness was unimpeded by crude host lysate (sugarcane). Further validation through multi-device and multi-operator testing underscored the assay’s 100% reproducibility and robustness. Application to infected plant samples resulted in the detection of all infected specimens without any false positives or negatives. This novel LAMP assay is accurate and reliable tool for Xav detection, with promising applications in routine diagnostics, biosecurity measures, microbial forensics, and epidemiological research.
Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators
Authors: Malone Taylor J. , Wu Jing , Zhang Yalan , Licznerski Pawel , Chen Rongmin , Nahiyan Sheikh , Pedram Maysam , Jonas Elizabeth A. , Kaczmarek Leonard K.
Published: February 2024

Neuronal activity stimulates mRNA translation crucial for learning and development. While FMRP (Fragile X Mental Retardation Protein) and CYFIP1 (Cytoplasmic FMR1 Interacting Protein 1) regulate translation, the mechanism linking translation to neuronal activity is not understood. We now find that translation is stimulated when FMRP and CYFIP1 translocate to the potassium channel Slack (KCNT1, Slo2.2). When Slack is activated, both factors are released from eIF4E (Eukaryotic Initiation Factor 4E), where they normally inhibit translation initiation. A constitutively active Slack mutation and pharmacological stimulation of the wild-type channel both increase binding of FMRP and CYFIP1 to the channel, enhancing the translation of a reporter for β-actin mRNA in cell lines and the synthesis of β-actin in neuronal dendrites. Slack activity-dependent translation is abolished when both FMRP and CYFIP1 expression are suppressed. The effects of Slack mutations on activity-dependent translation may explain the severe intellectual disability produced by these mutations in humans.

HIGHLIGHTS

Activation of Slack channels triggers translocation of the FMRP/CYFIP1 complex

Slack channel activation regulates translation initiation of a β-actin reporter construct

A Slack gain-of-function mutation increases translation of β-actin reporter construct and endogenous cortical β-actin

FMRP and CYFIP1 are required for Slack activity-dependent translation

IN BRIEF

Maloneet al. show that the activation of Slack channels triggers translocation of the FMRP/CYFIP1 complex from the translation initiation factor eIF4E to the channel. This translocation releases eIF4E and stimulates mRNA translation of a reporter for β-actin and cortical β-actin mRNA, elucidating the mechanism that connects neuronal activity with translational regulation.
Semantic plasticity across timescales in the human brain
Authors: Solomon S.H. , Kay K. , Schapiro A.C.
Published: February 2024

Our representations of the world need to be stable enough to support general knowledge but flexible enough to incorporate new information as our environment changes. How does the human brain manage this stability-plasticity trade-off? We analyzed a large dataset in which participants viewed objects embedded in thousands of natural scenes across many fMRI sessions. Semantic item representations were located by jointly leveraging a voxelwise encoding model to find reliable item representations and a word-embedding model to evaluate semantic content. Within the medial temporal lobe, semantic item representations in hippocampal subfield CA1, parahippocampal cortex, and perirhinal cortex gradually drifted across a period of multiple months. Whole-brain analyses revealed a gradient of plasticity in the temporal lobe, with drift more evident in anterior than posterior areas. On short timescales, rapid plasticity was observed only in parahippocampal cortex, such that item co-occurrence statistics warped item representations within a single session. Together, the results suggest that the brain solves the stability-plasticity trade-off through a gradient of plasticity across semantic regions.
Devaluation of response-produced safety signals reveals circuits for goal-directed versus habitual avoidance in dorsal striatum
Authors: Sears Robert M. , Andrade Erika C. , Samels Shanna B. , Laughlin Lindsay C. , Moloney Danielle M. , Wilson Donald A. , Alwood Matthew R. , Moscarello Justin M. , Cain Christopher K.
Published: February 2024

Active avoidance responses (ARs) are instrumental behaviors that prevent harm. Adaptive ARs may contribute to active coping, whereas maladaptive avoidance habits are implicated in anxiety and obsessive-compulsive disorders. The AR learning mechanism has remained elusive, as successful avoidance trials produce no obvious reinforcer. We used a novel outcome-devaluation procedure in rats to show that ARs are positively reinforced by response-produced feedback (FB) cues that develop into safety signals during training. Males were sensitive to FB-devaluation after moderate training, but not overtraining, consistent with a transition from goal-directed to habitual avoidance. Using chemogenetics and FB-devaluation, we also show that goal-directed vs. habitual ARs depend on dorsomedial vs. dorsolateral striatum, suggesting a significant overlap between the mechanisms of avoidance and rewarded instrumental behavior. Females were insensitive to FB-devaluation due to a remarkable context-dependence of counterconditioning. However, degrading the AR-FB contingency suggests that both sexes rely on safety signals to perform goal-directed ARs.
Nandrolone alters the behavioral response to cocaine as well as striatal and cortical dopamine receptors of prepubertal male rats
Authors: Freire-Arvelo Jaime A. , Rivero Carlos J. , Santiago-Marrero Iván G. , Mendez-Morales Andrea , González-Segarra Amanda J , Pérez-Cardona Enrique U. , Torres-Ramirez Ricardo J. , Segarra Annabell C.
Published: February 2024

Nandrolone is the anabolic androgenic steroid (AAS) most used by athletes and adolescents. The use of supraphysiologic doses has been associated with dysfunction in brain areas that regulate anxiety, motivation, and reward. This study investigated if exposure to nandrolone before puberty altered anxiety- and addictive-like behaviors. Changes in dopamine type 2 receptors (D2DR) in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were also examined. Male rats received 10 daily injections of nandrolone decanoate (20 mg/kg) starting on day 28. Afterwards, they were tested in the elevated plus maze (EPM) and open field (OF). Their locomotor response (sensitization) and preference (conditioned place preference (CPP)) to cocaine (15 mg/kg) was also assessed. Nandrolone reduced anxiety and ambulation. Nandrolone-treated males also displayed sensitization to cocaine at an earlier age (day 44) than oil-treated males (day 52) and showed a 27% reduction in CPP to cocaine. Expression of D2DR in the NAc, and in the PFC of males tested for CPP was increased by nandrolone, whereas treatment with cocaine reduced accumbal D2DR. We hypothesize that nandrolone accelerates the development of the neural circuitry that regulates behavioral sensitization and reduces the rewarding property of cocaine, as manifested in the reduction of CPP. It is possible that the observed increase in accumbal D2DR may partially mediate the reduced anxiety and ambulation as well accelerate the maturation of the neural circuitry responsible for the sensitized response to cocaine.
Changing rounds into squares or combining stripes: Diversity and formation of checkerboard patterns in Eukaryotes
Authors: Galipot Pierre , Zalko Julie
Published: February 2024

Important in many human artistic cultures, checkerboard patterns are rare in nature like many motifs based on squared geometry. Nevertheless, they are expected to be very detectable by the visual networks due to their periodic geometry, and diverse plant and animal species bear them, suggesting specific biological functions. Here, thanks to a biological survey, we first draw the diversity of species bearing checkerboard patterns. Then, we selected two genera, Sarcophaga flies and Fritillaria flowers to perform simulations and functional studies to decipher the mechanisms producing these very peculiar patterns. Although they share a similar geometry, these two genera appear to produce checkered patterns through two very different ways, showing a convergence of shape but not of mechanism. Together, this shows the extent of the mechanisms selected during evolution to generate complex forms, and confirms the importance of describing color patterns through the species diversity
Colonization by orchid mycorrhizal fungi primes induced systemic resistance against a necrotrophic pathogen
Authors: Pujasatria Galih Chersy , Miura Chihiro , Yamaguchi Katsushi , Shigenobu Shuji , Kaminaka Hironori
Published: February 2024

Orchids and arbuscular mycorrhiza (AM) plants evolved independently and have different structures and fungal partners, but they both facilitate nutrient uptake. Orchid mycorrhiza (OM) supports orchid seed germination, but unlike AM, its role in disease resistance of mature plants is largely unknown. Here, we examined whether OM induces systemic disease resistance against a necrotrophic pathogen in a similar fashion to AM. We investigated the priming effect of mycorrhizal fungi inoculation on resistance of a terrestrial orchid,Bletilla striata, to soft rot caused byDickeya fangzhongdai. We found that root colonization by a compatible OM fungus primedB. striataseedlings and induced systemic resistance against the infection. Transcriptome analysis showed that priming was mediated by the downregulation of jasmonate and ethylene pathways and that these pathways are upregulated once infection occurs. Comparison with the reported transcriptome of AM fungus–colonized rice leaves revealed similar mechanisms inB. striataand in rice. These findings highlight a novel aspect of commonality between OM and AM plants in terms of induced systemic resistance.

Highlight

Colonization by a compatible mycorrhizal fungus primes induced systemic resistance against a necrotrophic pathogen in a terrestrial orchid,Bletilla striata, by regulating jasmonate and ethylene pathways, similar to arbuscular mycorrhizal plants.
Social inequalities in pregnancy metabolic profile: findings from the multi-ethnic Born in Bradford cohort study
Authors: Elhakeem Ahmed , Clayton Gemma L , Soares Ana G , Taylor Kurt , Maitre Léa , Santorelli Gillian , Wright John , Lawlor Deborah A , Vrijheid Martine
Published: February 2024

Background

Lower socioeconomic position (SEP) is associated with adverse pregnancy and perinatal outcomes and with less favourable metabolic profile in nonpregnant adults. However, socioeconomic differences in pregnancy metabolic profile are unknown. We investigated association between a composite measure of SEP and pregnancy metabolic profile in White European (WE) and South Asian (SA) women.

Methods

We included 3,905 WE and 4,404 SA pregnant women from a population-based UK cohort. Latent class analysis was applied to nineteen individual, household, and area-based SEP indicators (collected by questionnaires or linkage to residential address) to derive a composite SEP latent variable. Targeted nuclear magnetic resonance spectroscopy was used to determine 148 metabolic traits from mid-pregnancy serum samples. Associations between SEP and metabolic traits were examined using linear regressions adjusted for gestational age and weighted by latent class probabilities. An interactive application was developed for exploring all association results (https://aelhak.shinyapps.io/SEP_NMR_BiB/).

Results

Five SEP sub-groups were identified and labelled ‘Highest SEP’ (48% WE and 52% SA), ‘High-Medium SEP’ (77% and 23%), ‘Medium SEP’ (56% and 44%) ‘Low-Medium SEP’ (21% and 79%), and ‘Lowest SEP’ (52% and 48%). Lower SEP was associated with more adverse levels of 113 metabolic traits, including lower high-density lipoprotein (HDL) and higher triglycerides and very low-density lipoprotein (VLDL) traits. For example, mean standardized difference (95%CI) inconcentration of small VLDL particles(vs. Highest SEP) was 0.12 standard deviation (SD) units (0.05 to 0.20) for ‘Medium SEP’ and 0.25SD(0.18 to 0.32) for ‘Lowest SEP’. There was statistical evidence of ethnic differences in associations of SEP with 31 traits, primarily characterised by stronger associations in WE women e.g., mean difference inHDL cholesterolin WE and SA women respectively (vs. Highest-SEP) was - 0.30SD(−0.41 to −0.20) and −0.16SD(−0.27 to −0.05) for ‘Medium SEP’, and −0.62SD(−0.72 to −0.52) and −0.29SD(−0.40 to −0.20) for ‘Lowest SEP’.

Conclusions

We found widespread socioeconomic differences in metabolic traits in pregnant WE and SA women residing in the UK, and clearer socioeconomic gradient for some traits in WE women. Supporting all pregnant women in the most disadvantaged socioeconomic groups may provide the greatest benefit for perinatal health.