bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Neuromuscular Controllers with Simplified Muscle Model and Enhanced Reflex Modulation: A Comparative Study in Hip Exoskeletons
Authors: Manzoori Ali Reza , Messara Sara , Di Russo Andrea , Ijspeert Auke , Bouri Mohamed
Published: May 2024

Abstract

Neuromuscular controllers (NMCs) offer a promising approach to adaptive and task-invariant control of exoskeletons for walking assistance, leveraging the bioinspired models based on the peripheral nervous system. This article expands on our previous development of a novel structure for NMCs with modifications to the virtual muscle model and reflex modulation strategy. The modifications consist firstly of simplifications to the Hill-type virtual muscle model, resulting in a more straightforward formulation and reduced number of parameters; and secondly, using a finer division of gait subphases in the reflex modulation state machine, allowing for a higher degree of control over the shape of the assistive profile. Based on the proposed general structure, we present two controller variants for hip exoskeletons, with four- and five-state reflex modulations (NMC-4 and NMC-5). We used an iterative data-driven approach with two tuning stages (i.e., muscle parameters and reflex gains) to determine the controller parameters. Biological joint torque profiles and optimal torque profiles for metabolic cost reduction were used as references for the final tuning outcome. Experimental testing under various walking conditions demonstrated the capability of both variants for adapting to the locomotion task with minimal parameter adjustments, mostly in terms of timing. Furthermore, NMC-5 exhibited better alignment with biological and optimized torque profiles in terms of timing characteristics and relative magnitudes, resulting in less negative mechanical work. These findings firstly validate the adequacy of the simplified muscle model for assistive controllers, and demonstrate the utility of a more nuanced reflex modulation in improving the assistance quality.
Leveraging the genetic diversity of trout in the rivers of the British Isles and northern France to understand the movements of sea trout (Salmo truttaL.) around the English Channel
Authors: King R. Andrew , Ellis Charlie D. , Bekkevold Dorte , Ensing Dennis , Lecointre Thomas , Osmond Daniel R. , Piper Adam , Roberts Dylan E. , Launey Sophie , Stevens Jamie R.
Published: May 2024

Populations of anadromous brown trout, also known as sea trout, have suffered recent marked declines in abundance due to multiple factors, including climate change and human activities. While much is known about their freshwater phase, less is known about the species’ marine feeding migrations. This situation is hindering the effective management and conservation of anadromous trout in the marine environment. Using a panel of 95 single nucleotide polymorphism markers we developed a genetic baseline, which demonstrated strong regional structuring of genetic diversity in trout populations around the English Channel and adjacent waters. Extensive baseline testing showed this structuring allowed high-confidence assignment of known-origin individuals to region of origin. This study presents new data on the movements of anadromous trout in the English Channel and southern North Sea. Assignment of anadromous trout sampled from 12 marine and estuarine localities highlighted contrasting results for these areas. The majority of these fisheries are composed predominately of stocks local to the sampling location. However, there were multiple cases of long-distance movements of anadromous trout, with several individuals originating from rivers in northeast England being caught in the English Channel and southern North Sea, in some cases more than 1000 km from their natal region. These results have implications for the management of sea trout in inshore waters around the English Channel and southern North Sea.
G6b-B antibody-based cis-acting platelet receptor inhibitors (CAPRIs) as a new family of anti-thrombotic therapeutics
Authors: Mazharian Alexandra , Bertin Ophélie , Sarkar Amrita , Augros Johanna , Bornert Alicia , Loubière Cécile , Jönsson Friederike , Warwicker Juli , Abbott W Mark , Dushek Omer , Vayne Caroline , Rauova Lubica , Fütterer Klaus , Rollin Jérôme , Poncz Mortimer , Senis Yotis A
Published: May 2024

Platelets are highly reactive fragments of megakaryocytes that play a fundamental role in thrombosis and hemostasis. Predictably, all conventional anti-platelet therapies elicit bleeding, raising the question whether the thrombotic activity of platelets can be targeted separately. In this study, we describe a novel approach of inhibiting platelet activation through the use of bispecific single-chain variable fragments (bi-scFvs), termed cis-acting platelet receptor inhibitors (CAPRIs) that harness the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing co-inhibitory receptor G6b-B (G6B) to suppress immunoreceptor tyrosine-based (ITAM)-containing receptor-mediated platelet activation. CAPRI-mediated hetero-clustering of G6B with either the ITAM-containing GPVI-FcR γ-chain complex or FcγRIIA (CD32A) inhibited collagen- or immune complex-induced platelet aggregation. G6B-GPVI CAPRIs strongly and specifically inhibited thrombus formation on collagen under arterial shear, whereas G6B-CD32A CAPRI strongly and specifically inhibited thrombus formation to heparin-induced thrombocytopenia, vaccine-induced thrombotic thrombocytopenia and antiphospholipid syndrome complexes on Von Willebrand Factor-coated surfaces and photochemical-injured endothelial cells under arterial shear. Our findings provide proof-of-concept that CAPRIs are highly effective at inhibiting ITAM receptor-mediated platelet activation, laying the foundation for a novel family of anti-thrombotic therapeutics with potentially improved efficacy and fewer bleeding outcomes compared with current anti-platelet therapies.
sangerFlow, a Sanger sequencing-based bioinformatics pipeline for pests and pathogens identification
Authors: Prodhan M. Asaduzzaman , Power Matthew , Kehoe Monica
Published: May 2024

Sequencing of a Polymerase Chain Reaction product (amplicon) is called amplicon sequencing. Amplicon sequencing allows for reliable identification of an organism by amplifying, sequencing, and analysing a single conserved marker gene or DNA barcode. As this approach generally involves a single gene, it is a light-weight protocol compared to multi-locus or whole genome sequencing for diagnostic purposes; yet considerably reliable. Therefore, Sanger-based high-quality amplicon sequencing is widely deployed for species identification and high-throughput biosecurity surveillance. However, keeping up with the data analysis in a large-scale surveillance or diagnostic settings could be a limiting factor because it involves manual quality control of the raw sequencing data, alignment of the forward and reverse reads, and finally web-based Blastn search of all the amplicons. Here, we present a bioinformatics pipeline that automates the entire analysis. As a result, the pipeline is scalable with high-volume of samples and reproducible. Furthermore, the pipeline leverages the modern open-source Nextflow and Singularity concept, thus it does not require software installation except Nextflow and Singularity, software subscription, or programming expertise from the end users making it widely adaptable.

Availability and implementation

sangerFlow source code and documentation are freely available for download at GitHub, implemented in Nextflow and Singularity.
Parallel maximal common subgraphs with labels for molecular biology
Authors: Agbeto Wilfried , Coti Camille , Reinharz Vladimir
Published: May 2024

Advances in graph algorithmics have allowed in-depth study of many natural objects from molecular biology or chemistry to social networks. Particularly in molecular biology and cheminformatics, understanding complex structures by identifying conserved sub-structures is a key milestone towards the artificial design of novel components with specific functions. Given a dataset of structures, we are interested in identifying all maximum common connected partial subgraphs between each pair of graphs, a task notoriously NP-Hard.

In this work, we present parallel algorithms over shared and distributed memory to enumerate all maximal connected common sub-graphs between pairs of arbitrary multi-directed graphs with labels on their edges. We offer an implementation of these methods and evaluate their performance on the non-redundant dataset of all known RNA 3D structures. We show that we can compute the exact results in a reasonable time for each pairwise comparison while taking into account a much more diverse set of interactions—resulting in much denser graphs—resulting in an order of magnitude more conserved modules. All code is available athttps://gitlab.info.uqam.ca/cbe/pasigraphand results in the branchresults.
Inferred Developmental Origins of Brain Tumors from Single Cell RNA-Sequencing Data
Authors: Wang Su , Curry Rachel Naomi , Erickson Anders W , Kleinman Claudia , Taylor Michael D. , Rao Ganesh , Deneen Benjamin , Harmanci Arif O. , Harmanci Akdes Serin
Published: May 2024

The reactivation of neurodevelopmental programs in cancer highlights parallel biological processes that occur in both normal development and brain tumors. Achieving a deeper understanding of how dysregulated developmental factors play a role in the progression of brain tumors is therefore crucial for identifying potential targets for therapeutic interventions. Single-cell RNA sequencing (scRNA-Seq) provides an opportunity to understand how developmental programs are dysregulated and reinitiated in brain tumors at single-cell resolution. Here, we introduce COORS (Cell Of ORigin like CellS), as a computational tool trained on developmental human brain single-cell datasets that enables annotation of “developmental-like” cell states in brain tumor cells. Applying COORS to various brain cancer datasets, including medulloblastoma (MB), glioma, and diffuse midline glioma (DMG), we identified developmental-like cells that represent putative cells of origin in these tumors. Our work adds to our cumulative understanding of brain tumor heterogeneity and helps pave the way for tailored treatment strategies.
Rhizaria in the oligotrophic ocean exhibit clear temporal and vertical variability
Authors: Barth Alexander , Blanco-Bercial Leocadio , Johnson Rod , Stone Joshua
Published: May 2024

Recently studies have shown that Rhizaria, a super-group of marine protists, have a large role in pelagic ecosystems. They are unique in that they construct mineral tests out of silica, calcium carbonate, or strontium sulfate. As a consequence, Rhizaria can have large impacts on the oceans cycling of carbon and other elements. However, less is known about Rhizaria ecology or their role in the pelagic food-web. Some taxa, like certain Radiolaria, are mixotrophic, hosting algal symbionts. While other taxa are flux-feeders or even predatory carnivores. Some prior research has suggested that Rhizaria will partition vertically in the water column, likely due to different trophic strategies. However, very few studies have investigated their populations over extended periods of time. In this study, we present data investigating Rhizaria abundance and vertical distribution from over a year of monthly cruises in the Sargasso Sea. This study represents the first quantification of Rhizaria throughout the mesopelagic zone in an oligotrophic system for an extended period of time. We use this data to investigate the hypothesis that Rhizaria taxonomic groups will partition due to trophic mode. We also investigate how their abundance varies in accordance with environmental parameters. Rhizaria abundance was quantified using an Underwater Vision Profiler (UVP5), an in-situ imaging device. Ultimately, we show that different Rhizaria taxa will have unique vertical distribution patterns. Models relating their abundance to environmental parameters have mixed results, yet particle concentration is a common predictive variable, supporting the importance of heterotrophy amongst many taxa.
Adverse pregnancy outcomes and coronary artery disease risk: A negative control Mendelian randomization study
Authors: Rogne Tormod , Gill Dipender
Published: May 2024

Background

Adverse pregnancy outcomes are predictive for future cardiovascular disease risk, but it is unclear whether they play a causal role. We conducted a Mendelian randomization study with males as a negative control population to estimate the associations between genetic liability to adverse pregnancy outcomes and risk of coronary artery disease.

Methods

We extracted uncorrelated (R2<0.01) single-nucleotide polymorphisms strongly associated (p-value<5e-8) with miscarriage, gestational diabetes, hypertensive disorders of pregnancy, preeclampsia, placental abruption, poor fetal growth and preterm birth from relevant genome-wide association studies. Genetic associations with risk of coronary artery disease were extracted separately for females and males. The main analysis was the inverse-variance weighted analysis, while MR Egger, weighted median and weighted mode regression, bidirectional analyses, and the negative control population with males were sensitivity analyses to evaluate bias due to genetic pleiotropy.

Results

The number of cases for the adverse pregnancy outcomes ranged from 691 (182,824 controls) for placental abruption to 49,996 (174,109 controls) for miscarriage, and there were 22,997 (310,499 controls) and 54,083 (240,453 controls) cases of coronary artery disease for females and males, respectively. We observed an association between genetic liability to hypertensive disorders of pregnancy and preeclampsia, and to some extent gestational diabetes, poor fetal growth and preterm birth, with an increased risk of coronary artery disease among females, which was supported by the MR Egger, weighted median and weighted mode regressions. However, in the negative control population of males, we observed largely the same associations as for females.

Conclusions

The associations between adverse pregnancy outcomes and coronary artery disease risk were likely driven by confounding (e.g., shared genetic liability). Thus, our study does not support the hypothesis that adverse pregnancy outcomes are causal risk factors for cardiovascular diseases.
Novel mark recapture surveys reveal stable pigmentation patterns but age-related melanism in the common frogRana temporaria
Authors: Petrovan Silviu O. , Sivakumar Sharvani , Li Carissa , Christie Alec
Published: May 2024

Variations in melanin-based pigmentation patterns are frequent evolutionary adaptations in vertebrates and allow the study of phenotypic diversity across populations as well as individual recognition. Age-related changes in such pigmentation patterns have been demonstrated for several species but remain rarely explored in adult amphibians. For the wide-ranging European common frog (Rana temporaria) dorsal melanism was discussed in the context of UV protection at high altitude or as thermal adaptation at high latitude, yet patterns remain unquantified across most of its range or in terms of individual variation over time. We investigated dorsal pigmentation patterns in a wild population ofR. temporariain a lowland site in England which was the focus of a 7 year high-intensity mark recapture programme. We collected dorsal photographs using phone cameras and analysed pigmentation patterns using visual classifications and ImageJ image processing software. Pigmentation was highly variable between individuals but overall: (i) the number of melanin-based spots was largely stable or decreased over time as enlarging spots sometimes merged but never disappeared; (ii) the total melanin-based pigmented area increased significantly over time on average, albeit not for all individuals; and (iii) pigmentation was similar in males compared to females although the darkest individuals tended to be males. Our analysis reveals important patterns in pigmentation change and stability in this widespread species but the mechanisms and specific drivers remain unknown.
Plant phenotypes as trajectories: 38-yr monitoring reveals that shape of lifetime fecundity schedule is under selection in a long-lived shrub
Authors: Herrera Carlos M.
Published: May 2024

Defining a phenotype is sometimes problematic in the case of modularly-built, nonunitary organisms with indeterminate growth such as plants. This paper presents a proof of concept of the evolutionary significance of considering lifetime trajectories of individual plants as a component of their phenotypes. Size and inflorescence production were monitored for the whole reproductive lifespans of N = 128 individuals of the Mediterranean woody shrubLavandula latifolia(Lamiaceae) over a 38-year period to address the following questions: Did individuals vary in lifetime trajectories of size and fecundity?, and Were parameters describing individual trajectories significant predictors of cumulative lifetime reproduction? Individuals differed widely in lifetime fecundity and in every parameter describing lifetime fecundity schedule (age at first and last reproduction, longevity, and mean, variance, skewness and kurtosis of lifetime temporal distribution of inflorescence production). Phenotypic selection analysis revealed significant relationships between parameters of individual lifetime schedules and a surrogate of relative fitness of individuals (cumulative lifetime production of inflorescences divided by the average for all individuals). Significant selection gradients involved positive and negative directional selection, as well as instances of nonlinear selection, which showed that plants with certain shapes of lifetime fecundity schedules had fitness advantage over others. The notion of plant phenotypes as trajectories was strongly supported by the combined findings that individuals differed greatly in their "appearances" with regard to the way in which size and fecundity unfolded over lifetime, and that selection efficaciously "saw" such variation.
FOSL2 Gene Expression Declines with Age in Bone Marrow-derived MSCs
Authors: Utley James , Briggs Daniel S
Published: May 2024

The FOSL2 gene, integral to the AP-1 transcription factor complex, orchestrates cellular responses to stimuli, including immune surveillance and tissue-resident memory T cell differentiation. This study investigates FOSL2's expression dynamics across ages to elucidate its role in aging and age-associated diseases. Leveraging gene expression profiles in response to environmental challenges, we hypothesize that FOSL2 serves as a critical regulator of aging-associated cellular alterations. Utilizing quantitative PCR and RNA sequencing, we charted FOSL2 expression in human bone marrow-derived mesenchymal stromal cells (hMSCs) aged 17-84 years. Statistical analyses reveal a significant negative correlation between FOSL2 expression and age (slope: -0.02442, R-value: -0.41759, P-value: 0.00081), suggesting FOSL2 as a potential biomarker for aging and its involvement in the decline of regenerative capacity. The observed decrease in FOSL2 expression aligns with its role in regulating cellular processes critical in aging. Understanding FOSL2's regulatory network offers insights into aging mechanisms and therapeutic targets for age-related diseases.
Association between depression and the prevalence and prognosis of prediabetes: a population-based study
Authors: Zhou Jin , Yang Xiaojiao
Published: May 2024

Background

Diagnosis and intervention of prediabetes is an emerging approach to preventing the progression and complications of diabetes. It has been reported that inflammatory factors and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may be potential pathogenesis mechanisms of diabetes and depression. However, the relationship between depression levels and the prevalence of prediabetes and its prognosis remains elusive. This study aimed to explore the relationship between depression and the prevalence of prediabetes and to further explore the all-cause mortality of different levels of depression in patients with prediabetes.

Methods

Our study used a data set from the National Health and Nutrition Examination Survey (NHANES). Participants were divided into two groups (with or without depression) and further divided into subgroups based on different levels of depression status to analyze the relationship between depression and prediabetes prevalence. We then analyzed the relationship between all-cause mortality and depressive status in patients with prediabetes. This study used a weighted multiple logistic/Cox regression model.

Results

A total of 4384 participants were included, divided into depression group (n=1379) and non-depression group (n=3005). Results showed that people with depression were at higher risk of developing prediabetes. After adjusting for covariates, moderate to severe depression was positively associated with prediabetes (moderate to severe depression vs no depression: OR=1.834, 95%CI: 0.713–4.721; severe depression vs no depression: OR= 1.004, 95% CI 0.429–2.351). In addition, we explored the relationship between all-cause mortality and depressive status in patients diagnosed with prediabetes (n=2240) and found that moderate to severe depression (HR=2.109, 95%CI 0.952-4.670) was associated with higher mortality in patients with prediabetes. Associated with increased all-cause mortality.

Conclusions

Overall, findings suggest that depression is positively associated with prediabetes prevalence and mortality. These results suggest that good management of mental health conditions may be a potential strategy to reduce the occurrence and progression of prediabetes.
Functional genomics reveals the mechanism of hypoxic adaptation in nontuberculous mycobacteria
Authors: Tateishi Yoshitaka , Ozeki Yuriko , Nishiyama Akihito , Morishige Yuta , Minato Yusuke , Baughn Anthony D. , Matsumoto Sohkichi
Published: May 2024

Mycobacterium intracellulareis a major etiological agent of the recently expandingMycobacterium avium–intracellularecomplex pulmonary disease (MAC-PD). Therapeutic regimens that include a combination of macrolides and antituberculous drugs have been implemented with limited success. To identify novel targets for drug development that accommodate the genomic diversity ofM. avium–intracellulare, we subjected eight clinical MAC-PD isolates and the type strain ATCC13950 to genome-wide profiling to comprehensively identify universally essential functions. Among these strains, we identified 131 shared essential or growth-defect-associated genes. Unlike the type strain, the clinical strains showed an increased requirement for genes involved in gluconeogenesis and the type VII secretion system under standard growth conditions, the same genes required for hypoxic pellicle-type biofilm formation in ATCC13950. Consistent with the central role of hypoxia in the evolution ofM. intracellulare, the clinical MAC-PD strains showed more rapid adaptation to hypoxic growth than the type strain. Importantly, the increased essentiality of hypoxic fitness genes was confirmed in a mouse lung infection model. These findings confirm the concordant gene essentiality under hypoxic conditionsin vitroand hypoxia-related conditionsin vivo, and highlight the importance of using clinical strains and host-relevant growth conditions to identify high-value targets for drug development.
Artificial Intelligence Uncertainty Quantification in Radiotherapy Applications - A Scoping Review
Authors: Wahid Kareem A. , Kaffey Zaphanlene Y. , Farris David P. , Humbert-Vidan Laia , Moreno Amy C. , Rasmussen Mathis , Ren Jintao , Naser Mohamed A. , Netherton Tucker J. , Korreman Stine , Balakrishnan Guha , Fuller Clifton D. , Fuentes David , Dohopolski Michael J.
Published: May 2024

Background/purpose

The use of artificial intelligence (AI) in radiotherapy (RT) is expanding rapidly. However, there exists a notable lack of clinician trust in AI models, underscoring the need for effective uncertainty quantification (UQ) methods. The purpose of this study was to scope existing literature related to UQ in RT, identify areas of improvement, and determine future directions.

Methods

We followed the PRISMA-ScR scoping review reporting guidelines. We utilized the population (human cancer patients), concept (utilization of AI UQ), context (radiotherapy applications) framework to structure our search and screening process. We conducted a systematic search spanning seven databases, supplemented by manual curation, up to January 2024. Our search yielded a total of 8980 articles for initial review. Manuscript screening and data extraction was performed in Covidence. Data extraction categories included general study characteristics, RT characteristics, AI characteristics, and UQ characteristics.

Results

We identified 56 articles published from 2015-2024. 10 domains of RT applications were represented; most studies evaluated auto-contouring (50%), followed by image-synthesis (13%), and multiple applications simultaneously (11%). 12 disease sites were represented, with head and neck cancer being the most common disease site independent of application space (32%). Imaging data was used in 91% of studies, while only 13% incorporated RT dose information. Most studies focused on failure detection as the main application of UQ (60%), with Monte Carlo dropout being the most commonly implemented UQ method (32%) followed by ensembling (16%). 55% of studies did not share code or datasets.

Conclusion

Our review revealed a lack of diversity in UQ for RT applications beyond auto-contouring. Moreover, there was a clear need to study additional UQ methods, such as conformal prediction. Our results may incentivize the development of guidelines for reporting and implementation of UQ in RT.
The Effects of Intermittent Vibrational Stimulation on Lower Limb Kinematics Two Months After Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Trial
Authors: Yona Tomer , Peskin Bezalel , Fischer Arielle
Published: May 2024

Objective

To investigate the immediate effects of intermittent vibrational stimulation on gait and stair ambulation among patients two months post anterior cruciate ligament reconstruction.

Design

Randomized, parallel, 2-group-randomized controlled trial.

Setting

Hospital setting.

Participants

There were 27 male and female participants aged 18-45, two months post-ACLR, and a convenience sample of 24 healthy controls.

Interventions

The participants were randomly assigned to two groups. One group received a device designed to apply intermittent vibrational stimulation above and below the knee; the other received a sham device.

Main Outcome Measure(s)

The main outcomes were the knee sagittal kinematics during gait at three speeds and stair ascent and descent. The assessment was performed with and without one of the study devices.

Results

Compared to the sham device, intermittent vibrational stimulation significantly increased the minimum knee flexion angles while walking at normal, slow, and fast paces and stair ascent.

Concblusion

Intermittent vibrational stimulation affects the lower limb kinematics during rehabilitation for individuals post-ACLR. However, further research is necessary to confirm long-term benefits and establish optimal application parameters.
Mutation frequency and copy number alterations determine prognosis and metastatic tropism in 60,000 clinical cancer samples
Authors: Calonaci Nicola , Krasniqi Eriseld , Scalera Stefano , Gandolfi Giorgia , Milite Salvatore , Ricciuti Biagio , Maugeri-Saccà Marcello , Caravagna Giulio
Published: May 2024

The intricate interplay between somatic mutations and copy number alterations critically influences tumour evolution and patient prognosis. Traditional genomic studies often overlook this interplay by analysing these two biomarker types in isolation. Leveraging an innovative computational model capable of detecting allele-specific copy number alterations from clinical targeted panels without matched normal, we conducted a comprehensive analysis of over 500,000 mutations across 60,000 clinical samples spanning 39 cancer types. Our findings uncovered 11 genes and 6 hotspots exhibiting recurrent tumour-specific patterns of co-existing mutations and copy-number alterations across 17 tumours. By stratifying more than 24,000 patients based on these composite genotypes across multiple oncogenes and tumour suppressor genes, we identified 66 groups with distinct prognostic significance, 25% more than using a standard mutation-centric stratification. Notably, 7 groups displayed a heightened propensity for metastasis, while 16 were associated with site-specific patterns of metastatic dissemination. This augmented insight into genomic drivers enhances our understanding of cancer progression and metastasis, holding the potential to significantly foster biomarker discovery.

Statement of significance

By leveraging large datasets and new computational modelling, this study demonstrates the critical interplay between somatic mutations and copy number alterations in driving patient prognosis, tumour progression and metastatic tropism. This work implies a shift towards a more integrative and comprehensive approach in clinical sequencing, with significant implications for biomarker discovery and target identification.
Deep Learning for Contrast Enhanced Mammography - a Systematic Review
Authors: Sorin Vera , Sklair-Levy Miri , Glicksberg Benjamin S. , Konen Eli , Nadkarni Girish N. , Klang Eyal
Published: May 2024

Background/Aim:

Contrast-enhanced mammography (CEM) is a relatively novel imaging technique that enables both anatomical and functional breast imaging, with improved diagnostic performance compared to standard 2D mammography. The aim of this study is to systematically review the literature on deep learning (DL) applications for CEM, exploring how these models can further enhance CEM diagnostic potential.

Methods

This systematic review was reported according to the PRISMA guidelines. We searched for studies published up to April 2024. MEDLINE, Scopus and Google Scholar were used as search databases. Two reviewers independently implemented the search strategy.

Results

Sixteen relevant studies published between 2018 and 2024 were identified. All studies but one used convolutional neural network models. All studies evaluated DL algorithms for classification of lesions at CEM, while six studies also assessed lesion detection or segmentation. In three studies segmentation was performed manually, two studies evaluated both manual and automatic segmentation, and ten studies automatically segmented the lesions.

Conclusion

While still at an early research stage, DL can improve CEM diagnostic precision. However, there is a relatively small number of studies evaluating different DL algorithms, and most studies are retrospective. Further prospective testing to assess performance of applications at actual clinical setting is warranted.

Graphic Abstract
Conservation of Regulatory Elements with Highly Diverged Sequences Across Large Evolutionary Distances
Authors: Phan Mai HQ , Zehnder Tobias M , Puntieri Fiona , Lo Bai-Wei , Lenhard Boris , Mueller Ferenc , Vingron Martin , Ibrahim Daniel M
Published: May 2024

Embryonic gene expression is remarkably conserved across vertebrates as observed, for instance, in the developing hearts of chicken and mouse which diverged >300 million years ago. However, most cis regulatory elements (CREs) are highly divergent, which makes orthology tracing based on sequence similarity difficult, especially at larger evolutionary distances. Some evidence suggests functional conservation of CREs despite sequence divergence. However, it remains unclear how widespread such functional conservation might be. Here, we address this question by profiling the regulatory genome in the embryonic hearts of chicken and mouse at equivalent developmental stages. Gene expression and 3D chromatin structure show remarkable similiarity, while the majority of CREs are non-alignable between the two species. To identify orthologous CREs independent of sequence alignability, we introduce a synteny-based strategy called Interspecies Point Projection (IPP). Compared to alignment-based approaches, IPP identifies up to 5-fold more putative orthologs in chicken, and up to 9-fold across distantly related vertebrates. We term these sequence-diverged orthologs indirectly conserved and characterize their functional conservation compared to sequence-alignable, directly conserved CREs. Indirectly and directly conserved elements show similar enrichment of functional chromatin signatures and cell-type specific enhancer sequence composition. Yet, shared transcription factor binding sites between orthologs are more heavily rearranged in indirectly conserved elements. Finally, we validate functional conservation of indirectly conserved chicken enhancers in mouse using in vivo reporter assays. Taken together, by overcoming the limitations of alignment-based methods our results reveal functional conservation of CREs across large evolutionary distances is more widespread than previously recognized.
Proteasomal control of anti-CRISPRs for the regulation of CRISPR/Cas9 activity using Cas9-ACROBAT
Authors: Martin Timothy D. , Watson Emma V. , Choi Mei Yuk , Nabet Behnam , Gray Nathanael S. , Xu Qikai , Elledge Stephen J.
Published: May 2024

Small molecule-mediated proteasomal degradation of proteins is a powerful tool for synthetic regulation of biological activity. To control Cas9 activity in cells, we engineered an anti-CRISPR protein, AcrIIA4, fused to a degradation (dTAG) or small molecule assisted shutoff (SMASh) tag. Co-expression of the tagged AcrIIA4 along with Cas9 and riboswitch-regulated sgRNAs enables precise tunable control of CRISPR activity by small molecule addition.
Bacterial microcompartment utilisation in the human commensalEscherichia coliNissle 1917
Authors: Clare Chania , Rutter Jack W. , Fedorec Alex J.H. , Frank Stefanie , Barnes Chris P.
Published: May 2024

Bacterial microcompartments (BMCs) are self-assembled protein structures often utilised by bacteria as a modular metabolic unit, enabling the catalysis and utilisation of less common carbon and nitrogen sources within a self-contained compartment. Theethanolamine (EA) utilisation (eut)BMC has been widely demonstrated in enteropathogens, such asSalmonella enterica, and current research is exploring its activity in the commensal species that populate the human gut.Escherichia coliNissle 1917 (EcN) is a strong coloniser and probiotic in gut microbial communities, and has been used extensively for microbiome engineering. In this study, the utilisation of ethanolamine as a sole carbon source and the formation of theeutBMC in EcN were demonstrated through growth assays and visualisation with transmission electron microscopy. Subsequently, flux balance analysis was used to further investigate the metabolic activity of this pathway. It was found that not only is the utilisation of theeutBMC for the degradation of EA as a carbon source in EcN comparable to that ofSalmonella enterica, but also that ammonium is released into solution as a byproduct in EcN but not inS. enterica. Control of EA-dependent growth was demonstrated using different concentrations of the operon inducer, vitamin-B12. We show that vitamin B12-dependent EA utilisation as the sole carbon source enables growth in EcN, and demonstrate the concurrent formation of the BMC shell and inducible control of theeutoperon.
Risk-free polio vaccine: Recombinant expression systems for production of stabilised virus-like particles
Authors: Sherry Lee , Bahar Mohammad W , Porta Claudine , Fox Helen , Grehan Keith , Nasta Veronica , Duyvesteyn Helen M E , de Colibus Luigi , Marsian Johanna , Murdoch Inga , Ponndorf Daniel , Kim Seong-Ryong , Shah Sachin , Carlyle Sarah , Swanson Jessica J , Matthews Sue , Nicol Clare , Lomonossoff George P , Macadam Andrew J , Fry Elizabeth E , Stuart David I , Stonehouse Nicola J , Rowlands David J
Published: May 2024

Polioviruses have caused crippling disease in humans for centuries, prior to the successful development of vaccines in the mid-1900’s, which dramatically reduced disease prevalence. Continued use of these vaccines, however, threatens ultimate disease eradication and achievement of a polio-free world. Virus-like particles (VLPs) that lack a viral genome represent a safer potential vaccine, although they require particle stabilization. Using our previously established genetic techniques to stabilize the structural capsid proteins, we demonstrate production of poliovirus VLPs of all three serotypes, from four different recombinant expression systems. We compare the antigenicity, thermostability and immunogenicity of these stabilized VLPs against the current inactivated polio vaccine, demonstrating equivalent or superior immunogenicity. Structural analyses of these recombinant VLPs provide a rational understanding of the stabilizing mutations and the role of potential excipients. Collectively, we have established these poliovirus stabilized VLPs as viable next-generation vaccine candidates for the future.
IFIT1 is rapidly evolving and exhibits disparate antiviral activities across 11 mammalian orders
Authors: McDougal Matthew B , De Maria Anthony M , Nakahara Emi , Boys Ian N , Schoggins John W
Published: May 2024

Mammalian mRNAs possess an N7-methylguanosine (m7G) cap and 2'O methylation of the initiating nucleotide at their 5' end, whereas certain viral RNAs lack these characteristic features. The human antiviral restriction factor IFIT1 recognizes and binds to specific viral RNAs that lack the 5' features of host mRNAs, resulting in targeted suppression of viral RNA translation. This interaction imposes significant host-driven evolutionary pressures on viruses, and many viruses have evolved mechanisms to evade the antiviral action of human IFIT1. However, little is known about the virus-driven pressures that may have shaped the antiviral activity of IFIT1 genes across mammals. Here, we take an evolution-guided approach to show that the IFIT1 gene is rapidly evolving in multiple mammalian clades, with positive selection acting upon several residues in distinct regions of the protein. In functional assays with 39 IFIT1s spanning diverse mammals, we demonstrate that IFIT1 exhibits a range of antiviral phenotypes, with many orthologs lacking antiviral activity against viruses that are strongly suppressed by other IFIT1s. We further show that IFIT1s from human and a bat, the black flying fox, inhibit Venezuelan equine encephalitis virus (VEEV) and strongly bind to Cap0 RNAs. Unexpectedly, chimpanzee IFIT1, which differs from human IFIT1 by only 8 amino acids, does not inhibit VEEV infection and exhibits minimal Cap0 RNA-binding. In mutagenesis studies, we determine that amino acids 364 and 366, with the latter undergoing positive selection, are sufficient to confer the differential anti-VEEV activity between human and chimpanzee IFIT1. These data suggest that virus-host genetic conflicts have influenced the antiviral specificity of IFIT1 across diverse mammalian orders.
Neandertal ancestry through time: Insights from genomes of ancient and present-day humans
Authors: Iasi Leonardo N. M. , Chintalapati Manjusha , Skov Laurits , Mesa Alba Bossoms , Hajdinjak Mateja , Peter Benjamin M. , Moorjani Priya
Published: May 2024

Gene flow from Neandertals has shaped the landscape of genetic and phenotypic variation in modern humans. We identify the location and size of introgressed Neandertal ancestry segments in more than 300 genomes spanning the last 50,000 years. We study how Neandertal ancestry is shared among individuals to infer the time and duration of the Neandertal gene flow. We find the correlation of Neandertal segment locations across individuals and their divergence to sequenced Neandertals, both support a model of single major Neandertal gene flow. Our catalog of introgressed segments through time confirms that most natural selection–positive and negative–on Neandertal ancestry variants occurred immediately after the gene flow, and provides new insights into how the contact with Neandertals shaped human origins and adaptation.
WUSCHEL-dependent chromatin regulation in maize inflorescence development at single-cell resolution
Authors: Bang Sohyun , Zhang Xuan , Gregory Jason , Chen Zongliang , Galli Mary , Gallavotti Andrea , Schmitz Robert J.
Published: May 2024

WUSCHEL (WUS) is transcription factor vital for stem cell proliferation in plant meristems. In maize,ZmWUS1is expressed in the inflorescence meristem, including the central zone, the reservoir of stem cells.ZmWUS1overexpression in theBarren inflorescence3mutant leads to defects in inflorescence development. Here, single-cell ATAC-seq analysis shows thatZmWUS1overexpression alters chromatin accessibility throughout the central zone. The CAATAATGC motif, a known homeodomain recognition site, is predominantly observed in the regions with increased chromatin accessibility suggesting ZmWUS1 is an activator in the central zone. Regions with decreased chromatin accessibility feature various motifs and are adjacent toAUXIN RESPONSE FACTORgenes, revealing negative regulation of auxin signaling in the central zone. DAP-seq of ZmWUS1 identified the TGAATGAA motif, abundant in epidermal accessible chromatin compared to the central zone. These findings highlight ZmWUS1’s context-dependent mechanisms for stem cell maintenance in the inflorescence meristem.
Differential roles of putative arginine fingers of AAA+ATPases Rvb1 and Rvb2
Authors: Warnock Jennifer L. , Ball Jacob A. , Najmi Saman M. , Henes Mina , Vazquez Amanda , Koshnevis Sohail , Wieden Hans-Joachim , Conn Graeme L. , Ghalei Homa
Published: May 2024

The evolutionarily conserved AAA+ATPases Rvb1 and Rvb2 proteins form a heteromeric complex (Rvb1/2) required for assembly or remodeling of macromolecular complexes in essential cellular processes ranging from chromatin remodeling to ribosome biogenesis. Rvb1 and Rvb2 have a high degree of sequence and structural similarity, and both contain the classical features of ATPases of their clade, including an N-terminal AAA+subdomain with the Walker A motif, an insertion domain that typically interacts with various binding partners, and a C-terminal AAA+subdomain containing a Walker B motif, the Sensor I and II motifs, and an arginine finger. In this study, we find that despite the high degree of structural similarity, Rvb1 and Rvb2 have distinct active sites that impact their activities and regulation within the Rvb1/2 complex. Using a combination of biochemical and genetic approaches, we show that replacing the homologous arginine fingers of Rvb1 and Rvb2 with different amino acids not only has distinct effects on the catalytic activity of the complex, but also impacts cell growth, and the Rvb1/2 interactions with binding partners. Using molecular dynamics simulations, we find that changes near the active site of Rvb1 and Rvb2 cause long-range effects on the protein dynamics in the insertion domain, suggesting a molecular basis for how enzymatic activity within the catalytic site of ATP hydrolysis can be relayed to other domains of the Rvb1/2 complex to modulate its function. Further, we show the impact that the arginine finger variants have on snoRNP biogenesis and validate the findings from molecular dynamics simulations using a targeted genetic screen. Together, our results reveal new aspects of the regulation of the Rvb1/2 complex by identifying a relay of long-range molecular communication from the ATPase active site of the complex to the binding site of cofactors. Most importantly, our findings suggest that despite high similarity and cooperation within the same protein complex, the two proteins have evolved with unique properties critical for the regulation and function of the Rvb1/2 complex.

Significance

AAA ATPases constitute a large family of proteins involved in various essential cellular functions in living organisms in all kingdoms of life. Members of this family typically form homo or hetero multimers that convert the energy from ATP hydrolysis to mechanical work. How the conserved features of AAA ATPases relay the energy from ATP hydrolysis to other functional domains of the complex remains largely unknown. Here, using arginine finger variants of Rvb1 and Rvb2, two evolutionarily conserved closely related AAA+ATPases that form a heterohexameric complex, we reveal how individual protomers in a heteromeric complex can uniquely contribute to the overall function of the complex and how changes in the ATP binding site can be relayed to distal functional domains.
Mycolic acid and cholesterol induced transcriptomic adaptations in wild type and Mce complex ATPase subunit deleted strain ofM. tuberculosisH37Rv
Authors: Rahman Mohammad Asadur , Izzi Valerio , Riley Lee W. , Venkatesan Rajaram
Published: May 2024

During infection and latency,Mycobacterium tuberculosis(Mtb) primarily relies on lipids as its main energy source. The Mtb mammalian cell entry (Mce) complexes function as lipid transporters with Mkl as the ATPase subunit for substrate translocation. Cholesterol and mycolic acid are essential to the infectiousness and pathogenicity of Mtb. Here, we have investigated the transcriptomic responses of wild type and∆mklstrains of Mtb to cholesterol and mycolic acid through RNAseq analysis. The number of differentially expressed genes was always higher when grown on cholesterol than on mycolic acid. In most cases,∆mklshowed the opposite gene expression pattern compared to the wild type. Among the fourmceoperons, significant changes in expression patterns were observed mainly in the genes ofmce3andmce4operons. The upregulation ofmce3operon and the downregulation ofmce4operon in the presence of mycolic acid and cholesterol is intriguing. The transcriptome profile of genes involved in mycolic acid synthesis did not show significant change to either mycolic acid or cholesterol. However, interestingly, both mycolic acid and cholesterol induce upregulation of methyl citrate cycle and dormancy related genes indicating their significance during Mtb persistence and provides insights on Mtb′s adaptive strategies under stress through transcriptional remodelling.