bluuebunny/crossref_metadata_2025 huggingface dataset:
Multivariate Profiling of Physical Resilience in Older Adults After Total Knee Replacement Surgery
Authors: Xue Qian-Li , Laskow Thomas , Alzahrani Mallak , Varadhan Ravi , Walston Jeremy D , Schrack Jennifer A , Newman Anne B , Sieber Frederick , Bandeen-Roche Karen
Published: October 2024

IMPORTANCE As individuals age, they often face a variety of health challenges. Physical resilience indicates how well a person can cope with and recover from physical challenges, which is crucial for maintaining independence and quality of life in older age. OBJECTIVE To develop a multivariate phenotype of physical resilience based on individual recovery dynamics before and after a clinical stressor. DESIGN, SETTING, AND PARTICIPANTS This observational study included 112 individuals aged 60 and older who underwent elective total knee replacement for degenerative joint disease between December 2, 2019, and January 4, 2023. Physical function was assessed before surgery and at 1, 6, and 12 months post-surgery to characterize resilience trajectories. EXPOSURE Elective total knee replacement surgery for degenerative joint disease. MAIN OUTCOMES AND MEASURES A multivariate resilience phenotype was derived from physical function trajectories assessed using the Short Physical Performance Battery, the Pittsburgh Fatigability Scale-Physical Subscale, the KOOS Quality of Life, and the SF36-Physical Component Score. This phenotype was validated against surrogate markers (i.e., frailty, self-reported health) and determinants (e.g., the Charlson Comorbidity Index) of recovery potential (aka resilience capacity). RESULTS The study identified distinct resilience profiles across four measures: 4 profiles for the Short Physical Performance Battery and the KOOS Quality of Life, 3 each for the Pittsburgh Fatigability Scale-Physical Subscale and the SF36-Physical Component Score, showing varied baseline levels and/or change rates over 12 months. By combining and analyzing resilience profiles across measures, two distinct groups emerged: 35.7% classified as non-resilient and 64.3% as resilient. The non-resilient group had a higher prevalence of frailty (35.0% vs. 9.7%, p<0.01), poor or fair self-reported health (45.0% vs. 5.6%, p<0.01), and a moderate/severe comorbidity burden (Charlson Comorbidity Index >2; 27.5% vs. 11.1%, p=0.06). CONCLUSIONS AND RELEVANCE The distinct recovery trajectories observed after the surgery indicated varying resilience levels that were not fully explained by baseline status. This research underscores the importance of resilience in surgical recovery and could pave the way for better patient care by focusing on individual resilience capacities and shifting the focus from managing health conditions to promoting recovery and overall well-being.
Segmentation of leukoaraiosis on noncontrast head CTs using CT-MRI paired data without human annotation
Authors: Ryu Wi-Sun , Song Jae W. , Lim Jae-Sung , Lee Ju Hyung , Sunwoo Leonard , Kim Dongmin , Lee Myungjae , Kim Beom Joon
Published: October 2024

Background

Compared to white matter hyperintensity (WMH) on MRI, evaluating leukoaraiosis (LA) on CT can be challenging due to its low contrast-to-noise ratio against white matter and similar attenuation to parenchymal gliosis and edema. We aimed to develop and validate a deep learning algorithm that segments LA using CT-MRIFLAIRpaired data from a multicenter, multi-vendor registry from Korea and from a head CT dataset from a US population.

Methods

We retrospectively identified CT-MRIFLAIRpairs from a nationwide ischemic stroke registry for training and internal validation (n=482), external testing (n=390), and clinical validation (n=867). Additionally, 100 scans from a US population were collected. WMH on MRI were segmented using previously validated software and the segmentation mask was registered onto the CT scan. Performance was assessed using Dice similarity coefficient (DSC), concordance correlation coefficient (ρ), and Pearson correlation. Predicted LA volumes were analyzed for associations with clinical outcomes.

Results

Mean age (SD) for training and external testing datasets were 68.1 (SD 12.7) and 69.2 (SD 13.5) years and 33.2% and 47.9% were female, respectively. External test showed a DSC of 0.527, with ρ values of 0.919 and 0.760 for predicted LA volumes compared to registered LA and WMH volumes on MRI, respectively. In external testing and US datasets, the predicted LA volumes were significantly correlated with Fazekas grade (Pearson correlation coefficient=0.832 and 0.891, respectively). Subgroup analysis demonstrated consistent performance across different CT vendors (ρ ranged from 0.875 to 0.950) and infarct volumes (≤10 mL vs >10 mL; ρ=0.912 and ρ=0.922). In an independent clinical dataset, the predicted LA volumes correlated with age and clinical outcomes after ischemic stroke.

Conclusion

Our deep learning algorithm offers a reproducible method for LA segmentation on CT, bridging the gap between CT and MRI assessments in patients with ischemic stroke.
A bifunctional snoRNA with separable activities in guiding rRNA 2’-O-methylation and scaffolding gametogenesis effectors
Authors: Leroy Estelle , Challal Drice , Pelletier Stéphane , Goncalves Coralie , Menant Alexandra , Marchand Virginie , Jaszczyszyn Yan , van Dijk Erwin , Naquin Delphine , Andreani Jessica , Motorin Yuri , Palancade Benoit , Rougemaille Mathieu
Published: October 2024

Small nucleolar RNAs are non-coding transcripts that guide chemical modifications of RNA substrates and modulate gene expression at the epigenetic and post-transcriptional levels. However, the extent of their regulatory potential and the underlying molecular mechanisms remain poorly understood. Here, we identify a conserved, previously unannotated intronic C/D-box snoRNA, termedsnR107, hosted in the fission yeast long non-coding RNAmamRNAand carrying two independent cellular functions. On the one hand,snR107guides site-specific 25S rRNA 2’-O-methylation and promotes pre-rRNA processing and 60S subunit biogenesis. On the other hand,snR107associates with the gametogenic RNA-binding proteins Mmi1 and Mei2, mediating their reciprocal inhibition and restricting meiotic gene expression during sexual differentiation. Both functions require distinctcis-motifs withinsnR107, including a conserved 2’-O-methylation guiding sequence. Together, our results positionsnR107as a dual regulator of rRNA modification and gametogenesis effectors, expanding our vision on the non-canonical functions exerted by snoRNAs in cell fate decisions.
A triple serine motif in the intracellular domains of sortilin-related receptors SorCS1-3 regulates neurotrophic activity
Authors: Dalby Anders , Kaas Mathias , Meinertz-Byg Lars , Christiansen Signe Bundgaard , Bøggild Simon , Qvist Per , Nyengaard Jens R. , Madsen Peder , Mølgaard Simon , Glerup Simon
Published: October 2024

The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS1-3 intracellular domains (ICDs) contain a conserved triple serine motif that potentially functions as a signaling switch to induce neurotrophic signaling in hippocampal neurons. We demonstrate that phosphorylation mimicking mutations of the SorCS1-3 triple serine motifs display neurotrophic activity independently of both their extracellular domains (ECDs) and BDNF, and that the substitution of serines to alanines renders neurons less responsive to BDNF. Hence, we develop triple serine motif-based cell-penetrating peptides that modulate downstream signaling kinases of the BDNF pathway, ultimately activating the transcription factor CREB. Taken together, we provide the first mechanistic insights into SorCS1-3 mediated neurotrophic signaling and use this knowledge to develop pharmacologically active modulators.
Ancestral complexity and constrained diversification of the ant olfactory system
Authors: Marty Simon , Couto Antoine , Dawson Erika H. , Brard Neven , d’Ettorre Patrizia , Montgomery Stephen H. , Sandoz Jean-Christophe
Published: October 2024

Ants are a monophyletic but diverse group of social insects whose heightened olfactory ability has been crucial to their evolutionary success. Their complex olfactory system is believed to have evolved due to the expansion of a specialized olfactory subsystem and the associated clade of olfactory receptors. Specifically, ants exhibit specialized antennal hairs known as basiconic sensilla, whose neurons project to a distinctive cluster of numerous, small glomeruli in their antennal lobes. This adaptation is believed to be linked to their social lifestyle, enabling the detection of recognition cues like cuticular hydrocarbons (CHCs), which are essential for nestmate recognition and maintaining colony cohesion. However, our understanding of the ant olfactory system remains incomplete, lacking evolutionary context and phylogenetic breadth, which leaves the complexity in their most recent common ancestor uncertain. We thus conducted a comparative study of neuroanatomical traits across the phylogeny of the Formicidae. Our findings reveal a common blueprint for the ant olfactory pathway, alongside lineage-specific adaptations. This highlights a dynamic evolution, particularly for the CHC-related subsystem. Ancestral trait reconstructions indicate that olfactory sophistication predates the most recent common ancestor of ants. Additionally, we found that the chemical complexity of species-specific recognition cues is associated with neuronal investment within the olfactory system. Lastly, behavioral experiments on anatomically divergent ant species show that, despite variation in neuroanatomical traits, ants consistently discriminate nestmates from non-nestmates. This suggests that the evolution of ants’ olfactory system integrates sensory adaptations to diverse chemical environments, facilitating communication, a key to social behaviors.
PoreMeth2: decoding the evolution of methylome alterations with Nanopore sequencing
Authors: Mattei Gianluca , Baragli Marta , Gega Barbara , Mingrino Alessandra , Chieca Martina , Ducci Tommaso , Frigè Gianmaria , Mazzarella Luca , D’Aurizio Romina , De Logu Francesco , Nassini Romina , Pelicci Pier Giuseppe , Magi Alberto
Published: October 2024

In epigenetic analysis, identifying differentially methylated regions (DMRs) typically involves detecting groups of consecutive CpGs that show significant changes in their average methylation levels. However, the methylation state of a genomic region can also be characterized by a mixture of patterns (epialleles) with variable frequencies, and the relative proportions of such patterns can provide insights into its mechanisms of formation.

Traditional methods based on bisulfite conversion and NGS, due to the read size (150 bp), allow epiallele frequency analysis only in high-CpG-density regions, limiting differential methylation studies to just 50% of the human methylome. Nanopore sequencing, with its long reads, enables the analysis of epiallele frequency across both high- and low-CpG-density regions.

We introduce a novel computational approach, PoreMeth2, an R library that integrates epiallelic diversity and methylation frequency changes from Nanopore data to identify DMRs, assess their formation mechanisms, and annotate them to genic and regulatory elements. We applied PoreMeth2 to cancer and glial cell datasets, demonstrating its ability to distinguish epigenomic changes with a strong effect on gene expression from those with a weaker impact on transcriptional activity.

PoreMeth2 is publicly available athttps://github.com/Lab-CoMBINE/PoreMeth2.
PUNCH2: explore the strategy for Intrinsically Disordered Protein predictor
Authors: Meng Di , Pollastri Gianluca
Published: October 2024

Intrinsically disordered proteins (IDPs) lack stable three-dimensional structures, which poses significant challenges for their computational prediction. This study introduces PUNCH2, a novel approach for predicting intrinsically disordered regions (IDRs) in proteins. We address key issues such as the scarcity of comprehensive IDR databases, effective feature extraction, and robust model architecture. By integrating sequences from experimental PDB datasets and fully disordered DisProt sequences for training, PUNCH2 achieves superior prediction accuracy. Various sequence embeddings, including One-Hot, MSA-based, and PLM-based methods, were evaluated, with ProtTrans-based embeddings showing the best performance. The optimal model architecture features multiple convolutional layers, enhancing predictive confidence. PUNCH2 and its lighter variant, PUNCH2-light, demonstrate high efficiency and accuracy in benchmarking against top predictors on the CAID2 dataset, offering promising tools for advancing IDP research and understanding.
Effects of Oral Exposure to HPAI H5N1 Pasteurized in Milk on Immune Response and Mortality in Mice
Authors: Brigleb Pamela H. , Roubidoux Ericka Kirkpatrick , Livingston Brandi , Sharp Bridgett , Meliopoulos Victoria A. , Tan Shaoyuan , Morris Dorothea R. , Lazure Lauren , Schultz-Cherry Stacey
Published: October 2024

In March 2024, there was the first reported outbreak of a highly pathogenic avian H5N1 influenza (HPAI) clade 2.3.4.4b virus in dairy cows in the United States. Since then, there have been several spillover events to cats, poultry, and humans. Multiple reports have discovered infectious virus in raw milk from infected dairy cows. Infectious virus can also last over a period on milking machine surfaces as a potential route of spread in cattle and contamination in raw milk. While the U.S. Food and Drug Administration has cleared commercial pasteurized milk as safe for consumption given the lack of infectious virus, there have been numerous reports that up to 30 percent of commercial milk tested were positive for HPAI H5N1 influenza virus genome copies. This is not necessarily unique to the HPAI H5N1 virus, as retrospective studies have identified H1N1 and H3N2 seropositivity in cows linked to decreased milk production. However, it is unknown how repeat exposure to the remaining viral proteins and genomic material in pasteurized milk modulates immune responses once ingested. We developed a successful in-house pasteurization protocol that inactivated high viral loads of the pandemic H1N1 strain A/California/04/2009 (Cal09) or bovine-derived HPAI H5N1 (A/bovine/Ohio.B24OSU-439/2024) viruses in raw milk. Mice were administered this milk daily for five days and rechallenged with each respective virus. We found that repeated oral exposure to inactivated virus was not sufficient to prevent or accelerate mortality from lethal challenge of HPAI H5N1, though it did result in a ∼0.5 log10reduction viral titers in the brain and delayed clinical signs. In contrast, oral gavage of mice with pre-existing immunity to H1N1 influenza virus with virus pasteurized in milk were protected from morbidity and mortality upon bovine H5N1 viral challenge. These findings suggest that ingestion of inactivated HPAI H5N1 has limited potential health risk and does not prevent protective immune history-mediated responses to lethal infection.
TECPR2 is a Rab5 effector that regulates endosomal cargo recycling
Authors: Paul Sankalita , Pant Rajat , Sharma Poonam , Walia Kshitiz , Gupta Suhasi , Aseem Adhil , Bajwa Kamlesh Kumari , George Ruben , Varma Yudish , Bhatia Tripta , Ramachandran Rajesh , Tuli Amit , Sharma Mahak
Published: October 2024

Small GTP-binding (G) proteins of the Rabs, Arfs, and Arls (Arf-like) family mediate the recruitment of their effectors to subcellular membrane-bound compartments, which in turn mediates vesicle budding, motility, and tethering. Here, we report that Tectonin-β-propeller repeat containing protein 2 (TECPR2), a protein mutated in a form of hereditary sensory and autonomic neuropathy (HSAN), is an effector of early endosomal Rab protein, Rab5, and interacts with Rab5 via its C-terminal TECPR repeats. The HSAN-associated TECPR2 (R1336W) missense variant was deficient in Rab5-binding and, consequently, in membrane recruitment. TECPR2-depletion led to perinuclear collapse of recycling endosomes and increased overlap of sorting and degradative subdomain markers on early endosomes. Consistent with a possible role in endocytic recycling, we observed impaired recycling and increased lysosomal degradation of α5β1 integrin receptors upon TECPR2 knockdown. TECPR2 regulates the early endosomal localization of the cargo adaptor for β1 integrins, SNX17, and its-associated protein complex WASH, which mediates actin polymerization on early endosomes. Finally, TECPR2 depletion in the zebrafish model resulted in delayed motility and changes in the neuromuscular junction. Our study supports an early endosomal role for TECPR2 in cargo recycling and provides insights into how its loss-of- function results in a neurodegenerative genetic disorder.
Unveiling the Promise of Peptide Nucleic Acids as Functional Linkers for Riboglow RNA Imaging Platform
Authors: Wierzba Aleksandra J. , Richards Erin M. , Lennon Shelby R. , Batey Robert T. , Palmer Amy E.
Published: October 2024

Linkers in chemical biology provide more than just connectivity between molecules; their intrinsic properties can be harnessed to enhance the stability and functionality of chemical probes. In this study, we explored the incorporation of a peptide nucleic acid (PNA)-based linker into RNA-targeting probes to improve their affinity and specificity. By integrating a PNA linker into a small molecule probe of Riboglow platform, we enabled dual binding events: cobalamin (Cbl)-RNA structure-based recognition and sequence-specific PNA-RNA interaction. We show that incorporating a six-nucleotide PNA sequence complementary to the region of wild type RNA aptamer (env8) results in a 30-fold improvement in binding affinity compared to the probe with nonfunctional PEG linker. Even greater improvements are observed when the PNA probe was tested against truncated versions of the RNA aptamer, with affinity increasing by up to 280-fold. Additionally, the PNA linker is able to rescue Cbl-RNA interaction even when the cobalamin binding pocket is compromised. We demonstrated that PNA probes effectively bind RNA bothin vitroand in live cells, enhancing visualization of RNA in stress granules and U-bodies at low concentrations. The modular nature of the Riboglow platform allows for flexible modifications of the PNA linker, fluorophore and RNA tag, while maintaining high specificity and affinity. This work establishes a new approach for enhancing RNA imaging platforms through the use of PNA linkers, highlighting the potential of combining short oligonucleotides with small molecules to improve the affinity and specificity of RNA-targeting probes. Furthermore, this dual-binding approach presents a promising strategy for driving advancements in RNA-targeted drug development.

Table of Contents graphic
Potent photoswitch for expression of biotherapeutics in mammalian cells by light
Authors: Gebel Jeannette , Ciglieri Elisa , Stahl Rainer , Duthie Fraser , Möglich Andreas , Müller-Hartmann Herbert , Schmidt Hanns-Martin , Wachten Dagmar
Published: October 2024

Abstract

Precise temporal and spatial control of gene expression is of great benefit for the study of specific cellular circuits and activities. Compared to chemical inducers, light-dependent control of gene expression by optogenetics achieves a higher spatial and temporal resolution. This could also prove decisive beyond basic research for manufacturing difficult-to-express proteins in pharmaceutical bioproduction. However, current optogenetic gene-expression systems limit this application in mammalian cells as expression levels and fold induction upon light stimulation are not sufficient. To overcome this limitation, we designed a photoswitch by fusing the blue light-activated light-oxygen-voltage receptor EL222 fromErythrobacter litoralisto the three tandem transcriptional activator domains VP64, p65, and Rta. The resultant photoswitch, dubbed DEL-VPR, allows an up to 400-fold induction of target gene expression by blue light, achieving expression levels that surpass those for strong constitutive promoters. Here, we utilized DEL-VPR to enable light-induced expression of complex monoclonal and bispecific antibodies with reduced byproduct expression, increasing the yield of functional protein complexes. Our approach offers temporally controlled yet strong gene expression and applies to both academic and industrial settings.
Protein Language Model Fitness Is a Matter of Preference
Authors: Gordon Cade , Lu Amy X. , Abbeel Pieter
Published: October 2024

Leveraging billions of years of evolution, scientists have trained protein language models (pLMs) to understand the sequence and structure space of proteins aiding in the design of more functional proteins. Although they have shown ability to improve efficiency in engineering, it remains unclear if such models capture true biological patterns or artifacts of the training data. We aim to predict the circumstances in which pLMs can successfully perform zero-shot fitness estimation. Our work studies trends observed over hundreds of deep mutational scans across multiple different fitness objectives. We find that the likelihood, or abstractly, implicit preference of a certain protein sequence imbued during pretraining is predictive of fitness prediction capabilities. Both over-preferred and under-preferred wild type sequences harm performance. Using influence functions to causally understand how individual data points increase protein likelihoods, we find that there exists a power law tail due to sequence homology. Lastly, under-performance on low likelihood wild type proteins can be remedied by unsupervised finetuning. These findings that pLM zero-shot fitness estimation can be predicted by the likelihood of the engineered sequence can motivate and improve pLMs’ deployment in protein maturation campaigns.
Semantic Dimensions Support the Cortical Representation of Object Memorability
Authors: Slayton Matthew , Howard Cortney M , Huang Shenyang , Hovhannisyan Mariam , Cabeza Roberto , Davis Simon W
Published: October 2024

Recent work in vision sciences contends that objects carry an intrinsic property, memorability, that describes the likelihood that an object can be successfully encoded and later retrieved from memory. It has been shown that object memorability is supported by semantic information, but the neural correlates involved are largely unexplored. The present study explores these premises and asks whether neural correlates of object memorability can be accounted for by semantic dimensions. To investigate these questions, we combine three datasets: (1) feature norms for a database of ∼1000 natural object images, (2) normative conceptual and perceptual memory data for those objects, and (3) neuroimaging data from an fMRI study collected using a subset (n=360) of those objects. We found that object-wise memorability elicits consistent brain activation across participants in key mnemonic regions (e.g., hippocampus and rhinal cortex), and that a substantial portion of the variance in this brain activity is mediated by the semantic factors describing these images. Regions with the strongest mediation effects are associated with sensory, motor, and visual processes, suggesting that the relationship between memorability and semantics may align with a sensory-functional account of the representation of concepts in the brain.
Independent, Ongoing Clade-Specific Expansions of IS5Elements inPseudomonas syringae
Authors: Baltrus David A. , Sweten Audrey , Conomos Thomas , Konkel Zachary , Jacobs Jonathan
Published: October 2024

Insertion Sequence (IS) elements are transposable regions of DNA which are present in a majority of bacterial genomes. It has been hypothesized that differences in distributions of IS elements across bacterial strains and species may reflect underlying differences in population biology. Therefore, shifts in IS element distributions between strains may be proxies for and reflective of changes in population dynamics. Here we investigate the presence and distribution of a subclass of IS5elements throughout genomes ofPseudomonas syringae, by querying complete genomes for the presence of InsH (the main transposase found within these IS5elements). We report that this one subclass of IS5elements appears to have recently undergone multiple independent expansions inP. syringaeclades and find that a majority of IS5insertion sites are not conserved across three closely relatedP. syringaepv. lachrymans genomes. We present further evidence, as has been shown for other members of the IS5family in different taxa, that elements from this IS5subclass can drive the expression of downstream genes inP. syringae. Taken together, our results highlight how dynamic IS5elements can be within and acrossP. syringaegenomes and point toward the potential for IS5elements to rewire the expression of theP. syringaechromosome.
Guided Visual Search is associated with a feature-based priority map in early visual cortex
Authors: Duecker Katharina , Shapiro Kimron L. , Hanslmayr Simon , Griffiths Benjamin J. , Pan Yali , Wolfe Jeremy , Jensen Ole
Published: October 2024

Visual search models have long emphasised that task-relevant items must be prioritised for optimal performance. While it is known that search efficiency also benefits from active distractor inhibition, the underlying neuronal mechanisms are debated. Here, we used MEG in combination with Rapid Invisible Frequency Tagging (RIFT) to probe how neuronal excitability in early visual cortex is modulated during feature-guided visual search. Participants were instructed to indicate the presence or absence of a letter “T” presented amongst 16 and 32 “L”s. In theguided searchcondition, participants were informed about the colour of the “T” and could infer the colour of the irrelevant distractors. In theunguided searchcondition, the target colour was unknown. We found thatguided searchwas associated with enhanced RIFT responses to the target colour, and decreased responses to the distractor colour compared tounguided search. These results conceptually replicated using both a conventional coherence approach, as well as with a General Linear Model approach based on a single-trial measure of the RIFT response. The present findings expand on previous reports based on electrophysiology and fMRI in humans and non-human primates by revealing that feature-guidance in visual search affects neuronal excitability as early as primary visual cortex.
Beyond Tumors: Reduced survival linked to pathogenicPIK3CAandTP53post-zygotic variants in the uninvolved breast tissue of recurrent cancer patients
Authors: Andreou Maria , Chojnowska Katarzyna , Filipowicz Natalia , Horbacz Monika , Madanecki Piotr , Duzowska Katarzyna , Lawrynowicz Urszula , Davies Hanna , Bruhn-Olszewska Bozena , Koszynski Mikolaj , Drezek-Chyla Kinga , Jaskiewicz Maciej , Jakalski Marcin , Kostecka Anna , Drzewiecka Marta , Nowikiewicz Magdalena , Las-Jankowska Manuela , Bala Dariusz , Hoffman Jacek , Srutek Ewa , Szylberg Lukasz , Jankowski Michal , Jankau Jerzy , Hodorowicz-Zaniewska Diana , Szpor Joanna , Zegarski Wojciech , Nowikiewicz Tomasz , Buckley Patrick G , Tiemann-Boege Irene , Mieczkowski Jakub , Koczkowska Madgalena , Dumanski Jan P. , Piotrowski Arkadiusz
Published: October 2024

Histologically normal mammary tissue from breast cancer patients can harbor significant genetic alterations. We analyzed the spectrum of DNA variants in 408 matched histologically normal tissue and tumors from 77 poor-prognosis patients, 49 patients recruited without prognosis bias, and mammary gland samples from 15 non-cancerous individuals. Whole exome sequencing revealed a higher prevalence of pathogenic post-zygotic variants in cancer-associated genes: AKT1, PIK3CA, PTEN, TBX3, and TP53, affecting poor-prognosis patients (29%), compared to 12.5% in those without prognosis criteria (p=0.0008578). PIK3CA variants were recurrent across patients, while TP53 variants were restricted to those with adverse prognoses. Duplex sequencing detected low-frequency pathogenicPIK3CAandTP53variants in distant normal tissues of poor-prognosis patients. Disease recurrence significantly reduced survival rates, with poor prognosis patients experiencing higher mortality within 24 months (p=0.0088), further worsened by the presence of pathogenic post-zygotic variants. These findings highlight the importance of genetic monitoring even in microscopically normal mammary tissue.
Effects of an acute bout of exercise on cognitive function in adults with cognitive impairment: A systematic review with meta-analysis of randomised controlled trials
Authors: Scott Charlotte L , Morgan Mia , Kelley George A , Nyman Samuel R
Published: October 2024

Objective

Examine the effects of an acute bout of physical exercise on cognitive function in adults with cognitive impairment (CI).

Design

Systematic review with meta-analysis of randomised controlled trials (RCTs) that investigated the effects of a single exercise session on cognitive function. Dual data abstraction, risk of bias assessment (RoB2) and strength of evidence assessment (GRADE) were conducted. Results were pooled using the inverse variance heterogeneity (IVhet) model or synthesised narratively.

Data sources

Six databases from inception to July 2024: (1) PubMed, (2) SportDiscus, (3) PsychINFO, (4) Cochrane Central, (5) PEDro, (6) Embase.

Eligibility criteria

RCT’s of acute exercise with male/female participants, aged 18+, and physician diagnosed or self-reported CI.

Results

15 studies (8 parallel group, 7 crossover) representing 500 participants were included, 10 in the meta-analysis. Acute exercise significantly improved executive function (“moderate” evidence, 9 studies, 330 participants,g=0.33, small effect, 95%CI [0.07, 0.59],p=0.01,I²=26.77, 95%CI [00.00, 65.82]. However, this was only for high risk of bias/crossover studies. Improvements in direction of benefit but non-significant for reaction time (“very low” evidence, 7 studies, 271 participants,g=0.17, small effect 95%CI [-0.20, 0.54],p=0.36,I²=50.18, 95%CI [00.00, 78.88]. Improvements in memory, but mixed evidence for attention, information processing and motor memory noted via narrative assessment.

Conclusion

In a healthy population, acute exercise improves cognition. For adults with CI, we found evidence of improvement in executive function, reaction time and memory. However, the review was limited by the inclusion of studies primarily with “high”/“some concerns” for bias and “very low”/“low” strength of evidence.

Summary box

Chronic exercise interventions have demonstrated significant improvements in cognition for healthy and cognitively impaired adults (1,2)

Acute exercise improves cognitive function in healthy adults (3–5) but evidence for the beneficial effects of acute exercise incognitively impairedadults is uncertain.

Our meta-analysis of 10 randomised controlled trials found that acute exercise improves executive function (small effect, moderate strength evidence) in adults with cognitive impairment.

It may also lead to improvements in reaction time (small effect, very low strength evidence) and memory (low strength evidence).
Intra-host evolution during relapsing parvovirus B19 infection in immunocompromised patients
Authors: Russcher Anne , Mohammed Yassene , Kraakman Margriet E.M. , Chow Xavier , Claas Eric C.J. , Wuhrer Manfred , Vossen Ann C.T.M. , Kroes Aloys C.M. , de Vries Jutte J.C.
Published: October 2024

Introduction

Parvovirus B19 (B19V) can cause severe relapsing episodes of anemia in immunocompromised individuals, which are commonly treated with intravenous immunoglobulins (IVIG). Few data is available on B19V intra-host evolution and the role of humoral immune selection. Here, we report the dynamics of genomic mutations and subsequent protein changes during relapsing infection.

Methods

Longitudinal plasma samples from immunocompromised patients with relapsing B19V infection in the period 2011-2019 were analyzed using whole genome sequencing to evaluate intra-host evolution. The impact of mutations on the 3D viral protein structure was predicted by deep neural network modeling.

Results

Of the three immunocompromised patients with relapsing infections for 3 to 9 months, one patient developed two consecutive nonsynonymous mutations in the VP1/2 region: T372S/T145S, and Q422L/Q195L. The first mutation was detected in multiple B19V IgG seropositive follow-up samples, and resolved after IgG seroreversion. Computational prediction of the VP1 3D structure of this mutant showed a conformational change in proximity of the antibody binding domain. No conformational changes were predicted for the other mutations detected.

Discussion

Analysis of relapsing B19V infections showed mutational changes occurring over time. Resulting amino acid changes were predicted to lead to a conformational capsid protein change in an IgG- seropositive patient. The impact of humoral response and IVIG treatment on B19V infections should be further investigated to understand viral evolution and potential immune escape.
Regional cerebral atrophy contributes to personalized survival prediction in ALS: a multicentre, machine learning, deformation based morphometry study
Authors: Lajoie Isabelle ,   Canadian ALS Neuroimaging Consortium (CALSNIC), Kalra Sanjay , Dadar Mahsa
Published: October 2024

Objective

Accurate personalized survival prediction in amyotrophic lateral sclerosis is essential for effective patient care planning. This study investigates whether gray and white matter changes measured by magnetic resonance imaging can improve individual survival predictions.

Methods

We analyzed data from 178 amyotrophic lateral sclerosis patients and 166 healthy controls in the Canadian ALS Neuroimaging Consortium study. A voxel-wise linear mixed- effects model assessed disease-related and survival-related atrophy detected through deformation-based morphometry, controlling for age, sex, and scanner variations. Additional linear mixed-effects models explored associations between regional imaging and clinical measurements, and their associations with time to the composite outcome of death, tracheostomy or permanent assisted ventilation. An individual survival distributions model was evaluated using clinical data alone, imaging data alone, and a combination of both features.

Results

Deformation-based morphometry uncovered distinct voxel-wise atrophy patterns linked to disease progression and survival, with many of these regional atrophy significantly associated with clinical manifestations of the disease. By integrating regional imaging features with clinical data, we observed a substantial enhancement in the performance of survival models across key metrics. Our analysis identified specific brain regions, such as the corpus callosum, rostral middle frontal gyrus, and thalamus, where atrophy predicted an increased risk of mortality.

Interpretation

This study suggests that brain atrophy patterns measured by deformation- based morphometry provide valuable insights beyond clinical assessments for prognosis. It offers a more comprehensive approach to prognosis and highlights brain regions involved in disease progression and survival, potentially leading to a better understanding of amyotrophic lateral sclerosis.
Economic Analysis of 15-valent and 20-valent Pneumococcal Conjugate Vaccines among Older Adults in Ontario, Canada
Authors: Gebretekle Gebremedhin B. , O’Reilly Ryan , Mac Stephen , Fadel Shaza , Crowcroft Natasha S. , Sander Beate
Published: October 2024

Introduction

Despite the availability of publicly funded 23-valent polysaccharide pneumococcal vaccine (PPV23) for all adults aged 65 years and older, pneumococcal disease remains a public health concern in Ontario, Canada. Health Canada approved two new pneumococcal conjugate vaccines (PCV), 15-valent (PCV15) and 20-valent (PCV20) and we assessed their cost-effectiveness for older Ontarians.

Methods

We conducted a cost-utility analysis using an individual-level state transition model to compare one dose of PCV (alone or in series with PPV23) with PPV23-only. We estimated sequential incremental cost-effectiveness ratio (ICER) expressed in costs (C$2022) per quality-adjusted life years (QALYs) from the healthcare payer perspective, discounted at 1.5% per annum. We performed sensitivity and scenario analyses to examine impact parameter uncertainties on the results.

Results

A sequential comparison of vaccination strategies with no indirect effect from childhood vaccination resulted in an ICER of $44,324/QALY for PCV15-alone compared to PPV23-only, and $70,751/QALY for PCV20-alone versus PCV15-alone. None of the PCV15/20 combined with PPV23 programs were cost-effective at a cost-effectiveness threshold of C$50,000/QALY. PCV20 alone had an ICER of C$46,961/QALY compared to PPV23-only. When considering the indirect effects, use of PCV15/20 alone or in series with PPV23 were not cost-effective strategies. ICERs were mostly influenced by vaccine characteristics (effectiveness, waning, cost) and the incidence of pneumococcal community- acquired pneumonia.

Conclusion

Vaccinating older adults with PCV15/20 is likely to reduce burden of pneumococcal disease and would be cost-effective initially, but is expected to be less economically attractive in the longer- term when herd immunity benefits from childhood vaccination programs are considered.
Bilingualism Modulates Executive Function Development in Pre-School Aged Children: A Preliminary Study
Authors: Sade Sally , Rathwell Scott , Kolb Bryan , Gonzalez Claudia , Gibb Robbin
Published: October 2024

This preliminary study was conducted to explore the effects of bilingualism on executive function development in children ages 3-5-years old. Two groups (bilinguals and monolinguals) were recruited across various sites in Southern Alberta. Children were assessed through parent rated executive function using the Behaviour Rating Inventory of Executive Function – Preschool version, a standardized assessment of executive function in children aged 2 years, 0 months through 5 years, 11 months. The questionnaire contains 63 items measuring 5 aspects of executive functioning, inhibit, shift, emotional control, working memory, and plan/organize. Children were also assessed using a battery of executive function tasks, which include the reverse categorization, pictorial Stroop, Dimensional Change Card Sort, backward digit span, and dyadic social play. Results show that bilingual children outperform monolinguals on the emotional control scale, dimensional change card sort and dyadic social play. Despite the controversial literature surrounding bilingualisms impact on executive function, the study reveals support for second language use to improve areas of executive function among young children.
Entanglement source and quantum memory analysis for zero-added-loss multiplexing
Authors: Shapiro Jeffrey H. , Raymer Michael G. , Embleton Clark , Wong Franco N.C. , Smith Brian J.
Published: October 2024

High-rate, high-fidelity entanglement distribution is essential to the creation of a quantum internet, but recent achievements in fiber (248 km at a 9-s−1 rate) and satellite-based (1200 km at a 1.1-s−1 rate) entanglement distribution fall far short of what is needed. Chen . [Phys. Rev. Appl. , 054209 (2023)] proposed a means for dramatically increasing entanglement-distribution rates via a scheme they called zero-added-loss multiplexing (ZALM). ZALM’s quantum transmitter employs a pair of Sagnac-configured spontaneous parametric down-converters (SPDCs), channelization via dense wavelength-division multiplexing (DWDM) filtering, and partial Bell-state measurements (BSMs) to realize a heralded source of frequency-multiplexed polarization-entangled biphotons. Each biphoton is transmitted to Alice and Bob along with a classical message identifying its frequency channel and whether a ψ− singlet or a ψ+ triplet was heralded. Alice’s and Bob’s quantum receivers then use DWDM filtering and temporal-mode conversion to interface their received biphotons to intracavity color-center quantum memories. This paper delves deeply into ZALM’s SPDCs, partial BSMs, and Duan-Kimble loading of Alice’s and Bob’s quantum memories. Its principal results—the density operators for the SPDC sources and the quantum memories—allow heralding probability, heralding efficiency, and fidelity to be evaluated for both the polarization-entangled biphotons and the loaded quantum memories, thus enabling exploration of the parameter space for optimizing ZALM’s performance. Even without a comprehensive optimization analysis, the paper’s examples already demonstrate two critical features of the ZALM architecture: (1) the necessity of achieving a near-separable channelized biphoton wave function to ensure that the biphoton sent to Alice and Bob is of high purity; and (2) the premium placed on Alice’s and Bob’s temporal-mode converters enabling narrowband push-pull memory loading to ensure that the arriving biphoton’s state is faithfully transferred to the intracavity color centers.

Published by the American Physical Society
2024
Energy landscape and flow dynamics measurements of driven-dissipative systems
Authors: Dumont Vincent , Bestler Markus , Catalini Letizia , Margiani Gabriel , Zilberberg Oded , Eichler Alexander
Published: October 2024

Many experimental techniques aim at determining the energy landscape of a system given and compare it to a model Hamiltonian. This landscape governs the system's evolution in the absence of dissipation. Here, we theoretically propose and experimentally demonstrate a method to measure the energy landscape of a system without knowing its functional form. A crucial ingredient for our method is the presence of dissipation, which enables sampling of the landscape over a large area of phase space through ringdown-type measurements, overcoming the main limitation of previous techniques. We apply the method to a driven-dissipative system–a parametric oscillator–observed in a rotating frame. We first measure the phase-space flow dynamics of the system via ringdown measurements, unveiling its attractors and separatrices. With these measurements, we reconstruct the (quasi-)energy landscape of the system. Furthermore, we demonstrate that our method provides direct experimental access to the so-called symplectic norm of the stationary states of the system, which is tied to the particle- or holelike nature of excitations of these states. In this way, we establish a method to identify qualitative differences between the fluctuations around stabilized minima and maxima of the nonlinear out-of-equilibrium stationary states. Our method constitutes a versatile approach to characterize a wide class of driven-dissipative systems.

Published by the American Physical Society
2024
Randomized SearchRank: A semiclassical approach to a quantum search engine
Authors: Ortega Sergio A. , Martin-Delgado Miguel A.
Published: October 2024

The quantum SearchRank algorithm is a promising tool for a future quantum search engine based on PageRank quantization. However, this algorithm loses its functionality when the N/M ratio between the network size N and the number of marked nodes M is sufficiently large. We propose a modification of the algorithm, replacing the underlying Szegedy quantum walk with a semiclassical walk. To maintain the same time complexity as the quantum SearchRank algorithm we propose a simplification of the algorithm. This new algorithm is called randomized SearchRank, since it corresponds to a quantum walk over a randomized mixed state. The performance of the SearchRank algorithms is first analyzed on an example network and then statistically on a set of different networks of increasing size and different number of marked nodes. On the one hand, to test the search ability of the algorithms, it is computed how the probability of measuring the marked nodes decreases with N/M for the quantum SearchRank, but remarkably it remains at a high value around 0.9 for our semiclassical algorithms, solving the quantum SearchRank problem. The time complexity of the algorithms is also analyzed, obtaining a quadratic speedup with respect to the classical ones. On the other hand, the ranking functionality of the algorithms has been investigated, obtaining a good agreement with the classical PageRank distribution. Finally, the dependence of these algorithms on the intrinsic PageRank damping parameter has been clarified. Our results suggest that this parameter should be below a threshold so that the execution time does not increase drastically.

Published by the American Physical Society
2024
J-coupling NMR spectroscopy with nitrogen vacancy centers at high fields
Authors: Alsina-Bolívar Pol , Biteri-Uribarren A. , Munuera-Javaloy C. , Casanova J.
Published: October 2024

A diamond-based sensor utilizing nitrogen-vacancy (NV) center ensembles permits the analysis of micron-sized samples through nuclear magnetic resonance (NMR) techniques at room temperature. Current efforts are directed towards extending the operating range of NV centers into high magnetic fields, driven by the potential for larger nuclear spin polarization of the target sample and the presence of enhanced chemical shifts. Especially interesting is the access to J-couplings as they carry information of chemical connectivity inside molecules. In this work, we present a protocol to access J-couplings in both homonuclear and heteronuclear cases with NV centers at high magnetic fields. Our protocol leads to a clear spectrum exclusively containing J-coupling features with high resolution. This resolution is limited primarily by the decoherence of the target sample, which is mitigated by the noise-filtering capacities of our method.

Published by the American Physical Society
2024
Anomaly inflow, dualities, and quantum simulation of Abelian lattice gauge theories induced by measurements
Authors: Okuda Takuya , Parayil Mana Aswin , Sukeno Hiroki
Published: October 2024

Previous work [] has demonstrated that quantum simulation of Abelian lattice gauge theories (Wegner models including the toric code in a limit) in general dimensions can be achieved by local adaptive measurements on symmetry-protected topological (SPT) states with higher-form generalized global symmetries. The entanglement structure of the resource SPT state reflects the geometric structure of the gauge theory. In this work we explicitly demonstrate the anomaly inflow mechanism between the deconfining phase of the simulated gauge theory on the boundary and the SPT state in the bulk by showing that the anomalous gauge variation of the boundary state obtained by bulk measurement matches that of the bulk theory. Moreover, we construct the resource state and the measurement pattern for the measurement-based quantum simulation of a lattice gauge theory with a matter field (Fradkin-Shenker model), where a simple scheme to protect gauge invariance of the simulated state against errors is proposed. We further consider taking an overlap between the wave function of the resource state for lattice gauge theories and that of a parameterized product state, and we derive precise dualities between partition functions with insertion of defects corresponding to gauging higher-form global symmetries, as well as measurement-induced phases where states induced by a partial overlap possess different (symmetry-protected) topological orders. Measurement-assisted operators to dualize quantum Hamiltonians of lattice gauge theories and their noninvertibility are also presented.

Published by the American Physical Society
2024