bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractIn 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

AbstractSmall 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

ABSTRACTLinkers 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

AbstractPrecise 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

AbstractLeveraging 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

ABSTRACTRecent 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

AbstractInsertion 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

AbstractVisual 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.
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

AbstractObjectiveExamine the effects of an acute bout of physical exercise on cognitive function in adults with cognitive impairment (CI).DesignSystematic 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 sourcesSix databases from inception to July 2024: (1) PubMed, (2) SportDiscus, (3) PsychINFO, (4) Cochrane Central, (5) PEDro, (6) Embase.Eligibility criteriaRCT’s of acute exercise with male/female participants, aged 18+, and physician diagnosed or self-reported CI.Results15 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.ConclusionIn 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 boxChronic 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

AbstractIntroductionParvovirus 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.MethodsLongitudinal 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.ResultsOf 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.DiscussionAnalysis 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

AbstractObjectiveAccurate 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.MethodsWe 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.ResultsDeformation-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.InterpretationThis 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

ABSTRACTIntroductionDespite 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.MethodsWe 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.ResultsA 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.ConclusionVaccinating 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

AbstractThis 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.