bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control
Authors: Detrés Román Carlos R. , Rudloff Michael W. , Revetta Frank , Favret Natalie R. , Murray Kristen A. , Roetman Jessica J. , Erwin Megan M. , Washington Mary K. , Philip Mary 
Published: February 2024

ABSTRACTBackgroundImmune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however only a subset of patients with certain types of cancer achieves durable remissions. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term tumor immune reprogramming and arrest cancer progression. We developed a clinically-relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumor-specific CD8 T cells (TST) differentiate in mice with early sporadic lesions as compared to late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, reprogram TST and impact liver cancer progression.MethodsMice with a germline floxed allele of the SV40 large T antigen (TAG) undergo spontaneous recombination and activation of the TAG oncogene, leading to rare early pre-cancerous lesions that inevitably progress to established liver cancer. We assessed the immunophenotype and function of TAG-specific CD8 T cells in mice with early and late liver lesions. We vaccinated mice, either alone or in combination with ICB, to test whether these immunotherapeutic interventions could stop liver cancer progression.ResultsIn mice with early lesions, a subset of TST were PD1+TCF1+TOX-and could produce IFNγ, while TST present in mice with late liver cancers were PD1+TCF1lo/-TOX+and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitope-expressingListeria monocytogenes(LMTAG) blocked liver cancer development and led to a population of TST that were TCF1+TOX-TST and polyfunctional cytokine producers. In contrast, ICB administration did not slow cancer progression or improve LMTAGvaccine efficacy.ConclusionVaccination, but not ICB, generated a population of progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. In patients with early cancers or at high-risk of cancer recurrence, immunization may be the most effective strategy.What is already known on this topicImmunotherapy, including immune checkpoint blockade and cancer vaccines, fails to induce long-term remissions in most patients with cancer.What this study addsHosts with early lesions but not hosts with advanced cancer retain a progenitor TCF1+ TST population. This population can be reprogrammed and therapeutically exploited by vaccination, but not ICB, to block tumor progression.How this study might affect research, practice, or policyFor people at high-risk of cancer progression, vaccination administered when a responsive progenitor TST population is present may be the optimal immunotherapy to induce long-lasting progression-free survival.
Detecting Somatic Mutations Without Matched Normal Samples Using Long Reads
Authors: Simpson Jared T. 
Published: February 2024

AbstractDNA sequencing of tumours to identify somatic mutations has become a critical tool to guide the type of treatment given to cancer patients. The gold standard for mutation calling is comparing sequencing data from the tumour to a matched normal sample to avoid mis-classifying inherited SNPs as mutations. This procedure works extremely well, but in certain situations only a tumour sample is available. While approaches have been developed to find mutations without a matched normal, they have limited accuracy or require specific types of input data (e.g. ultra-deep sequencing). Here we explore the application of single molecule long read sequencing to calling somatic mutations without matched normal samples. We develop a simple theoretical framework to show how haplotype phasing is an important source of information for determining whether a variant is a somatic mutation. We then use simulations to assess the range of experimental parameters (tumour purity, sequencing depth) where this approach is effective. These ideas are developed into a prototype somatic mutation caller, smrest, and its use is demonstrated on two highly mutated cancer cell lines. Finally, we argue that this approach has potential to measure clinically important biomarkers that are based on the genome-wide distribution of mutations: tumour mutation burden and mutation signatures.
Trajectorygeometry suggests cell fate decisions involve branches rather than bifurcations
Authors: Laddach Anna , Shapiro Michael 
Published: February 2024

AbstractDifferentiation of multipotential progenitor cells is a key process in the development of any multi-cellular organism and often continues throughout its life. It is often assumed that a bi-potential progenitor develops along a (relatively) straight trajectory until it reaches a decision point where the trajectory bifurcates. At this point one of two directions is chosen, each direction representing the unfolding of a new transcriptomic programme. However, we have lacked quantitative means for testing this model. Accordingly, we have developed the R package TrajectoryGeometry. Applying this to published data we find several examples where, rather than bifurcate, developmental pathwaysbranch. That is, the bipotential progenitor develops along a relatively straight trajectory leading to one of its potential fates. A second relatively straight trajectory branches off from this towards the other potential fate. In this sense only cells that branch off to follow the second trajectory make a “decision”. Our methods give precise descriptions of the genes and cellular pathways involved in these trajectories. We speculate that branching may be the more common behaviour and may have advantages from a control-theoretic viewpoint.
Secondary structure of the SARS-CoV-2 genome is predictive of nucleotide substitution frequency
Authors: Hensel Zach 
Published: February 2024

AbstractAccurate estimation of the effects of mutations on SARS-CoV-2 viral fitness can inform public-health responses such as vaccine development and predicting the impact of a new variant; it can also illuminate biological mechanisms including those underlying the emergence of variants of concern (Carabelliet al., 2023). Recently, Lanet al. reported a model of SARS-CoV-2 secondary structure and its underlying dimethyl sulfate (DMS) reactivity data (Lanet al., 2022). I investigated whether base reactivities and secondary structure models derived from them can explain some variability in the frequency of observing different nucleotide substitutions across millions of patient sequences in the SARS-CoV-2 phylogenetic tree. Nucleotide basepairing was compared to the estimated “mutational fitness” of substitutions, a measurement of the difference between a substitution’s observed and expected frequency that is correlated with other estimates of viral fitness (Bloom and Neher, 2023). This comparison revealed that secondary structure is often predictive of substitution frequency, with significant decreases in substitution frequencies at basepaired positions. Focusing on the mutational fitness of C→U, the most common type of substitution, I describe C→U substitutions at basepaired positions that characterize major SARS-CoV-2 variants; such mutations may have a greater impact on fitness than appreciated when considering substitution frequency alone.
The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19
Authors: Penrice-Randal Rebekah , Bentley Eleanor G. , Sharma Parul , Kirby Adam , Donovan-Banfield I’ah , Kipar Anja , Mega Daniele F. , Bramwell Chloe , Sharp Joanne , Owen Andrew , Hiscox Julian A. , Stewart James P. 
Published: February 2024

SynopsisObjectivesImmunocompromised individuals are susceptible to severe COVID-19 and potentially contribute to the emergence of variants with altered pathogenicity due to persistent infection. This study investigated the impact of immunosuppression on SARS-CoV-2 infection in k18-hACE2 mice and the effectiveness of antiviral treatments in this context during the first 7 days of infection.MethodsMice were immunosuppressed using cyclophosphamide and infected with a B daughter lineage of SARS-CoV-2. Molnupiravir and nirmatrelvir, alone and in combination, were administered and viral load and viral sequence diversity was assessed.ResultsTreatment of infected but immune compromised mice with both compounds either singly or in combination resulted in decreased viral loads and pathological changes compared to untreated animals. Treatment also abrogated infection of neuronal tissue. However, no consistent changes in the viral consensus sequence were observed, except for the emergence of the S:H655Y mutation. Molnupiravir, but not nirmatrelvir or immunosuppression alone, increased the transition/transversion (Ts/Tv) ratio, representative of G>A and C>U mutations and this increase was not altered by the co-administration of nirmatrelvir with molnupiravir.Notably, immunosuppression itself did not appear to promote the emergence of mutational characteristic of variants of concern (VOCs).ConclusionsFurther investigations are warranted to fully understand the role of immunocompromised individuals in VOC development, especially by taking persistence into consideration, and to inform optimised public health strategies. It is more likely that immunodeficiency promotes viral persistence but does not necessarily lead to substantial consensus-level changes in the absence of antiviral selection pressure. Consistent with mechanisms of action, molnupiravir showed a stronger mutagenic effect than nirmatrelvir in this model.
Pre-challenge gut microbial signature predicts RhCMV/SIV vaccine efficacy in rhesus macaques
Authors: Brochu Hayden N. , Smith Elise , Jeong Sangmi , Carlson Michelle , Hansen Scott G. , Tisoncik-Go Jennifer , Law Lynn , Picker Louis J. , Gale Michael , Peng Xinxia 
Published: February 2024

ABSTRACTBackgroundRhCMV/SIV vaccines protect ∼59% of vaccinated rhesus macaques against repeated limiting-dose intra-rectal exposure with highly pathogenic SIVmac239M, but the exact mechanism responsible for the vaccine efficacy is not known. It is becoming evident that complex interactions exist between gut microbiota and the host immune system. Here we aimed to investigate if the rhesus gut microbiome impacts RhCMV/SIV vaccine-induced protection.MethodsThree groups of 15 rhesus macaques naturally pre-exposed to RhCMV were vaccinated with RhCMV/SIV vaccines. Rectal swabs were collected longitudinally both before SIV challenge (after vaccination) and post challenge and were profiled using 16S rRNA based microbiome analysis.ResultsWe identified ∼2,400 16S rRNA amplicon sequence variants (ASVs), representing potential bacterial species/strains. Global gut microbial profiles were strongly associated with each of the three vaccination groups, and all animals tended to maintain consistent profiles throughout the pre-challenge phase. Despite vaccination group differences, using newly developed compositional data analysis techniques we identified a common gut microbial signature predictive of vaccine protection outcome across the three vaccination groups. Part of this microbial signature persisted even after SIV challenge. We also observed a strong correlation between this microbial signature and an early signature derived from whole blood transcriptomes in the same animals.ConclusionsOur findings indicate that changes in gut microbiomes are associated with RhCMV/SIV vaccine-induced protection and early host response to vaccination in rhesus macaques.
Blood metabolomic profiling reveals new targets in the management of psychological symptoms associated with severe alcohol use disorder
Authors: Leclercq Sophie , Ahmed Hany , Amadieu Camille , Petit Géraldine , Koistinen Ville , Leyrolle Quentin , Poncin Marie , Stärkel Peter , Kok Eloise , Karhunen Pekka J. , De Timary Philippe , Layé Sophie , Neyrinck Audrey M. , Kärkkäinen Olli , Hanhineva Kati , Delzenne Nathalie M. 
Published: February 2024

ABSTRACTAlcohol use disorder (AUD) is a global health problem with limited therapeutic options. The biochemical mechanisms that lead to this disorder are not yet fully understood, and in this respect, metabolomics represents a promising approach to decipher metabolic events related to AUD. The plasma metabolome contains a plethora of bioactive molecules that reflects the functional changes in host metabolism but also the impact of the gut microbiome and nutritional habits. In this study, we investigated the impact of severe AUD (sAUD), and of a three-week period of alcohol abstinence, on the blood metabolome (non-targeted LC-MS metabolomics analysis) in 96 sAUD patients hospitalized for alcohol withdrawal. We found that the plasma levels of different lipids ((lyso)phosphatidylcholines, long-chain fatty acids), short-chain fatty acids (i.e. 3-hydroxyvaleric acid) and bile acids were altered in sAUD patients. In addition, several microbial metabolites, including indole-3-propionic acid, p-cresol sulfate, hippuric acid, pyrocatechol sulfate, and metabolites belonging to xanthine class (paraxanthine, theobromine and theophylline) were sensitive to alcohol exposure and alcohol withdrawal. 3-Hydroxyvaleric acid, caffeine metabolites (theobromine, paraxanthine and theophylline) and microbial metabolites (hippuric acid and pyrocatechol sulfate) were correlated with anxiety, depression and alcohol craving. Metabolomics analysis in post-mortem samples of frontal cortex and cerebrospinal fluid of those consuming a high level of alcohol revealed that those metabolites can be found also in brain tissue. Our data allow to for the identification of neuroactive metabolites, from interactions between food components and microbiota, which may represent new targets in the management of neuropsychiatric diseases such as sAUD.
Virological traits of the SARS-CoV-2 BA.2.87.1 lineage
Authors: Zhang Lu , Dopfer-Jablonka Alexandra , Nehlmeier Inga , Kempf Amy , Graichen Luise , Hampel Noemí Calderón , Cossmann Anne , Stankov Metodi V. , Ramos Gema Morillas , Schulz Sebastian R. , Jäck Hans-Martin , Behrens Georg M. N. , Pöhlmann Stefan , Hoffmann Markus 
Published: February 2024

AbstractThe highly mutated SARS-CoV-2 BA.2.87.1 lineage was recently detected in South Africa, but its transmissibility is unknown. Here, we report that BA.2.87.1 efficiently enters human cells but is more sensitive to antibody-mediated neutralization than the currently dominating JN.1 variant. Acquisition of adaptive mutations might thus be needed for high transmissibility.
Influence of feedback transparency on motor imagery neurofeedback performance: the contribution of agency
Authors: Dussard Claire , Pillette Léa , Dumas Cassandra , Pierrieau Emeline , Hugueville Laurent , Lau Brian , Jeunet-Kelway Camille , George Nathalie 
Published: February 2024

AbstractObjectiveNeurofeedback (NF) is a cognitive training procedure based on real-time feedback (FB) of a participant’s brain activity that they must learn to self-regulate. A classical visual FB delivered in a NF task is a filling gauge reflecting a measure of brain activity. This abstract visual FB is not transparently linked—from the subject’s perspective—to the task performed (e.g., motor imagery). This may decrease the sense of agency, that is, the participants’ reported control over FB. Here, we assessed the influence of FB transparency on NF performance and the role of agency in this relationship.ApproachParticipants performed a NF task using motor imagery to regulate brain activity measured using electroencephalography. In separate blocks, participants experienced three different conditions designed to vary transparency: FB was presented as either 1) a swinging pendulum, 2) a clenching virtual hand, 3) a clenching virtual hand combined with a motor illusion induced by tendon vibration. We measured self-reported agency and user experience after each NF block.Main resultsWe found that FB transparency influences NF performance. Transparent visual FB provided by the virtual hand resulted in significantly better NF performance than the abstract FB of the pendulum. Surprisingly, adding a motor illusion to the virtual hand significantly decreased performance relative to the virtual hand alone. When introduced in incremental linear mixed effect models, self-reported agency was significantly associated with NF performance and it captured the variance related to the effect of FB transparency on NF performance.SignificanceOur results highlight the relevance of transparent FB in relation to the sense of agency. This is likely an important consideration in designing FB to improve NF performance and learning outcomes.
Syngap1regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex
Authors: Francavilla Ruggiero , Chattopadhyaya Bidisha , Kamda Jorelle Linda Damo , Jadhav Vidya , Kourrich Saïd , Michaud Jacques L. , Di Cristo Graziella 
Published: February 2024

AbstractSYNGAP1 haploinsufficiency-related intellectual disability (SYNGAP1-ID) is characterized by moderate to severe ID, generalized epilepsy, autism spectrum disorder, sensory processing dysfunction and other behavioral abnormalities. While numerous studies have highlighted a role of Syngap1 in cortical excitatory neurons development; recent studies suggest that Syngap1 plays a role in GABAergic inhibitory neuron development as well. However, the molecular pathways by which Syngap1 acts on GABAergic neurons, and whether they are similar or different from the mechanisms underlying its effects in excitatory neurons, is unknown. Here, we examined whether, and how, embryonic-onsetSyngap1haploinsufficiency restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE) impacts their synaptic and intrinsic properties in adult primary auditory cortex (A1). We found thatSyngap1haploinsufficiency affects the intrinsic properties, overall leading to increased firing threshold, and decreased excitatory synaptic drive of Parvalbumin (PV)+ neurons in adult Layer IV A1, whilst Somatostatin (SST)+ interneurons were mostly resistant toSyngap1haploinsufficiency. Further, the AMPA component of thalamocortical evoked-EPSC was decreased in PV+ cells from mutant mice. Finally, we found that the selective blocking of voltage-gated D-type K+ currents was sufficient to rescue PV+ mutant cell-intrinsic properties to wild-type levels. Together, these data suggest thatSyngap1plays a specific role in the maturation of PV+ cell intrinsic properties and synaptic drive, and its haploinsufficiency may lead to reduced PV cell recruitment in the adult A1, which could in turn contribute to the auditory processing alterations found in SYNGAP1-ID preclinical models and patients.
How distinct sources of nuisance variability in natural images and scenes limit human stereopsis
Authors: White David N. , Burge Johannes 
Published: February 2024

2AbstractStimulus variability—a form of nuisance variability—is a primary source of perceptual uncertainty in every-day natural tasks. How do different properties of natural images and scenes contribute to this uncertainty? Using binocular disparity as a model system, we report a systematic investigation of how various forms of natural stimulus variability impact performance in a stereo-depth discrimination task. With stimuli sampled from a stereo-image database of real-world scenes having pixel-by-pixel ground-truth distance data, three human observers completed two closely related double-pass psychophysical experiments. In the two experiments, each human observer responded twice to ten thousand unique trials, in which twenty thousand unique stimuli were presented. New analytical methods reveal, from this data, the specific and nearly dissociable effects of two distinct sources of natural stimulus variability—variation in luminance-contrast patterns and variation in local-depth structure—on discrimination performance, as well as the relative importance of stimulus-driven-variability and internal-noise in determining performance limits. Between-observer analyses show that both stimulus-driven sources of uncertainty are responsible for a large proportion of total variance, have strikingly similar effects on different people, and—surprisingly—make stimulus-by-stimulus responses more predictable (not less). The consistency across observers raises the intriguing prospect that image-computable models can make reasonably accurate performance predictions in natural viewing. Overall, the findings provide a rich picture of stimulus factors that contribute to human perceptual performance in natural scenes. The approach should have broad application to other animal models and other sensory-perceptual tasks with natural or naturalistic stimuli.1SignificanceLinking properties of the external world, and of sensory stimuli, to how neurons and animals respond has proven an important approach to understanding how the brain works. Much is known about how nervous systems respond to simple stimuli. Less is known about how systems respond during real-world viewing. Using data from two human stereo-depth discrimination experiments, we develop a new approach that reveals how distinct features of natural scenes and images contribute to perceptual performance. Results show that stimulus-by-stimulus variation has highly consistent effects on different people. The approach should have broad application to other animal models and other sensory-perceptual tasks.
Unraveling the Interplay between Phytochemicals and Rhizosphere Bacteria inFicus racemosa
Authors: Balkrishna Acharya , Kaushik Priya , Ghosh Sourav , Arya Vedpriya 
Published: February 2024

AbstractPlant-microbe interactions in the rhizosphere play crucial roles in plant health and ecosystem functioning. Despite extensive research, gaps persist in understanding the relationship between phytochemicals and rhizosphere bacteria, particularly in species likeFicus racemosa. This study aims to investigate this interplay by characterizing the diversity and abundance of rhizosphere bacteria inFicus racemosaand assessing the influence of phytochemical composition on microbial community structure and function. Through a multidisciplinary approach integrating microbiology and phytochemistry, our findings contribute to a holistic understanding of rhizosphere ecology and inform strategies for optimizing plant-microbe interactions in agricultural and environmental contexts.
A Systematic Review on Malaria and Tuberculosis (TB) Vaccine Challenges in Sub-Saharan African Clinical Trials
Authors: Hamisi Maonezi Abas , Mohd Asri Nur Ain , Mat Yassim Aini Syahida , Suppian Rapeah 
Published: February 2024

Abstract Objective: For decades, developing novel and effective vaccines against malaria and tuberculosis (TB) infections has been a challenge. This review sought to investigate the reasons for the slow progress of malaria and TB vaccine candidates in sub-Saharan African clinical trials. Methods: The systematic review protocol was registered on PROSPERO on July 26, 2023 (CRD42023445166). The research articles related to the immunogenicity, efficacy, or safety of malaria or TB vaccines that were published between January 1, 2012, and August 31, 2023, were searched on three databases: Web of Science (WoS), PubMed, and ClinicalTrials.gov. Results: A total of 2342 articles were obtained, 50 of which met the inclusion criteria. 28 (56%) articles reported on malaria vaccine attributes, while 22 (44%) articles reported on TB vaccines. In both cases, the major challenges in sub-Saharan African clinical trials were immunogenicity and efficacy, rather than safety. Conclusion: Factors such as population characteristics, pathogen genetic diversity, vaccine nature, strategy, and formulation were associated with slow progress of the malaria and TB vaccine candidates in sub-Saharan African clinical trials.