bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological Variables Mediate Symptoms in Persistent Postural-Perceptual Dizziness (PPPD): A Cross-Sectional Self-Report Study
Authors: Sereda Ariel , Lam Ju Cheng , Hazar Ali-Mert , Ellmers Toby , Golding John , Kaski Diego
Published: October 2024

Background

Persistent Postural-Perceptual Dizziness (PPPD) is a prevalent long-term functional neurological disorder characterised by non-spinning vertigo, perceived instability, and visual motion sensitivity. Current diagnostic criteria inadequately incorporate psychological variables widely associated with PPPD symptom onset and maintenance.

Objectives

This study explored PPPD-specific psychological variables to differentiate PPPD patients from healthy controls and, exploratorily, from Bilateral Vestibulopathy (BVP) patients. We evaluated these variables as potential treatment targets through mediation analysis. Our aim was to inform more precise diagnostic criteria and guide targeted interventions for PPPD.

Methods

We conducted a cross-sectional study with 164 participants, including 59 diagnosed cases of PPPD, 16 cases of BVP, and 89 healthy controls. Participants completed a series of questionnaires assessing negative illness perception, balance vigilance, anxiety, visual sensitivity, dizziness and other related metrics.

Results

Psychological variables, particularly anxiety, cognitive fusion, and justice appraisal significantly mediated the relationship between key PPPD symptoms (dizziness, visual sensitivity, and balance vigilance) and PPPD diagnosis compared to healthy controls. Logistic regression suggested psychological differences between PPPD and BVP, but limited BVP sample size constrained generalisability. Between PPPD and healthy controls, psychological variables significantly improved classification accuracy compared to measures of dizziness alone.

Conclusion

Incorporating psychological variables in the diagnosis and management of PPPD could enhance the understanding of the disorder and may aid in developing better-targeted interventions. The study supports revising existing diagnostic criteria to include validated psychological assessments and highlights the potential of treatments addressing cognitive and emotional aspects of PPPD to improve patient outcomes.
Neural and behavioral reinstatement jointly reflect retrieval of narrative events
Authors: Nau Matthias , Greene Austin , Tarder-Stoll Hannah , Lossio-Ventura Juan Antonio , Pereira Francisco , Chen Janice , Baldassano Christopher , Baker Chris I.
Published: October 2024

When recalling past events, patterns of gaze position and neural activity resemble those observed during the original experience. We hypothesized that these two phenomena, known as gaze reinstatement and neural reactivation, are linked through a common process that underlies the reinstatement of past experiences during memory retrieval. Here, we tested this proposal based on the viewing and recall of a narrative movie, which we assessed through fMRI, deep learningbased gaze prediction, and language modeling of spoken recall. In line with key predictions, gaze behavior adhered to the same principles as neural activity; it was event-specific, robust across individuals, and generalized across viewing and recall. Additionally, gaze-dependent brain activity overlapped substantially across tasks. Collectively, these results suggest that retrieval engages mechanisms that direct our eyes during natural vision, reflecting common constraints within the functional organization of the nervous system. Moreover, they highlight the importance of considering behavioral and neural reinstatement together in our understanding of remembering.
Specialized cells and transporters mediate integument-absorption of environmental peptides in cichlids larvae
Authors: Con Pazit , Cnaani Avner
Published: October 2024

Nutrient absorption through the skin and gills into the organisms’ tissues has been documented in several aquatic invertebrates from different phyla. However, the actual absorption mechanism is still unknown. In teleost fish, as in all jawed vertebrates, intestinal absorption is considered as the sole source of nutrients. The proton-dependent peptide transporters (PepT) of theslc15agene family are the only known mechanism for cellular absorption of di- and tri-peptides within the animal kingdom. In this study, we explored the expression and localization of PepT2 in Mozambique tilapia (Oreochromis mossambicus) larvae. Transcript levels of PepT2 in dissected yolk-sacs from larvae showed significant expression during the larval developmental period. Immunofluorescence staining of PepT2 with Na/K-ATPase (NKA) and Na+/K+/2Cl-co-transporter (NKCC) on the yolk-sac membrane revealed co-staining with NKA and differential-staining with NKCC. While NKA staining was observed on the ionocytes’ basolateral membrane, PepT2 staining was restricted to the apical pit of the ionocytes, facing the surrounding water. In this study, we identified a nutrient transporter located on integument-specific cells, facing the outside aquatic environment. This is the first indication of environmental nutrients absorption in teleosts, and the first evidence of a possible absorption mechanism through PepT2, in specialized yolk-sac ionocytes.
Glutamine Transport via Neurotransmitter Transporter 4 (NTT4, SLC6A17) Maintains Presynaptic Glutamate Supply at Excitatory Synapses in the Central Nervous System
Authors: Nicoli Angela L. , Al Abed A. Shaam , Hulme Sarah R. , Das Abhijit , Gauthier-Coles Gregory , Bröer Angelika , Balkrishna Sarojini , Burgio Gaetan , Dehorter Nathalie , Rae Caroline D. , Bröer Stefan , Billups Brian
Published: October 2024

The glutamate-glutamine cycle is thought to be the principle metabolic pathway that recycles glutamate at excitatory synapses. In this cycle, synaptically released glutamate is sequestered by astrocytes and converted to glutamine before being returned to the presynaptic terminal for conversion back into glutamate to replenish the neurotransmitter pool. While many aspects of this cycle have been extensively studied, a key component remains unknown: the nature of the transporter responsible for the presynaptic uptake of glutamine. We hypothesise that neurotransmitter transporter 4 (NTT4/SLC6A17) plays this role. Accordingly, we generated NTT4 knockout mice to assess its contribution to presynaptic glutamine transport and synaptic glutamate supply. Using biochemical tracing of [1-13C] glucose and [1,2-13C] acetate in awake mice, we observe a reduction of neuronal glutamate supply when NTT4 is absent. In addition, direct electrical recording of hippocampal mossy fibre boutons reveals a presynaptic glutamine transport current that is entirely inhibited by genetic or pharmacological elimination of NTT4. The role of NTT4 in neurotransmission was demonstrated by electrophysiological recordings in acute hippocampal slices, which reveal that NTT4 is required to maintain vesicular glutamate content and to sustain adequate levels of glutamate supply during periods of high-frequency neuronal activity. Finally, behavioural studies in mice demonstrate a deficit in trace fear conditioning; a hippocampus-dependent memory paradigm, and abnormalities in nest building, anxiety behaviour, and social preference. These results demonstrate that NTT4 is a presynaptic glutamine transporter which is a central component of the glutamate-glutamine cycle. NTT4 and hence the glutamate-glutamine cycle maintain neuronal glutamate supply for excitatory neurotransmission during high-frequency synaptic activity, and are key regulators of memory retention and normal behaviour.
Autonomous biogenesis of the entire protein translation machinery excluding ribosomes
Authors: Schwarz-Schilling Matthaeus , Dupin Aurore , Avidan Noa , Barak Yoav , Shimizu Yoshihiro , Daube Shirley S. , Bar-Ziv Roy H.
Published: October 2024

Recreating the conditions for autonomous biogenesis of the protein translation machinery is fundamental to our understanding of living systems and is essential for the assembly of minimal cell models. All components of the translation machinery, including the ribosomes, translation factors and aminoacyl tRNA synthetases, are made of proteins and are therefore involved in their own synthesis, posing a unique challenge for self-biogenesis. Here, we created physicochemical conditions for autonomous biogenesis of all the translation machinery, excluding the ribosome. We surface-immobilized synthetic genes coding for all thirty components as densely packed DNA brushes forming a reaction center that localizes, concentrates and catalyzes their simultaneous synthesis. To demonstrate their activity, we first determined empirically the minimal critical concentration of each translation protein required to initiate its own self-biogenesis in bulk solution. We then assembled a minimal gene expression reaction with all translation proteins at their critical concentrations. Under these dilute conditions, reporter proteins were not synthesized unless the DNA brushes encoded all the translation proteins, thereby demonstrating their co-synthesis, functionality and engagement in their own synthesis. This scenario of a complex biochemical process that amplifies itself can be generalized and extended to impact our understanding toward the design of autonomous self-replicating biological system.
Ten-Fold Expansion MALDI Mass Spectrometry Imaging of Tissues and Cells at 500 nm Resolution
Authors: Xie Chengyi , Wang Jianing , Diao Xin , Guo Lei , Lam Thomas Ka-Yam , Li Ruxin , Chen Yanyan , Zhang Yue , Wang Xiaoxiao , Fang Jiacheng , Cai Zongwei
Published: October 2024

Achieving high spatial resolution in matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is crucial for detailed molecular mapping in biological tissues and cells. However, conventional MALDI-MSI platforms are typically limited to spatial resolutions of 5-20 μm, restricting their ability to visualize fine subcellular structures. Here, we present a novel ten-fold expansion MALDI-MSI (10X ExMSI) method that attains 500 nm spatial resolution without the need for specialized optics or customized instrumentation. By physically expanding biological samples using a swellable hydrogel matrix, our method maintains high retention and broadens the detection range of lipids, ensuring comprehensive lipid profiling. We demonstrated the effectiveness of 10X ExMSI by visualizing intricate subcellular structures within mouse brain tissues, including individual nuclei, astrocytes, Purkinje cells, and, notably, dendritic arborizations-features previously unresolvable using mass spectrometry imaging. Applying 10X ExMSI to single-cell analysis of cultured cells revealed detailed spatial distributions of lipids at the subcellular to organelle level. Notably, the method is fully compatible with standard commercial MALDI-MSI platforms, enabling widespread adoption without significant additional investment. The 10X ExMSI offers a transformative tool for high-resolution molecular imaging, opening new avenues for molecular analysis in diverse biological and biomedical fields, including neuroscience, pathology, and cellular biology.
An attention-based deep neural network model to detect cis-regulatory elements at the single-cell level from multi-omics data
Authors: Murakami Ken , Iida Keita , Okada Mariko
Published: October 2024

Cis-regulatory elements (cREs) play a crucial role in regulating gene expression and determining cell differentiation and state transitions. To capture the heterogeneous transitions of cell states associated with these processes, detecting cRE activity at the single-cell level is essential. However, current analytical methods can only capture the average behavior of cREs in cell populations, thereby obscuring cell-specific variations. To address this limitation, we proposed an attention-based deep neural network framework that integrates DNA sequences, genomic distances, and single-cell multi-omics data to detect cREs and their activities in individual cells. Our model shows higher accuracy in identifying cREs within single-cell multi- omics data from healthy human peripheral blood mononuclear cells than other existing methods. Furthermore, it clusters cells more precisely based on predicted cRE activities, enabling a finer differentiation of cell states. When applied to publicly available single-cell data from patients with glioma, the model successfully identified tumor-specific SOX2 activity. Additionally, it revealed the heterogeneous activation of the ZEB1 transcription factor, a regulator of epithelial-to-mesenchymal transition-related genes, which conventional methods struggle to detect. Overall, our model is a powerful tool for detecting cRE regulation at the single-cell level, which may contribute to revealing drug resistance mechanims in cell sub- populations.
Dorsal-caudal and ventral hippocampus target different cell populations in the medial frontal cortex in rodents
Authors: Alemán-Andrade Paola , Witter Menno P. , Tsutsui Ken-Ichiro , Ohara Shinya
Published: October 2024

Direct projections from the ventral hippocampus (vHPC) to the medial frontal cortex (MFC) play crucial roles in memory and emotional regulation. Using anterograde transsynaptic tracing andin vitroelectrophysiology in mice, we document a previously unexplored pathway that parallels the established vHPC-MFC connectivity. This pathway connects the dorsal-caudal hippocampus (dcHPC) to specific subregions of the ventral MFC, in particular the dorsal peduncular cortex. Notably, this pathway exerts a strong inhibitory influence on ventral MFC by targeting a substantial proportion of inhibitory neurons. Retrograde transsynaptic tracing in rats indicated that ventral MFC subregions project disynaptically back to vHPC. These results, altogether, suggest the existence of a remarkable functional circuit connecting distinct functional areas: the cognition-related dcHPC with the emotion-related ventral MFC and vHPC. These findings further provide valuable insights in the cognitive and emotional abnormalities associated with the HPC-MFC connectivity in neurological and psychiatric disorders.
Wartime food availability in the Gaza Strip, October 2023 to August 2024: a retrospective analysis
Authors: Checchi Francesco , Ververs Mija-Tesse , Jamaluddine Zeina
Published: October 2024

Background

The Israeli operation in the Gaza Strip has damaged much of the territory’s food system, exposing vulnerable population groups to poor nutrition. We retrospectively estimated food availability per capita and the contribution of different food sources and categories during the first ten months of the war.

Methods

We described the composition and caloric value of food trucked into Gaza based on United Nations data over the period 7 October 2023 to 31 August 2024 and compared these with the Israeli government’s. We supplemented trucking data with information on baseline stocks, agricultural output, air or seaborne deliveries, population denominators and pre-war caloric intake estimates into a probabilistic simulation to estimate caloric availability in both northern and south-central governorates.

Results

Between October 2023 and April 2024, food trucks entering Gaza remained below pre-war levels. Israeli data offered higher estimates of food weight trucked in but appeared to feature extreme approximation. Following Israel’s takeover of crossings in May 2024, United Nations data likely featured underreporting, though even Israeli data indicated declining deliveries. The share of food categories changed little during the period analysed, but trucked-in food’s caloric value was lowest just as food was scarcest (February-March 2024). Trucks accounted for three-fourths of food in south-central Gaza, but <20% in the north; air and sea deliveries made up a small percentage. During at least 12 weeks in northern and 4 weeks in south-central Gaza, per-capita caloric availability was below the recommended intake.

Conclusions

Israel, as occupying power, did not ensure sufficient food availability throughout the analysis period, and its data appear unreliable. Existing stocks probably mitigated caloric deficits resulting from insufficient deliveries, but air and sea routes added little. Strengthened coordination of food deliveries may be warranted to optimise caloric quantity and dietary diversity despite aid restrictions.
Cost-effectiveness analysis of 21-valent pneumococcal conjugated vaccine among adults in Canada
Authors: Ximenes Raphael , Simmons Alison E. , Gebretekle Gebremedhin B. , Nam Austin , Wong Eva , Salvadori Marina I. , Golden Alyssa R. , Sander Beate , Hildebrand Kyla J. , Tunis Matthew , Tuite Ashleigh R.
Published: October 2024

Background

A 21-valent pneumococcal conjugate vaccine (PCV21) was recently authorized in Canada to protect adults against invasive pneumococcal disease (IPD).

Objective

To assess the cost-effectiveness of PCV21 compared to current Canadian vaccination recommendations for adults of different age and risk groups.

Methods

We used a static cohort model to estimate lifetime incremental cost-effectiveness ratios (ICERs), in 2023 Canadian dollars per quality-adjusted life year (QALY), discounted at 1.5%, in population cohorts aged 33 (midpoint of the 18-49 year age group), 50, and 65 years from the health system and societal perspectives. The primary analysis used 2022 serotype distributions for IPD cases. Additional analyses incorporated indirect effects from pediatric vaccination and used IPD serotype distributions from 2015-2019, to explore the impact of changes over time observed in some age groups.

Results

For population groups currently recommended to receive PCV20 in Canada (65 years and older, 50-64 years with additional risk factors for IPD, or 18-49 years with immunocompromising conditions), PCV21 was cost-effective at a $50,000 per QALY threshold and dominated PCV20 in most scenarios when PCV21 serotypes were more prevalent. When PCV20 serotypes were equally or more prevalent than PCV21 serotypes, results were more sensitive to assumptions about indirect effects and serotype replacement. For groups not currently recommended a conjugate vaccine (50-64 years without additional IPD risk factors and 18-49 years with chronic medical conditions or unhoused populations), use of a higher-valency conjugate vaccine was a cost-effective intervention compared to no vaccination, with the optimal vaccine dependent on the proportion of IPD attributable to PCV20 and PCV21 serotypes in the population of interest. Results were sensitive to vaccine price in most scenarios.

Interpretation

The use of PCV21 may be cost-effective in some populations, depending on the prevalence of IPD serotypes covered by PCV20 and PCV21.
On-scalp magnetoencephalography based on optically pumped magnetometers to investigate temporal lobe epilepsy
Authors: Feys Odile , Wens Vincent , Depondt Chantal , Rikir Estelle , Gaspard Nicolas , Paesschen Wim Van , Aeby Alec , Bodart Olivier , Carrette Evelien , Holmes Niall , Brookes Matthew , Ferez Maxime , Corvilain Pierre , Tiège Xavier De
Published: October 2024

Cryogenic magnetoencephalography (MEG) has a lower yield in temporal lobe epilepsy (TLE) than in extra-TLE (ETLE). The advent of optically pumped magnetometers (OPMs) might change this thanks to on-scalp MEG, which allows sensors to be placed closer to the brain and the design of bespoke sensor arrays to target specific brain regions. This study aims to investigate the detection and localization accuracy of interictal epileptiform discharges (IEDs) using on-scalp MEG in TLE and the added-value of face-OPMs for temporal IED detection/localization.

Eleven patients underwent a 1-h MEG recording with OPMs placed both on the scalp (flexible cap, scalp-OPMs) and on the face (3D-printed glass-like structure, face-OPMs). Nine patients also underwent cryogenic MEG. IEDs were visually detected, averaged and localized using distributed source reconstruction. On-scalp MEG IED amplitude and signal-to-noise (SNR) were assessed and compared with cryogenic MEG when more than 10 IEDs were detected. Neural sources with and without face-OPMs were compared. The correlation between face- and scalp-OPMs was assessed.

A mean of 13 IEDs/patient was detected using on-scalp MEG (mean amplitude: 3.3pT, mean SNR: 9.4) and localized in the (medial, anterior, basal, lateral or posterior) temporal lobe. Three patients had >10 IEDs in on-scalp and cryogenic MEG signals with amplitude and SNR that were either higher or similar for the on-scalp MEG recording compared with cryogenic MEG, and sources were separated by 8-11 mm. In two other patients, on-scalp MEG source locations were confirmed by gold-standard methods (surgical resection cavity, n=1; stereo-electroencephalography, n=1). Face-OPMs had a clear added-value (i.e., IED detection and localization) in one patient with antero-medial TLE. Face-OPM signals were correlated with scalp-OPM signals in most patients, showing that face-OPMs recorded brain activity.

This study shows that on-scalp MEG is able to detect and localize IEDs in TLE and to discriminate irritative zones from different key (medial, anterior, basal, lateral or postero-lateral) temporal areas with similar or enhanced SNR than cryogenic MEG. Face-OPMs have a clear added-value in patients with anterior/medial TLE and increase the spatial coverage of the temporal lobe. This study paves the way for the future use of on-scalp MEG in patients with refractory TLE or with other brain disorders affecting the temporal lobe such as, e.g., Alzheimer’s disease.
Parental income and psychiatric disorders from age 10 to 40: a genetically informative population study
Authors: Sunde Hans Fredrik , Eilertsen Espen Moen , Kinge Jonas Minet , Kleppesto Thomas H. , Nordmo Magnus , Caspi Avshalom , Moffitt Terrie E. , Torvik Fartein Ask
Published: October 2024

Background

Lower parental income is associated with more psychiatric disorders among offspring, but it is unclear if this association reflects effects of parental income (social causation) or shared risk factors (social selection). Prior research finds contradictory results, which may be due to age differences between the studied offspring.

Methods

Here, we studied the entire Norwegian population aged 10 to 40 between 2006 and 2018 (N = 2,468,503). By linking tax registries to administrative health registries, we describe prevalence rates by age, sex, and parental income rank. Next, we used kinship-based models with extended families of twins and siblings to distinguish direct effects of parents from shared genetic and environmental risk factors.

Results

We show that lower parental income rank was associated with more psychiatric disorders at all ages from age 10 to 40 (rbetween −.06 and −.15). The kinship-based models indicated that direct effects of parental income played a large role (38%) in explaining the parent-offspring correlation among adolescents, while shared risk factors accounted for the entire parent-offspring correlation among adults.

Conclusion

Our findings indicate that social causation plays a significant role during adolescence, while social selection fully explains the parent-offspring association in adulthood.
Deciphering the dynamic clinical patterns inSCN8A-related disorders using real-world data
Authors: Magielski Jan H. , Cohen Stacey , Kaufman Michael C. , Parthasarathy Shridhar , Xian Julie , Brimble Elise , Fitter Nasha , Furia Francesca , Gardella Elena , Møller Rikke S. , Helbig Ingo , McKee Jillian L.
Published: October 2024

Background and Objectives

SCN8A-related disorders encompass a range of neurodevelopmental and epilepsy phenotypes. However, despite representing one of the most common epilepsy-associated channelopathies, the longitudinal progression of its clinical features remains largely uncharacterized.

Methods

Here, we harmonized electronic medical record data of 82 individuals withSCN8A-related disorders. Clinical data was mapped to the standardized language of the Human Phenotype Ontology to reconstruct the natural history ofSCN8A-related disorders in comparison to a cohort of 2,833 individuals with known or presumed genetic epilepsies.

Results

Compared to other known or presumed genetic epilepsies, those withSCN8A-related disorders had earlier generalized seizures, including a ten-fold risk for generalized-onset seizures at 9 months (P= 4.98 × 10−17, OR 10.65, CI 6.07-18.77) and >40-fold risk bilateral tonic-clonic seizures at 1 year (P= 1.76 × 10−8, OR 46.09, CI 10.72-275.01). Individuals carrying gain-of-functionSCN8Avariants had particularly high generalized seizure risk at 9 months (P= 0.005, OR 3.85, CI 1.35-11.55), as well as an increased risk for global developmental delay as early as 3 months (P= 0.002, OR 5.67, CI 1.74-20.23) when compared to the broaderSCN8Acohort. Individuals with loss-of-function variants were more likely to experience absence seizures, most prominently at 4.25 years (P= 0.013, OR 32.71, CI 1.44-2193.51). Compared to the widerSCN8Acohort, individuals with the recurrent p.Arg850Gln variant were more likely to have infantile spasms at 6 months (P= 0.016, OR 12.02, CI 1.20-164.23), those with variants at the p.Arg1872Trp/Gln/Leu hotspot were more likely to have neonatal seizures (P= 0.025, OR 16.84, CI 0.99-291.58). Individuals with the recurrent p.Gly1475Arg variant were more likely to have active epilepsy after 5 years of age. Focal seizures in later childhood were more prominent in individuals with the recurrent p.Arg1617Gln variant.

Discussion

SCN8A-related disorders distinguish themselves from other genetic epilepsies by the frequent generalized-onset seizures in infancy, prominent early epileptic and developmental features in gain-of-function variant carriers, and unique seizure phenotypes in those with recurrent variants. Our study provides a longitudinal perspective on this genetic condition, paving the way for the future precision medicine approaches.
Mendelian randomisation with proxy exposures: challenges and opportunities
Authors: Rahu Ida , Tambets Ralf , Fauman Eric B. , Alasoo Kaur
Published: October 2024

A key challenge in human genetics is the discovery of modifiable causal risk factors for complex traits and diseases. Mendelian randomisation (MR) using molecular traits as exposures is a particularly promising approach for identifying such risk factors. Despite early successes with the application of MR to biomarkers such as low-density lipoprotein cholesterol and C-reactive protein, recent studies have revealed a more nuanced picture, with widespread horizontal pleiotropy. Using data from the UK Biobank, we illustrate the issue of horizontal pleiotropy with two case studies, one involving glycolysis and the other involving vitamin D synthesis. We demonstrate that, although the measured metabolites (pyruvate or histidine, respectively) do not have a direct causal effect on the outcomes of interest (red blood cell count or vitamin D level), we can still use variant effects on these downstream metabolites to infer how they perturb protein function in different gene regions. This allows us to use variant effects on metabolite levels as proxy exposures in acis-MR framework, thus rediscovering the causal roles of histidine ammonia lyase (HAL) in vitamin D synthesis and glycolysis pathway in red blood cell survival. We also highlight the assumptions that need to be satisfied forcis-MR with proxy exposures to yield valid inferences and discuss the practical challenges of meeting these assumptions.
Mycobiome Dysbiosis and Genetic Predisposition for Elevated IL-17A Drive Fibrosis in MASLD
Authors: Thielemann Nadja , Siliceo Sara Leal , Rau Monika , Schöninger Annika , Reus Nathalie , Aldejohann Alexander M. , Shehata Aia , Behr Isabell S. , Nieuwenhuizen Natalie E. , Herz Michaela , Hermanns Heike M. , Mirhakkak Mohammad , Löffler Jürgen , Dandekar Thomas , Hünniger-Ast Kerstin , Martin Ronny , Panagiotou Gianni , Geier Andreas , Kurzai Oliver
Published: October 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease in Western countries. Progression to metabolic dysfunction-associated steatohepatitis (MASH) occurs when fat accumulation in the liver triggers Th17 activation and other inflammatory processes. In this study, we identify theIL17Ars2275913 minor allele variant as a risk factor for fibrosis progression in MASLD patients. In patients with advanced fibrosis, we also observed an increased abundance of fungal CTG species includingCandida albicansandDebaryomyces hansenii, which are potent triggers of Th17 responses. Integrating genetic risk-predisposition and mycobiome composition, we show inex vivoT cell stimulation assays, that donors carrying the minor allele variant ofIL17Ars2275913 secreted significantly higher IL-17A levels in response to CTG species. Additionally, MASH patients carrying theIL17Ars2275913 risk allele have elevated Th17/Treg ratios in peripheral blood. Taken together, our data indicate that genetic predisposition for enhanced Th17 responses in the context of mycobiome dysbiosis can trigger MASH progression and liver fibrosis.

Graphical Abstract

This Graphical Abstract was created withBioRender.com.

Brief summary

Increased antifungal immune responses triggered by gut mycobiome dysbiosis in genetically predisposed patients can lead to severe stages of metabolic dysfunction-associated steatotic liver disease.
Benzoxazinoid-mediated microbiome feedbacks enhance Arabidopsis growth and defense
Authors: Stengele Katja , Stauber Lea , Thoenen Lisa , Janse van Rensburg Henry , D'Adda Viola , Schlaeppi Klaus
Published: October 2024

Plants modulate their surrounding microbiome via root exudates and this conditioned soil microbiome feeds back on the performance of the next generation of plants. How plants can perceive this altered microbiome and modulate their performance in response to such microbiome feedbacks however remains largely unknown. We made use of two maize lines, which differ in their ability to exude benzoxazinoids, to condition two contrasting soil microbiomes in the same starting soil. Based on these conditioned soils we have established a model system withArabidopsis thaliana(Arabidopsis) to investigate the mechanisms of microbiome feedbacks. Arabidopsis plants grown on the benzoxazinoids conditioned soil developed larger rosettes, for which the soil microbiome was required. Arabidopsis roots also harbored differential bacterial communities. Further, these plants showed enhanced defense signatures in their shoot and were more resistant to the fungal pathogenBotrytis cinerea. We could establish Arabidopsis as a model to study benzoxazinoid-mediated microbiome feedbacks, which will allow future studies to investigate underlying mechanisms. Arabidopsis also responded with both improved growth and enhanced resistance to a complex benzoxazinoids conditioned microbiome, and we hypothesize that this simultaneous increase of growth and defense is mediated by priming of defenses.
Insights into Diversity, Host-Range, and Temporal Stability ofBacteroidesandPhocaeicolaProphages
Authors: Stopnisek Nejc , Hedžet Stina , Accetto Tomaž , Rupnik Maja
Published: October 2024

Background

Phages are critical components of the gut microbiome, influencing bacterial composition and function as predators, parasites, and modulators of bacterial phenotypes. Prophages, integrated forms of these phages, are prevalent in many bacterial genomes and play a role in bacterial adaptation and evolution. However, the diversity and stability of prophages within gut commensals, particularly in the generaBacteroidesandPhocaeicola, remain underexplored. This study aims to screen and characterize prophages in these genera, providing insights into their diversity, host range, and temporal dynamics in the human gut.

Results

Using a combination of three bioinformatic tools—Cenote-Taker 3, Vibrant, and PHASTER—we conducted a comprehensive analysis of prophages inBacteroidesandPhocaeicola. Cenote-Taker 3 identified the most diverse set of prophages, with significant overlaps observed between the tools. After clustering high-quality prophages, we identified 22 unique viral operational taxonomic units (vOTUs). Notably, comparisons between prophages identified in isolated bacterial genomes, metaviromes, and large public gut virome databases revealed a broader host range than initially observed in single isolates. Certain prophages were consistent across time points and individuals, suggesting temporal stability. All identified prophages belonged to theCaudoviricetesclass and contained genes related to antibiotic resistance, toxin production, and metabolic processes.

Conclusions

The combined use of multiple prophage detection tools allowed for a more comprehensive assessment of prophage diversity inBacteroidesandPhocaeicola. The identified prophages were not only prevalent but also exhibited broad host ranges and temporal stability. The presence of antibiotic resistance and toxin genes suggests that these prophages may significantly influence bacterial community structure and function in the gut, with potential implications for human health. These findings highlight the importance of using diverse detection tools to accurately assess prophage diversity and dynamics.
Priority effects of heritable seed-borne bacteria drive early assembly of the wheat rhizosphere microbiome
Authors: Garrido-Sanz Daniel , Keel Christoph
Published: October 2024

Microbial communities play a critical role in supporting plant health and productivity, making the ability to obtain reproducible plant-associated microbiomes an essential asset for experimentally testing hypotheses related to microbiome manipulation and fundamental principles governing community dynamics. We used a sequential propagation strategy to generate a complex and reproducible wheat rhizosphere microbiome (RhizCom) that was shaped by host selection and periodic habitat resetting. Heritable seed-borne rhizosphere bacteria (SbRB) emerged as the dominant microbiome source after coalescing with the soil community, driven by priority effects and efficient niche exploitation during early habitat development. Functional analyses revealed that niche partitioning through the ability of SbRB to degrade specific saccharides and niche facilitation contributed to the assembly of the RhizCom. Our results advance our understanding of the principles governing microbial community dynamics in early plant development and provide strategies for future microbiome manipulation aimed at improving crop productivity and health.
Towards a unifying phylogenomic framework for tailed phages
Authors: Weinheimer Alaina R. , Ha Anh D. , Aylward Frank O.
Published: October 2024

Background

Classifying viruses systematically has remained a key challenge of virology due to the absence of universal genes and vast genetic diversity of viruses. In particular, the most dominant and diverse group of viruses, the tailed double-stranded DNA viruses of prokaryotes belonging to the class Caudoviricetes, lack sufficient homology in the genetic machinery that unifies them to reconstruct inclusive, stable phylogenies of these genes. While previous approaches to organize tailed phage diversity have managed to distinguish various taxonomic levels, these methods are limited in scalability and reproducibility, and they do not include modes of evolution, like gene gains and losses.

Results

Here, we present a novel, comprehensive and reproducible framework for examining evolutionary relationships of tailed phages. In this framework, we compare phage genomes based on presences and absences of a fixed set of gene families which is used as binary trait data that is input into maximum likelihood models, which include heterogeneous rates of trait losses and gains. Our resulting phylogeny stably recovers known taxonomic families of tailed phages, with and without the inclusion of metagenomic phages. We also quantify the mosaicism of replication and structural genes among known families. Our results suggest that these exchanges likely underpin the emergence of new families. Additionally, we apply this framework to large phages (>100 kilobases) to map emergences of traits associated with genome expansion.

Conclusion

Taken together, this evolutionary framework for charting and organizing tailed phage diversity improves the systemization of phage taxonomy, which can unify phage studies and advance our understanding of their evolution.
Transcriptomic landscape identifies two unrecognized ependymoma subtypes and novel pathways in medulloblastoma
Authors: Arora Sonali , Nuechterlein Nicholas , Jensen Matt , Glatzer Gregory , Sievers Philipp , Varadharajan Srinidhi , Korshunov Andrey , Sahm Felix , Mack Stephen C. , Taylor Michael D. , Holland Eric C
Published: October 2024

Medulloblastoma and ependymoma are prevalent pediatric central nervous system tumors with significant molecular and clinical heterogeneity. We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. Following rigorous batch effect correction, normalization, and dimensionality reduction, we constructed a unified landscape to explore gene expression, signaling pathways, gene fusions, and copy number variations. Our analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with specific gene fusions and molecular signatures. In medulloblastoma, we achieved precise stratification of Group 3/4 tumors by subtype and in SHH tumors by patient age. Our landscape serves as a vital resource for identifying biomarkers, refining diagnoses, and enables the mapping of new patients’ bulk RNA-seq data onto the reference framework to facilitate accurate disease subtype identification. The landscape is accessible via Oncoscape, an interactive platform, empowering global exploration and application.

One Sentence Summary

A landscape built using only Transcriptomic analysis for medulloblastoma and ependymoma reveals novel insights about subtype specific biology.
Hearing thresholds in the bat Carollia perspicillata vary by sex but not age
Authors: Molano Olivia , Dale Emily , Portfors Christine , Coffin Allison
Published: October 2024

Bats rely heavily on auditory perception for critical behaviors including navigation (echolocation) and conspecific communication. However, there is little information on the impacts of age and sex on the bat auditory system. Here, we used auditory brainstem response recordings to measure auditory thresholds inCarollia perspicillata(Seba’s short-tailed bat). We did not detect an age-related threshold shift at the age range examined (1-8 years old), suggesting that bats may be relatively resistant to age-related hearing loss. We had considerably more young bats (aged 1-2 years) than older animals (aged 4-8 years) so our results should be interpreted with caution. However, they are consistent with other studies showing that bats exhibit fewer signs of aging relative to other small mammals. In addition, we show significantly lower auditory thresholds among females compared to age-matched males, similar to sex differences reported in other mammals. Finally, we found increased thresholds in a single non-pigmented bat relative to age- and sex-matched conspecifics. While preliminary, this finding suggests that pigmentation may be important for inner ear function in bats, similar to results from other mammals.
Quality assessment and control of unprocessed anatomical, functional, and diffusion MRI of the human brain using MRIQC
Authors: Hagen McKenzie Paige , Provins Celine , MacNicol Eilidh , Li Jamie , Gomez Teresa , Garcia Melanie , Seeley Saren , Haitz Legarreta Jon , Norgaard Martin , Bissett Patrick , Poldrack Russell A. , Rokem Ariel G , Esteban Oscar
Published: October 2024

Quality control of MRI data prior to preprocessing is fundamental, as substandard data are known to increase variability spuriously. Currently, no automated or manual method reliably identifies subpar images, given pre-specified exclusion criteria. In this work, we propose a protocol describing how to carry out the visual assessment of T1-weighted, T2-weighted, functional, and diffusion MRI scans of the human brain with the visual reports generated by MRIQC. The protocol describes how to execute the software on all the images of the input dataset using typical research settings (i.e., a high-performance computing cluster). We then describe how to screen the visual reports generated with MRIQC to identify artifacts and potential quality issues and annotate the latter with the "rating widget" - a utility that enables rapid annotation and minimizes bookkeeping errors. Integrating proper quality control checks on the unprocessed data is fundamental to producing reliable statistical results and crucial to identifying faults in the scanning settings, preempting the acquisition of large datasets with persistent artifacts that should have been addressed as they emerged.
The spatio-temporal dynamics of phoneme encoding in aging and aphasia
Authors: Kries Jill , De Clercq Pieter , Vandermosten Maaike , Gwilliams Laura
Published: October 2024

During successful language comprehension, speech sounds (phonemes) are encoded within a series of neural patterns that evolve over time. Here we tested whether these neural dynamics of speech encoding are altered for individuals with a language disorder. We recorded EEG responses from individuals with post-stroke aphasia and healthy age-matched controls (i.e., older adults) during 25 min of natural story listening. We estimated the duration of phonetic feature encoding, speed of evolution across neural populations, and the spatial location of encoding over EEG sensors. First, we establish that phonetic features are robustly encoded in EEG responses of healthy older adults. Second, when comparing individuals with aphasia to healthy controls, we find significantly decreased phonetic encoding in the aphasic group after shared initial processing pattern (0.08-0.25s after phoneme onset). Phonetic features were less strongly encoded over left-lateralized electrodes in the aphasia group compared to controls, with no difference in speed of neural pattern evolution. Finally, we observed that phonemes with high uncertainty about word identity were encoded longer in controls than in individuals with aphasia. This indicates that encoding phonetic information until word identity is resolved might be a crucial mechanism for successful speech comprehension. Together, our results suggest that aphasia may entail failure to maintain lower-order information long enough to recognize lexical items.

Significance statement

This study reveals robust phonetic decoding with EEG recordings in older adults, as well as decreased phonetic processing in individuals with a language disorder (aphasia) compared to healthy controls. This was most prominent over left-sided electrodes. Additionally, we observed that healthy controls, but not individuals with aphasia, encode phonetic features longer when uncertainty about word identity is high, indicating that this mechanism - encoding phonetic information until word identity is resolved - is crucial for successful language processing. These insights deepen our understanding of disrupted mechanisms in a language disorder, and show how the integration between language processing levels works in the healthy aging, neurotypical brain.
Associations between Urinary Pesticide Metabolites and Serum Inflammatory Biomarkers in Adolescents Living in an Agricultural Region
Authors: Hussari Mohammed N. , Chronister Briana N.C. , Yang Kun , Tu Xin , Martinez Danilo , Parajuli Rajendra P , Suarez-Torres Jose , Barr Dana Boyd , Hong Suzi , Suarez-Lopez Jose R.
Published: October 2024

Background

In-vitro and in-vivo studies have shown evidence for the immuno-modulatory properties of different pesticides. However, few epidemiological studies on inflammation and pesticide exposure exist, with none in children and adolescents. Associations between pesticide metabolites in urine and inflammatory biomarkers in serum were evaluated among children and adolescents (n=512) of rural Ecuador as part of the ESPINA study

Methods

Seventeen urinary biomarkers of insecticide, herbicide and N, N-diethyl-meta-toluamide (DEET) insect repellent exposure were measured. Among them, acetamiprid-N-desmethyl [AND], 3,5,6-Trichloro-2-pyridinol [TCPy],para-nitrophenol [PNP], malathion dicarboxylic acid [MDA], 3-phenoxybenzoic acid [3-PBA], 2,4-Dichlorophenoxyacetic acid [2,4-D], glyphosate and 3-(diethylcarbamoyl) benzoic acid [DCBA] were included in analyses as they were detected in >30% of participants. Serum analysis included c-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-⍺ (TNF-⍺), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), serum amyloid A (SAA), and soluble CD14 (sCD14). Associations were evaluated by generalized estimating equations (GEE) and partial least squares (PLS) regression, adjusting for demographic, anthropometric and socioeconomic variables.

Results

Positive quadratic associations were found between 2,4-D and CRP (β2=0.13, [0.00, 0.27]), IL-6 (β2=0.10, [0.04, 0.15]), SAA (β2=0.13, [0.01, 0.30]), sICAM-1 (β2=53.25, [27.26, 79.24]) and sVCAM-1 (β2=61.11, [30.52, 91.70]). The pesticide metabolites PLS composite variable was positively associated with IL-6 (β=0.09, [0.01. 0.17]), SAA (β=0.43, [0.13, 0.17]), sICAM-1 (β=63.52, [9.92, 117.13]), sVCAM-1 (β=69.03, [8.29, 129.76]) and TNF-⍺ (β=0.08, [0.00, 0.16]), and negatively associated with CRP (β=-0.28, [-0.49, -0.08], Figure 1).

Conclusions

Our findings demonstrate a novel pesticide/herbicide-inflammation link in adolescents, which may be an underlying mechanism of the health impacts of pesticides/herbicides.
Robust uncertainty quantification in popular estimators of the instantaneous reproduction number
Authors: Steyn Nicholas , Parag Kris V
Published: October 2024

The instantaneous reproduction number (Rt) is a key measure of the rate of spread of an infectious disease. Correctly quantifying uncertainty inRtestimates is crucial for making well-informed decisions. PopularRtestimators leverage smoothing techniques to distinguish signal from noise. Examples include EpiEstim and EpiFilter, which are both controlled by a “smoothing parameter” that is traditionally selected by users. We demonstrate that the values of these smoothing parameters are unknown, vary markedly with epidemic dynamics, and show that data-driven smoothing is crucial for accurate uncertainty quantification ofRtestimates. We derive model likelihoods for the smoothing parameters in both EpiEstim and EpiFilter and develop a Bayesian framework to automatically marginalise these parameters when fitting to epidemiological time-series data. This yields novel marginal posterior predictive distributions which prove integral to rigorous model evaluation. Applying our methods, we find that default parameterisations of these widely-used estimators can negatively impactRtinference, delaying detection of epidemic growth, and misrepresenting uncertainty (typically producing overconfident estimates), with implications for public health decision-making. Our extensions mitigate these issues, provide a principled approach to uncertainty quantification, improve the robustness of real-timeRtinference, and facilitate model comparison using observable quantities.