bluuebunny/crossref_metadata_2025 huggingface dataset:
Penalized Decomposition Using Residuals (PeDecURe) for Nuisance Variable Adjustment in Multivariate Pattern Analysis
Authors: Weinstein Sarah M. , Davatzikos Christos , Doshi Jimit , Linn Kristin A. , Shinohara Russell T. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2022

Summary

In neuroimaging studies, multivariate methods provide a framework for studying associations between complex patterns distributed throughout the brain and neurological, psychiatric, and behavioral phenotypes. However, mitigating the influence of nuisance variables, such as confounders, remains a critical challenge in multivariate pattern analysis (MVPA). In studies of Alzheimer’s Disease, for example, imbalance in disease rates across age and sex may make it difficult to distinguish between structural patterns in the brain (as measured by neuroimaging scans) attributable to disease progression and those characteristic of typical human aging or sex differences. Concerningly, when not properly adjusted for, nuisance variables can obscure interpretations and preclude the generalizability of findings from neuroimaging studies. Motivated by this critical issue, in this work we examine the impact of nuisance variables on features extracted from image decomposition methods and propose Penalized Decomposition Using Residuals (PeDecURe), a new MVPA method for obtaining nuisance variable-adjusted features. PeDecURe estimates primary directions of variation which maximize covariance between residualized imaging features and a variable of interest (e.g., Alzheimer’s diagnosis) while simultaneously mitigating the influence of nuisance variation through a penalty on the covariance between residualized imaging features and those variables. Using features estimated using PeDecURe’s first direction of variation, we train an accurate and generalizable predictive model, as evidenced by its robustness in testing samples with different underlying nuisance variable distributions. We compare PeDecURe to commonly used decomposition methods (principal component analysis (PCA) and partial least squares) as well as a confounder-adjusted variation of PCA. We find that features derived from PeDecURe offer greater accuracy and generalizability and lower partial correlations with nuisance variables compared with the other methods. While PeDecURe is primarily motivated by MVPA in the context of neuroimaging, it is broadly applicable to datasets where the dimensionality or complexity of the covariance structure calls for novel methods to handle sources of nuisance variation.
High spatial overlap but diverging age-related trajectories of cortical MRI markers aiming to represent intracortical myelin and microstructure
Authors: Parent Olivier , Olafson Emily , Bussy Aurélie , Tullo Stephanie , Blostein Nadia , Salaciak Alyssa , Bedford Saashi A. , Farzin Sarah , Béland Marie-Lise , Valiquette Vanessa , Tardif Christine L. , Devenyi Gabriel A. , Mallar Chakravarty M.
Published: January 2022

Cortical thickness (CT), gray-white matter contrast (GWC), boundary sharpness coefficient (BSC), and T1-weighted/T2-weighted ratio (T1w/T2w) are cortical metrics derived from standard T1- and T2-weighted magnetic resonance imaging (MRI) images that are often interpreted as representing or being influenced by intracortical myelin content. However, there is little empirical evidence to justify these interpretations nor have the homologies or differences between these measures been examined. We examined differences and similarities in group mean and age-related trends with the underlying hypothesis that different measures sensitive to similar changes in underlying myelo- and microstructural processes should be highly related. We further probe their sensitivity to cellular organization using the BigBrain, a high-resolution digitized volume stemming from a whole human brain histologically stained for cell bodies with the Merker stain.

The measures were generated on both the MRI-derived images of 127 healthy subjects, aged 18 to 81, and on the BigBrain volume using cortical surfaces that were generated with the CIVET 2.1.0 pipeline. Comparing MRI markers between themselves, our results revealed generally high overlap in spatial distribution (i.e., group mean), but mostly divergent age trajectories in the shape, direction, and spatial distribution of the linear age effect. Significant spatial relationships were found between the BSC and GWC and their BigBrain equivalent, as well as a correlation approaching significance between the BigBrain intensities and the T1w/T2w ratio in gray matter (GM) both sampled at half cortical depth.

We conclude that the microstructural properties at the source of spatial distributions of MRI cortical markers (e.g. GM myelin) can be different from microstructural changes that affect these markers in aging. While our findings highlight a discrepancy in the interpretation of the biological underpinnings of the cortical markers, they also highlight their potential complementarity, as they are largely independent in aging. Our BigBrain results indicate a general trend of GM T1w signal and myelin being spatially related to the density of cells, which is possibly more pronounced in superficial cortical layers.

Highlights

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Different MRI cortical markers aim to represent myelin and microstructure

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These markers show high spatial overlap, but mostly divergent age trajectories

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It is unlikely that myelin changes are the source of the age effect for all markers

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Trend of MRI signal being related to cell density in more superficial cortical layers
Structural covariance and heritability of the optic tract and primary visual cortex in living human brains
Authors: Miyata Toshikazu , Benson Noah C. , Winawer Jonathan , Takemura Hiromasa
Published: January 2022

Individual differences among human brains exist at many scales, spanning gene expression, white matter tissue properties, and the size and shape of cortical areas. One notable example is an approximately 3-fold range in the size of human primary visual cortex (V1), a much larger range than is found in overall brain size. A previous study (Andrews et al., 1997) reported a correlation between optic tract cross-section area and V1 size in post-mortem human brains, suggesting that there may be a common developmental mechanism for multiple components of the visual pathways. We evaluated the relationship between properties of the optic tract and V1 in a much larger sample of living human brains by analyzing the Human Connectome Project 7 Tesla Retinotopy Dataset. This dataset includes retinotopic maps measured with functional MRI (fMRI) and fiber tract data measured with diffusion MRI (dMRI). We found a negative correlation between optic tract fractional anisotropy and V1 surface area (r= -0.2). This correlation, though small, was consistent across multiple dMRI datasets differing in acquisition parameters. Further, we found that both V1 size and optic tract properties were correlated among twins, with higher correlations for monozygotic than dizygotic twins, indicating a high degree of heritability for both properties. Together, these results demonstrate covariation across individuals in properties of the retina (optic tract) and cortex (V1) and show that each is influenced by genetic factors.

Significance statement

The size of human primary visual cortex (V1) has large inter-individual differences. These differences cannot be explained by differences in overall brain size. A previous post-mortem study reported a correlation between the size of the human optic tract and V1. In this study, we evaluated the relationship between the optic tract and V1 in living humans by analyzing a neuroimaging dataset that included functional and diffusion MRI data. We found a small, but robust correlation between optic tract tissue properties and V1 size, supporting the existence of structural covariance between the optic tract and V1 in living humans. The results suggest that characteristics of retinal ganglion cells, reflected in optic tract measurements, are related to individual differences in human V1.
Cross-modality supervised image restoration enables nanoscale tracking of synaptic plasticity in living mice
Authors: Xu YKT , Graves AR , Coste GI , Huganir RL , Bergles DE , Charles AS , Sulam J
Published: January 2022

Synaptic plasticity encodes learning as changes in the strength of synapses, sub-micron structures that mediate communication between brain cells. Due to their small size and high density, synapses are extremely difficult to image in vivo, limiting our ability to directly relate synaptic plasticity with behavior. Here, we developed a combination of computational and biological methods to overcome these challenges. First, we trained a deep learning image restoration algorithm that combines the advantages of ex vivo super-resolution and in vivo imaging modalities to overcome limitations specific to each optical system. Applied to in vivo images from transgenic mice expressing fluorescently labeled synaptic proteins, this restoration algorithm super-resolved diffraction-limited synapses, enabling identification and logitudinal tracking of synaptic plasticity underlying behavior with unprecedented spatial resolution. More generally, our method demonstrates the capabilities of image enhancement to learn from ex vivo data and imaging techniques to improve in vivo imaging resolution.
Anterior insular cortex inputs to the dorsolateral striatum govern the maintenance of binge alcohol drinking
Authors: Haggerty David L. , Muñoz Braulio , Pennington Taylor , Di Prisco Gonzalo Viana , Grecco Gregory G. , Atwood Brady K.
Published: January 2022

How does binge drinking alcohol change synaptic function, and do these changes maintain binge consumption? The anterior insular cortex (AIC) and dorsolateral striatum (DLS) are brain regions implicated in alcohol use disorder. In mice, we found that binge drinking alcohol produced glutamatergic synaptic adaptations selective to AIC inputs within the DLS. Photoexciting AIC→DLS circuitry during binge drinking decreased alcohol, but not water consumption and altered alcohol drinking mechanics. Further, drinking mechanics alone from drinking session data predicted alcohol-related circuit changes. AIC→DLS manipulation did not alter operant, valence, or anxiety-related behaviors. These findings suggest that alcohol-mediated changes at AIC inputs govern behavioral sequences that maintain binge drinking and may serve as a circuit-based biomarker for the development of alcohol use disorder.
Extrinsic mortality and senescence: a guide for the perplexed
Authors: de Vries Charlotte , Galipaud Matthias , Kokko Hanna
Published: January 2022

Do environments or species traits that lower the mortality of individuals create selection for delaying senescence? Reading the literature creates an impression that mathematically oriented biologists cannot agree on the validity of George Williams’ prediction (who claimed ‘yes’). The abundance of models and opinions may bewilder those that are new to the field. Here we provide heuristics as well as simple models that outline when the Williams prediction holds, why there is a ‘null model’ where extrinsic mortality does not change the evolution of senescence at all, and why it is also possible to expect the opposite of William’s prediction, where increased extrinsic mortality favours slower senescence. We hope to offer intuition by quantifying how much delaying the ‘placement’ of an offspring into the population reduces its expected contribution to the gene pool of the future. Our first example shows why sometimes increased extrinsic mortality has no effect (the null result), and why density dependence can change that. Thereafter, a model with ten different choices for population regulation shows that high extrinsic mortality favours fast life histories (Williams) if increasing density harms the production of juveniles or their chances to recruit into the population. If instead increasing density harms the survival of older individuals in a population, then high extrinsic mortality favours slow life histories (anti-Williams). We discuss the possibility that empirically found Williams-like patterns provide indirect evidence for population regulation operating via harming the production or fitness prospects of juveniles, as opposed to the survival of established breeders.
BA.1 and BA.2 sub-lineages of Omicron variant have comparable replication kinetics and susceptibility to neutralization by antibodies
Authors: Singh Janmejay , Panwar Aleksha , Anantharaj Anbalagan , Rani Chitra , Bhardwaj Monika , Kumar Parveen , Pargai Kamal , Chattopadhyay Partha , Devi Priti , Maurya Ranjeet , Mishra Pallavi , Pandey Anil Kumar , Pandey Rajesh , Medigeshi Guruprasad R.
Published: January 2022

The Omicron variant of SARS-CoV-2 is capable of infecting unvaccinated, vaccinated and previously-infected individuals due to its ability to evade neutralization by antibodies. With three sub-lineages of Omicron emerging in the last four months, there is inadequate information on the quantitative antibody response generated upon natural infection with Omicron variant and whether these antibodies offer cross-protection against other sub-lineages of Omicron variant. In this study, we characterized the growth kinetics of Kappa, Delta and Omicron variants of SARS-CoV-2 in Calu-3 cells. Relatively higher amounts infectious virus titers, cytopathic effect and disruption of epithelial barrier functions was observed with Delta variant whereas infection with Omicron variant led to a more robust induction of interferon pathway, lower level of virus replication and mild effect on epithelial barrier. The replication kinetics of BA.1 and BA.2 sub-lineages of the Omicron variant were comparable in cell culture and natural Omicron infection in a subset of individuals led to a significant increase in binding and neutralizing antibodies to both BA.1 and BA.2 sub-lineages but these levels were lower than that produced against the Delta variant. Finally, we show that Cu2+, Zn2+ and Fe2+ salts inhibited in vitro RdRp activity but only Cu2+ and Fe2+ inhibited both the Delta and Omicron variants in cell culture. Thus, our results suggest that high levels of interferons induced upon infection with Omicron variant may counter virus replication and spread. Waning neutralizing antibody titers rendered subjects susceptible to infection by Omicron variant and natural Omicron infection elicits neutralizing antibodies that can cross-react with other sub-lineages of Omicron and other variants of concern.
Investigating the Characteristics of Genes and Variants Associated with Self-Reported Hearing Difficulty in Older Adults in the UK Biobank
Authors: Lewis Morag A. , Schulte Bradley A. , Dubno Judy R. , Steel Karen P.
Published: January 2022

Background

Age-related hearing loss is a common, heterogeneous disease with a strong genetic component. More than 100 loci have been reported to be involved in human hearing impairment to date, but most of the genes underlying human adult-onset hearing loss remain unknown. Most genetic studies have focussed on very rare variants (such as family studies and patient cohort screens) or very common variants (genome-wide association studies). However, the contribution of variants present in the human population at intermediate frequencies is hard to quantify using these methods, and as a result, the landscape of variation associated with adult-onset hearing loss remains largely unknown.

Results

Here we present a study based on exome sequencing and self-reported hearing difficulty in the UK Biobank, a large-scale biomedical database. We have carried out variant load analyses using different minor allele frequency and impact filters, and compared the resulting gene lists to a manually-curated list of nearly 700 genes known to be involved in hearing in humans and/or mice. An allele frequency cutoff of 0.1, combined with a high predicted variant impact, was found to be the most effective filter settings for our analysis. We also found that separating the participants by sex produced markedly different gene lists. The gene lists obtained were investigated using gene ontology annotation, functional prioritisation and expression analysis, and this identified good candidates for further study.

Conclusions

Our results suggest that relatively common as well as rare variants with a high predicted impact contribute to age-related hearing impairment, and that the genetic contributions to adult hearing difficulty may differ between the sexes. Our manually-curated list of deafness genes is a useful resource for candidate gene prioritisation in hearing loss.
Calprotectin and inflammation-associated serum biomarkers determine critical illness in COVID-19
Authors: Kassianides Georgios , Siampanos Athanassios , Poulakou Garyphalia , Adamis George , Rapti Aggeliki , Milionis Haralampos , Dalekos George N. , Petrakis Vasileios , Sympardi Styliani , Metallidis Symeon , Alexiou Zoi , Gkavogianni Theologia , Giamarellos-Bourboulis Evangelos J. , Theoharides Theoharis C.
Published: January 2022

Little is known on the key contributing factors towards progression into acute respiratory distress syndrome (ARDS) necessitating mechanical ventilation (MV) in COVID-19. We determined serum levels, within 24 hours of diagnosis, of alarmins, as well as pro- and anti-inflammatory molecules in asymptomatic, moderate, severe and intubated patients compared to non-infected comparators. Levels of the pro-inflammatory interleukin (IL)-8, IL-18, matrix metalloproteinase-9, platelet-derived growth factor (PDGF)-B and calprotectin (S100A8/A9) were specific drivers of ARDS. Levels of the anti-inflammatory IL-1ra and IL-33r were increased; IL-38 was increased only in asymptomatic patients, but significantly decreased in the more severe COVID-19 cases. Multivariate ordinal regression showed that pathways of IL-6, IL-33 and calprotectin gave significant probability for worse outcome. These results indicate a dysfunctional response to the presence of alarmins that may be used for prognosis and development of effective treatments.
The progressive loss of brain network fingerprints in Amyotrophic Lateral Sclerosis predicts clinical impairment
Authors: Romano Antonella , Lopez Emahnuel Trosi , Liparoti Marianna , Polverino Arianna , Minino Roberta , Trojsi Francesca , Bonavita Simona , Mandolesi Laura , Granata Carmine , Amico Enrico , Sorrentino Giuseppe , Sorrentino Pierpaolo
Published: January 2022

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by functional connectivity alterations in both motor and extra-motor brain regions. In network analysis, fingerprint represent a valid approach able to assess the subject-specific connectivity features of a given population. Here, we applied the Clinical Connectome Fingerprint (CCF) analysis to source-reconstructed magnetoencephalography (MEG) signals in a cohort of seventy-eight subjects: thirty-nine ALS patients and thirty-nine healthy controls. We set out to develop an identifiability matrix to assess the extent to which each subject was recognisable based on his/her connectome. The analysis was performed in all five canonical frequency bands. Then we built a multilinear regression model to test the ability of “clinical fingerprint” to predict the clinical evolution of disease assessed by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-r), the King’s disease staging system and the Milano-Torino Staging (MiToS) disease staging system. We found a drop in patients’ identifiability in the alpha band compared to the healthy controls. Furthermore, the “clinical fingerprint” was predictive of ALSFRS-r (p=0.0397; β=32.8), King’s (p=0.0001; β= -7.40) and MiToS (p=0.0025; β= -4.9) scores and negatively correlated with King’s and MiToS scales according to Spearman’s correlation. Our results demonstrated the ability of the CCF approach in assessing the individual motor condition and its relationship with ALS disease. Thanks to the subject-specific characteristic of this approach, we hope that further exploration related to its clinical application may help improve the management of disease.
Critical success factors for high routine immunization performance: A case study of Nepal
Authors: Hester Kyra A , Sakas Zoe , Ellis Anna S. , Bose Anindya Sekhar , Darwar Roopa , Gautam Jhalak , Jaishwal Chandni , James Hanleigh , Keskinocak Pinar , Nazzal Dima , Ogutu Emily Awino , Rodriguez Katie , Zunino Francisco Castillo , Dixit Sameer , Bednarczyk Robert A. , Freeman Matthew C. ,   the Vaccine Exemplars Research Consortium
Published: January 2022

Introduction

The essential components of a vaccine delivery system are well-documented, but robust evidence on how and why the related processes and implementation strategies drive catalytic improvements in vaccination coverage are not well established. To address this gap, we identified critical success factors that may have led to substantial improvements in routine childhood immunization coverage in Nepal from 2000 through 2019.

Methods

We identified Nepal as an exemplar in the delivery of early childhood vaccines through analysis of DTP1 and DTP3 coverage data. Through interviews and focus group discussions at the national, regional, district, health post, and community level, we investigated factors that contributed to high and sustained vaccine coverage. We conducted a thematic analysis through application of implementation science frameworks to determine critical success factors. We triangulated these findings with quantitative analyses using publicly available data.

Results

The following success factors emerged: 1) Codification of health as a human right, along with other vaccine-specific legislation, ensured the stability of vaccination programming; 2) National and multi-national partnerships supported information sharing, division of labor, and mutual capacity building; 3) Pro-vaccine messaging through various mediums, which was tailored to local needs, generated public awareness; 4) Female Community Health Volunteers educated community members as trusted and compassionate neighbors; and 5) Cultural values fostered collective responsibility and community ownership of vaccine coverage.

Conclusion

This case study of Nepal suggests that the success of its national immunization program relied on the engagement and understanding of the beneficiaries. The immunization program was supported by consistent and reliable commitment, collaboration, awareness, and collective responsibility between the government, community, and partners. These networks are strengthened through a collective dedication to vaccination programming and a universal belief in health as a human right.
Collaborative research methods and best practice with children and young people: Protocol for a mixed-method review of the health and social sciences literature
Authors: Nowland R. , Robertson L. , Farrelly N. , Roy A. , Sharpe D. , Harris C. , Morocza N. , Larkins C.
Published: January 2022

Introduction

Children and young people have the right to participate in research on matters that affect them, and their contribution improves research quality and insights from findings. Discrete participatory approaches are used across different disciplines. This review will provide a synthesis of existing literature from different disciplines by working with young people and adults experienced in participatory research to develop a broad definition of child and youth led research and to identify best practice.

Methods and Analysis

Comprehensive searches will be conducted in eight electronic databases (PsycINFO, Medline, CINAHL, Embase, SocINDEX, ASSIA: Applied Social Sciences Index and Abstracts (Proquest), Social Care Online and SCOPUS). Grey literature reports will also be sourced using Google searching. Eligible studies will be English language primary studies and reviews on collaborative research with children and young people (aged 5-25 years). Qualitative and quantitative data will be integrated in a single qualitative synthesis following the JBI convergent integrated approach. Study quality will be assessed by developed checklists based on existing participation tools co-created with the project steering group and co-creation activities with young people.

Ethics and Dissemination

Ethical approval is not required as no primary data will be collected. The review will develop guidance on best practice for collaborative research with children and young people, synthesising learnings from a wide variety of disciplines. Dissemination will be via peer-reviewed publications, presentations at academic conferences and lay summaries for various stakeholders. Opportunities for co-creation of outputs will be sought with the young researchers and the project steering committee.

PROSPERO registration number: CRD42021246378

Article Summary

Strengths and limitations of the study

First systematic review to synthesise findings across different approaches to collaborative research with children and young people

Research focus, questions and analysis framework have been co-designed with young researchers experienced in participatory research

Mixed method review methodology will enable an in-depth evidence synthesis across a disparate evidence base

Provides an interdisciplinary perspective on best practice for collaborative research with children and young people
An optimized method for the isolation of urinary extracellular vesicles for molecular phenotyping: detection of biomarkers for radiation exposure
Authors: Hinzman Charles P. , Jayatilake Meth , Bansal Sunil , Fish Brian L. , Li Yaoxiang , Zhang Yubo , Bansal Shivani , Girgis Michael , Iliuk Anton , Xu Xiao , Fernandez Jose A. , Griffin John H. , Ballew Elizabeth A , Unger Keith , Boerma Marjan , Medhora Meetha , Cheema Amrita K.
Published: January 2022

Background

Urinary extracellular vesicles (EVs) are a source of biomarkers with broad potential applications across clinical research, including monitoring radiation exposure. A key limitation to their implementation is minimal standardization in EV isolation and analytical analysis methods. Further, most urinary EV isolation protocols necessitate large volumes of sample. This study aimed to compare and optimize isolation and analytical methods for EVs from small volumes of urine.

Methods

3 EV isolation methods were compared: ultracentrifugation, magnetic bead-based, and size-exclusion chromatography from 0.5 mL or 1 mL of rat and human urine. EV yield and mass spectrometry signals (Q-ToF and Triple Quad) were evaluated from each method. Metabolomic profiling was performed on EVs isolated from the urine of rats exposed to ionizing radiation 1-, 14-, 30- or 90-days post-exposure, and human urine from patients receiving thoracic radiotherapy for the treatment of lung cancer pre- and post-treatment.

Results

Size-exclusion chromatography is the preferred method for EV isolation from 0.5 mL of urine. Mass spectrometry-based metabolomic analyses of EV cargo identified biochemical changes induced by radiation, including altered nucleotide, folate, and lipid metabolism. We have provided standard operating procedures for implementation of these methods in other laboratories.

Conclusions

We demonstrate that EVs can be isolated from small volumes of urine and analytically investigated for their biochemical contents to detect radiation induced metabolomic changes. These findings lay a groundwork to develop future methods to monitor response to radiotherapy and can be extended to an array of molecular phenotyping studies aimed at characterizing EV cargo.
Mapping SARS-CoV-2 antigenic relationships and serological responses
Authors: Wilks Samuel H. , Mühlemann Barbara , Shen Xiaoying , Türeli Sina , LeGresley Eric B. , Netzl Antonia , Caniza Miguela A. , Chacaltana-Huarcaya Jesus N. , Corman Victor M. , Daniell Xiaoju , Datto Michael B. , Dawood Fatimah S. , Denny Thomas N. , Drosten Christian , Fouchier Ron A. M. , Garcia Patricia J. , Halfmann Peter J. , Jassem Agatha , Jeworowski Lara M. , Jones Terry C. , Kawaoka Yoshihiro , Krammer Florian , McDanal Charlene , Pajon Rolando , Simon Viviana , Stockwell Melissa S. , Tang Haili , van Bakel Harm , Veguilla Vic , Webby Richard , Montefiori David C. , Smith Derek J.
Published: January 2022

During the SARS-CoV-2 pandemic, multiple variants escaping pre-existing immunity emerged, causing concerns about continued protection. Here, we use antigenic cartography to analyze patterns of cross-reactivity among a panel of 21 variants and 15 groups of human sera obtained following primary infection with 10 different variants or after mRNA-1273 or mRNA-1273.351 vaccination. We find antigenic differences among pre-Omicron variants caused by substitutions at spike protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and >3 months post-2nd dose. We find changes in immunodominance of different spike regions depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine strain selection.

One sentence summary:

Antigenic Cartography of SARS-CoV-2 variants reveals amino acid substitutions governing immune escape and immunodominance patterns.
From microbes to mammals: pond biodiversity homogenization across different land-use types in an agricultural landscape
Authors: Ionescu D. , Bizic M. , Karnatak R. , Musseau C. L. , Onandia G. , Kasada M. , Berger S.A. , Nejstgaard J.C. , Ryo M. , Lischeid G. , Gessner M. O. , Wollrab S. , Grossart H.-P.
Published: January 2022

Local biodiversity patterns are expected to strongly reflect variation in topography, land use, dispersal boundaries, nutrient supplies, contaminant spread, management practices and other anthropogenic influences. In contrast, studies focusing on specific taxa revealed a biodiversity homogenization effect in areas subjected to long-term intensive industrial agriculture. We investigated whether land use affects biodiversity and metacommunity structure in 67 kettle holes (KH) representing small aquatic islands embedded in the patchwork matrix of a largely agricultural landscape comprising grassland, forest, and arable fields. These KH, similar to millions of standing water bodies of glacial origin, spread across northern Europe, Asia, and North America, are physico-chemically diverse, differ in the degree of coupling with their surroundings. We assessed biodiversity patterns of eukaryotes, Bacteria and Archaea in relation to environmental features of the KH, using deep-amplicon-sequencing of eDNA. First, we asked whether deep sequencing of eDNA provides a representative picture of KH biodiversity across the three domains of life. Second, we investigated if and to what extent KH biodiversity is influenced by the surrounding land-use. Our data shows that deep eDNA amplicon sequencing is useful for in-depth assessments of cross-domain biodiversity comprising both micro- and macro-organisms, but, has limitations with respect to single-taxa conservation studies. Using this broad method, we show that sediment eDNA, integrating several years to decades, depicts the history of agricultural land-use intensification. The latter, coupled with landscape wide nutrient enrichment (including by atmospheric deposition), groundwater connectivity between KH and organismal movement in the tight network of ponds, resulted in a biodiversity homogenization in the KH water, levelling off today’s detectable differences in KH biodiversity between land-use types.
mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder
Authors: Gurgone Antonia , Pizzo Riccardo , Raspanti Alessandra , Chiantia Giuseppe , Devi Sunaina , Morello Noemi , Pilotto Federica , Gnavi Sara , Lupori Leonardo , Mazziotti Raffaele , Sagona Giulia , Putignano Elena , Nocentini Alessio , Supuran Claudiu T. , Marcantoni Andrea , Pizzorusso Tommaso , Giustetto Maurizio
Published: January 2022

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology.

To this aim, we studied metabotropic glutamate receptors 5 (mGluR5) for their important role in critical mechanisms involved in CDD, i.e.: synaptogenesis, dendritic spines formation/maturation and synaptic plasticity, and because mGluR5 function depends on the postsynaptic protein Homer1bc that is downregulated in the cerebral cortex of CDKL5−/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the strength of Homer1bc-mGluR5 binding, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators, i.e.: 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioural defects shown by CDKL5−/y mice. Notably, the cerebral cortex of 2 CDD patients show similar changes in the synaptic organization to mutant CDKL5 mice, including a reduced mGluR5 expression, suggesting that mGluR5 represent a promising therapeutic target for CDD patients.
Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT2creceptor-containing neurons
Authors: Flanigan M.E. , Hon O.J. , D’Ambrosio S. , Boyt K.M. , Hassanein L. , Castle M. , Haun H.L. , Pina M.M. , Kash T.L.
Published: January 2022

Serotonin 5HT2creceptors have been implicated in the pathophysiology of both mood disorders and alcohol use disorder, but the circuits mediating the effects of systemic pharmacological manipulations of this receptor on behavior have not been identified. Binge alcohol consumption induces discrete social and arousal disturbances in human populations, which are thought to promote increased drinking. However, whether models of binge drinking in rodents can induce these same long-term negative behavioral symptoms is unknown. In this study, we employed multiple anatomical, physiological, and behavioral approaches to identify two populations of neurons expressing serotonin 5HT2creceptors, one in the lateral habenula (LHb5HT2c) and one in the bed nucleus of the stria terminalis (BNST5HT2c), that display coordinatedin-vivoresponses to social, arousal, and alcohol-related stimuli and are physiologically modulated by binge alcohol consumption in a sex-specific manner. Critically, these physiological changes were associated with sex-specific behavioral disturbances that closely mirror social and arousal symptoms observed in humans during abstinence from binge drinking. Specifically, we observed that one week of abstinence from three weeks of binge alcohol drinking induced social recognition deficits in females and potentiated acoustic startle responses in males. While both populations of neurons (BNST and LHb) and the 5HT2creceptor itself contribute to the sex-specific effects of alcohol on social and arousal behaviors to some degree, the primary causal mechanism underlying these phenomena appears to be excessive activation of LHb5HT2cneurons. These findings may have implications for the development of sex-specific treatments for mood and alcohol use disorders targeting the brain’s serotonin system.
Curiosity and mesolimbic functional connectivity drive information seeking in real life
Authors: Eschmann Kathrin C. J. , Pereira Duarte F. M. M. , Valji Ashvanti , Dehmelt Vera , Gruber Matthias J.
Published: January 2022

Curiosity reflects the intrinsic motivation of an individual to seek information in order to close information gaps. Laboratory-based experiments have shown that both curiosity and information seeking are associated with enhanced neural dynamics in the mesolimbic dopaminergic circuit. However, it is unclear whether curiosity and its associated neural dynamics in the dopaminergic circuit drive information seeking in real life. The present study investigated (i) whether curiosity traits predict different characteristics of real-life information seeking and (ii) whether functional connectivity within the mesolimbic dopaminergic circuit is associated with information seeking outside of the laboratory. Up to 15 month before the COVID-19 pandemic, we conducted curiosity and anxiety questionnaires as well as a 10-minute resting-state fMRI session. In a follow-up survey early during the COVID-19 pandemic, participants repeated the questionnaires and filled out an additional questionnaire about their COVID-19-related information seeking. Curiosity but not anxiety remained stable over time. Individual differences in curiosity were positively associated with the frequency of information-seeking behaviour. Anxiety during the pandemic was not linked to any characteristics of real-life information seeking. Interestingly, the frequency of information seeking was also independently predicted by individual differences in resting-state functional connectivity between the ventral tegmental area and the nucleus accumbens. The present translational study paves the way for future studies on the role of curiosity in real-life information seeking by showing that curiosity drives information seeking in real-life situations and that the curiosity-promoting mesolimbic dopaminergic functional network supports the frequency of real-life information-seeking behaviour.

SIGNIFICANCE STATEMENT

Curiosity is a key driver of learning and information seeking in everyday life. However, the temporal stability of curiosity traits, their relationship to real-life information seeking, and the associated dopaminergic brain activity are poorly understood. The present study provides evidence that curiosity traits are stable over time – even through a major event, such as the COVID-19 pandemic – and that both curiosity and intrinsic functional connectivity within the mesolimbic dopaminergic circuit are associated with the frequency of real-life information seeking. These findings contribute to a better understanding of cognitive and neural differences that shape how individuals seek out information and may offer the opportunity to help individuals with suboptimal information-seeking behaviour that negatively affects their well-being or mental health.
A Chemical Mutagenesis Approach to Insert Post-Translational Modifications in Aggregation-Prone Proteins
Authors: Ge Ying , Masoura Athina , Yang Jingzhou , Aprile Francesco A.
Published: January 2022

Neurodegenerative diseases are a class of disorders linked to the formation in the nervous system of fibrillar protein aggregates called amyloids. This aggregation process is affected by a variety of post-translational modifications, whose specific mechanisms are not fully understood yet. Emerging chemical mutagenesis technology is currently striving to address the challenge of introducing protein post-translational modifications, while maintaining proteins stable and soluble during the modification reaction. Several amyloidogenic proteins are highly aggregation-prone, and current modification procedures lead to unexpected precipitation of these proteins, affecting their yield and downstream characterization. Here, we present a method for maintaining amyloidogenic proteins soluble during chemical mutagenesis. As proof-of-principle, we applied our method to mimic the phosphorylation of the serine 26 and the acetylation of the lysine 28 of the 40-residue long variant of amyloid-β peptide, whose aggregation is linked to Alzheimer’s disease.
A study of thermally-induced sex reversal in casque-headed lizards
Authors: Suárez-Varón Gabriel , Mendoza-Cruz Eva , Acosta Armando , Cruz Maricela Villagrán-Santa , Cortez Diego , Hernández-Gallegos Oswaldo
Published: January 2022

Non-avian reptiles, unlike mammals and birds, have undergone numerous sex determination turnovers. For example, casque-headed lizards replaced the ancestral XY system shared across pleurodonts with a new pair of XY chromosomes. However, the evolutionary forces that triggered this transition have remained unclear. An interesting evolutionary hypothesis suggests that species with intermediate states, with sex chromosomes but also thermal-induced sex reversal at specific incubation temperatures, could be more susceptible to sex determination turnovers. We contrasted genotypic data (presence/absence of the Y chromosome) against the histology of gonads of embryos from stages 35-37 incubated at various temperatures, including typical male-producing (26°C) and female-producing (32°C) temperatures. We observed perfect concordance between genotype and phenotype at all temperatures. However, analysis of transcriptomic data from embryos incubated at 26°C and 32°C identified transcript variants of the chromatin modifiers JARID2 and KDM6B that have been linked to temperature-dependent sex determination in other reptiles. Besides, our work reports for the first time to our knowledge the histology of gonads, including morphological changes, from stages 35-37 of development in the Corytophanidae family. We also observed that all embryos developed hemipenes, suggesting sex-linked developmental heterochrony.Our work tested the validity of a mixed sex determination system in the Corytophanidae family. We showed that XY chromosomes are dominant, however, our work supports the hypothesis of a conserved transcriptional response to incubation temperatures across non-avian reptiles that could be the reminiscence of an ancestral sex determination system.
Mechanodetection of neighbor plants elicits adaptive leaf movements through calcium dynamics
Authors: Pantazopoulou Chrysoula K. , Buti Sara , Nguyen Chi Tam , Oskam Lisa , Farmer Edward E. , Kajala Kaisa , Pierik Ronald
Published: January 2022

Plants detect their neighbors via various cues, including reflected light and touching of leaf tips, which elicit in upward leaf movement (hyponasty). It is currently unknown how touch is sensed and how the signal is transferred from the leaf tip to the petiole base that drives hyponasty. Here, we show that touch-induced hyponasty involves a signal transduction pathway that is distinct from light-mediated hyponasty. We found that mechanostimulation of the leaf tip upon touching causes cytosolic calcium ([Ca2+]cyt induction in leaf tip trichomes that spreads towards the petiole. Both perturbation of the calcium response and the absence of trichomes inhibit touch-induced hyponasty. Finally, using plant competition assays, we show that touch-induced hyponasty is adaptive in dense stands of Arabidopsis. We thus establish a novel, adaptive mechanism regulating hyponastic leaf movement in response to mechanostimulation by neighbors in dense vegetation.
Vagus nerve stimulation recruits the central cholinergic system to enhance perceptual learning
Authors: Martin Kathleen A. , Papadoyannis Eleni S. , Schiavo Jennifer K. , Fadaei Saba Shokat , Valencia Sofia Orrey , Temiz Nesibe Z. , McGinley Matthew J. , McCormick David A. , Froemke Robert C.
Published: January 2022

Perception can be refined by experience up to certain limits. It is unclear if perceptual limitations are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest the utility of peripheral nerve stimulation - specifically vagus nerve stimulation (VNS) - for altering neural activity and augmenting experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS occurring during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Using two-photon imaging, we identified changes to auditory cortical responses and activation of cortically-projecting cholinergic axons with VNS. Anatomical and optogenetic experiments indicated that VNS could enhance task performance via activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS, perhaps enabling further refinement of VNS methodology for clinical conditions.
A methodology for co-simulation-based optimization of biofabrication protocols
Authors: Giannantoni Leonardo , Bardini Roberta , Di Carlo Stefano
Published: January 2022

Biofabrication processes are complex and often unsatisfactory. Trial-and-error methods are costly and yield only incremental innovation, starting from sub-optimal and poorly represented existing processes. Although computational techniques might support efficient process design to find optimal process configurations, intelligent computational approaches must comprise biological complexity to provide meaningful insights. This paper proposes a novel co-simulation-based optimization methodology for the systematic design of protocols for cell culture and biofabrication. The proposed strategy integrates evolutionary computation and simulation for efficient design space exploration and assessment of candidate protocols. A generic library supports the modular and flexible composition of multiscale and multidomain co-simulation scenarios. The feasibility of the presented approach was demonstrated in the automatic generation of protocols for the biofabrication of an epithelial cell monolayer. The results are twofold. First, the prototype co-simulation library helps build flexible, loosely coupled simulation scenarios. Second, the in-silico experimentation on the use case shows that the proposed approach is a viable first step towards standard and automated design in biofabrication.