bluuebunny/crossref_metadata_2025 huggingface dataset:
Hybrid immunity from SARS-CoV-2 infection and vaccination in Canadian adults: cohort study
Authors: Brown Patrick E. , Fu Sze Hang , Newcombe Leslie , Tang Xuyang , Nagelkerke Nico , Birnboim H Chaim , Bansal Aiyush , Colwill Karen , Mailhot Geneviève , Delgado-Brand Melanie , Tursun Tulunay , Qi Freda , Gingras Anne-Claude , Slutsky Arthur S. , Pasic Maria D. , Companion Jeffrey , Bogoch Isaac I. , Morawski Ed , Lam Teresa , Reid Angus , Jha Prabhat ,   Ab-C Study Collaborators
Published: December 2023

Background

Few national-level studies have evaluated the impact of “hybrid” immunity (vaccination coupled with recovery from infection) from the Omicron variants of SARS-CoV-2.

Methods

From May 2020 to December 2022, we conducted serial assessments (each of ∼4000-9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test–confirmed infections and mailed self-collected dried blood spots to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels.

Results

Spike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than six months earlier, spike levels fell notably and continuously for the nine months post-vaccination. By contrast, among adults infected within six months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than six months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% CI 11-14%) before omicron to 78% (76-80%) by December 2022, equating to 25 million infected adults cumulatively. However, the COVID-19 weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity.

Conclusions

Strategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected dried blood spots are a practicable biological surveillance platform.

Funding

Funding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael’s Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.
Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy
Authors: Wang Hui , Chang Timothy S , Dombroski Beth A , Cheng Po-Liang , Patil Vishakha , Valiente-Banuet Leopoldo , Farrell Kurt , Mclean Catriona , Molina-Porcel Laura , Rajput Alex , De Deyn Peter Paul , Bastard Nathalie Le , Gearing Marla , Kaat Laura Donker , Van Swieten John C , Dopper Elise , Ghetti Bernardino F , Newell Kathy L , Troakes Claire , de Yébenes Justo G , Rábano-Gutierrez Alberto , Meller Tina , Oertel Wolfgang H , Respondek Gesine , Stamelou Maria , Arzberger Thomas , Roeber Sigrun , Müller Ulrich , Hopfner Franziska , Pastor Pau , Brice Alexis , Durr Alexandra , Ber Isabelle Le , Beach Thomas G , Serrano Geidy E , Hazrati Lili-Naz , Litvan Irene , Rademakers Rosa , Ross Owen A , Galasko Douglas , Boxer Adam L , Miller Bruce L , Seeley Willian W , Van Deerlin Vivanna M , Lee Edward B , White Charles L , Morris Huw , de Silva Rohan , Crary John F , Goate Alison M , Friedman Jeffrey S , Leung Yuk Yee , Coppola Giovanni , Naj Adam C , Wang Li-San ,   PSP genetics study group, Dickson Dennis W , Höglinger Günter U , Schellenberg Gerard D , Geschwind Daniel H , Lee Wan-Ping
Published: December 2023

Background

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).

Method

In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.

Results

Our analysis of common SNVs and indels confirmed known genetic loci atMAPT,MOBP, STX6,SLCO1A2,DUSP10, andSP1, and further uncovered novel signals inAPOE,FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed theAPOEε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association inZNF592and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, includingIGH,PCMT1,CYP2A13, andSMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P= 6.73×10-3) in PSP.

Conclusions

Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.
Stimulus-related modulation in the 1/f spectral slope suggests an impaired inhibition of irrelevant information in people with multiple sclerosis
Authors: Akbarian Fahimeh , Rossi Chiara , Costers Lars , D’hooghe Marie B , D’haeseleer Miguel , Nagels Guy , Van Schependom Jeroen
Published: December 2023

Background

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized by neuronal and synaptic loss, resulting in an imbalance of excitatory and inhibitory synaptic transmission. MS leads to cognitive impairment such as reduced information processing speed and impaired working memory (WM). Recent studies have suggested that the 1/f slope of EEG/MEG power spectra can be associated with the excitation/inhibition (E/I) balance. A normal E/I balance is crucial for normal information processing and working memory.

Methods

We analyzed magnetoencephalographic (MEG) recordings of 38 healthy control subjects and 79 people with multiple sclerosis (pwMS) while performing an n-back working task. We computed and compared the steepness of the 1/f spectral slope through the FOOOF algorithm in the time windows [-1 0] and [0 1] s peristimulus time for both target and distractor stimulus for each brain parcel and for different working memory loads (0-back, 1-back, 2-back).

Results

The spectral slope was significantly steeper after the stimulus onset and was correlated with reaction time. We also observed a steeper 1/f slope after distractor stimuli in healthy subjects compared to pwMS. Finally, we observed significant correlations between the 1/f spectral slope modulation and visuospatial working memory functioning in both healthy subjects and pwMS.

Conclusion

Our findings are consistent with an increased inhibition following stimulus onset. In pwMS, this increase is reduced, suggesting dysfunctional inhibition of irrelevant information. Finally, this impaired modulation is significantly associated with a pencil-paper test of visuospatial working memory.

Highlights

The flatter 1/f slope after distractor stimuli in people with multiple sclerosis (pwMS) compared to healthy subjects suggests a less pronounced inhibition of irrelevant information in pwMS.

The significantly flatter 1/f slope was observed in the left inferior dorsal prefrontal cortex of pwMS in both 1-back and 2-back conditions. This particular brain parcel is known for its key role in motor planning, and the maintenance of sustained attention and working memory and executive functions.

A steeper 1/f slope after target and distractor stimuli suggests an increase in inhibition following stimulus onset in both healthy controls (HCs) and people with MS (pwMS).

The 1/f slope modulation correlates with visuospatial working memory performance.
WITHDRAWN: Phylogenetic Analysis Detected Newly Identified Phylogroups in UropathogenicEscherichia coliIsolates in Iraq
Authors: Hamza Hiba J. , Al-Hasnawy Huda H. , Mohammad Layth Jasim , Judi Mohammed R. , Al-Shirifi Hider M.H. , Karimi Isaac , Yakhchalian Nima
Published: December 2023

Withdrawal Statement

medRxiv has withdrawn this manuscript as it was submitted and made public without the full consent of all the authors. Therefore, this work should not be cited as reference for the project. If you have any questions, please contact the corresponding author.
Air cleaners and respiratory infections in schools: A modeling study using epidemiological, environmental, and molecular data
Authors: Banholzer Nicolas , Jent Philipp , Bittel Pascal , Zürcher Kathrin , Furrer Lavinia , Bertschinger Simon , Weingartner Ernest , Ramette Alban , Egger Matthias , Hascher Tina , Fenner Lukas
Published: December 2023

Background

Using a multiple-measurement approach, we examined the real-world effectiveness of portable HEPA-air filtration devices (air cleaners) in a school setting.

Methods

We collected environmental (CO2, particle concentrations), epidemiological (absences related to respiratory infections), audio (coughing), and molecular data (bioaerosol and saliva samples) over seven weeks during winter 2022/2023 in two Swiss secondary school classes. Using a cross-over study design, we compared particle concentrations, coughing, and the risk of infection with vs without air cleaners.

Results

All 38 students (age 13−15 years) participated. With air cleaners, mean particle con-centration decreased by 77% (95% credible interval 63%−86%). There were no differences in CO2levels. Absences related to respiratory infections were 22 without vs 13 with air cleaners. Bayesian modeling suggested a reduced risk of infection, with a posterior probability of 91% and a relative risk of 0.73 (95% credible interval 0.44−1.18). Coughing also tended to be less frequent (posterior probability 93%). Molecular analysis detected mainly non-SARS-CoV-2 viruses in saliva (50/448 positive), but not in bioaerosols (2/105 positive) or HEPA-filters (4/160). The detection rate was similar with vs without air cleaners. Spatiotemporal analysis of positive saliva samples identified several likely transmissions.

Conclusions

Air cleaners improved air quality, showed a potential benefit in reducing respiratory infections, and were associated with less coughing. Airborne detection of non-SARS-CoV-2 viruses was rare, suggesting that these viruses may be more difficult to detect in the air. Future studies should examine the importance of close contact and long-range transmission, and the cost-effectiveness of using air cleaners.
Sudden shifts in expression after small-scale duplication in vertebrates and strong support for the ortholog conjecture
Authors: Begum Tina , Duchen Pablo , Bucao Christabel Floi , Robinson-Rechavi Marc
Published: December 2023

Gene duplication is a potential source of innovation, but the evolutionary dynamics of functional change are still poorly understood. Under the debated “ortholog conjecture”, most functional change and innovation is assumed to follow duplication. Testing the ortholog conjecture allows to better understand and characterize the way in which gene function evolves. Most models of functional evolution assume continuous change, an assumption which we challenge here. We have applied a Lévy model of evolutionary trait jumps to the evolution of gene expression in vertebrates, with a special focus on duplication in teleost fishes. We show for the first time that trait jumps strongly affects paralogs, in addition to other modes of functional evolution. We find that at least 25% of teleost fish small-scale duplicates follow a rapid evolutionary rate shift model for both expression level and tissue-specificity, much more than after speciations. However, genome-wide duplicates (ohnologs) do not support such a trait jump model, and thus follow a different evolutionary dynamic. While there is some evidence for more positive selection at the protein-coding level after duplication, it is not strongly linked to jumps in expression. Finally, both small-scale paralogs and ohnologs strongly support the ortholog conjecture by contrasting speciation branches pre- and post-duplication to the duplication branches themselves, with trait jumps explaining much of the higher phylogenetic independent contrasts between small-scale paralogs.

Significance statement

The debate on the ortholog conjecture, i.e. that gene function changes little between orthologs but changes frequently between paralogs, provides a framework to understand better the evolution of gene function. Here we add two pieces to the puzzle: a novel way to use phylogenetic contrasts to test the ortholog conjecture, by comparing not only duplication to speciation, but speciation according to whether they were preceded by a duplication; and a model of jumps rather than continuous change of gene function. We tested these on vertebrates, with emphasis on teleost fishes, distinguishing small-scale duplications and whole-genome duplication; in all cases we support strongly the ortholog conjecture. We find that trait jumps strongly affect small-scale paralogs but not genome duplication paralogs, providing an exciting new model for gene function evolution.
Time-resolved transcriptomics reveal a mechanism of host niche defense: beneficial root endophytes deploy a host-protective antimicrobial GH18-CBM5 chitinase
Authors: Eichfeld Ruben , Mahdi Lisa K. , De Quattro Concetta , Armbruster Laura , Endeshaw Asmamaw B. , Miyauchi Shingo , Hellmann Margareta J. , Cord-Landwehr Stefan , Grigoriev Igor , Peterson Daniel , Singan Vasanth , Lail Kathleen , Savage Emily , Ng Vivian , Langen Gregor , Moerschbacher Bruno , Zuccaro Alga
Published: December 2023

Associations between plants and beneficial root-endophytic fungi enhance plant performance by improving nutrient uptake, abiotic stress tolerance and disease resistance. To successfully colonize different host plants and defend their host niche against competing microbes, but also to cooperate with beneficial bacterial members of the microbiota, root endophytes such as Sebacinales secrete a multitude of tightly regulated effector-proteins and carbohydrate-active enzymes. However, the functions, specificity, and regulation of these proteins remain poorly understood. In this study, we employ time-resolved transcriptomics to analyse the gene expression profiles of two Sebacinales members interacting with organisms from different kingdoms of life. We identified crucial genes for plant colonization and intermicrobial competition, including a fungal GH18-CBM5 chitinase specifically upregulated in response to the phytopathogenic fungus Bipolaris sorokiniana. This chitinase protects the plant hosts against the pathogen, reducing fungal biomass and disease symptoms in barley and Arabidopsis thaliana. Our findings shed light on interaction partner specific gene expression in Sebacinales endophytes, with potential applications in enhancing plant health and resilience.
Mechanisms underpinning osteosarcoma genome complexity and evolution
Authors: Espejo Valle-Inclan Jose , De Noon Solange , Trevers Katherine , Elrick Hillary , Tanguy Melanie , Butters Thomas , Muyas Francesc , Amary Fernanda , Tirabosco Roberto , Giess Adam , Sosinky Alona , Elgar Greg , Flanagan Adrienne M , Cortes-Ciriano Isidro
Published: December 2023

Osteosarcoma is the most common primary cancer of bone with a peak incidence in children and young adults. Despite progress, the genomic aberrations underpinning osteosarcoma evolution remain poorly understood. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of tumours. Chromothripsis drives the acquisition of oncogenic mutations and generates highly unstable derivative chromosomes, the evolution of which drives clonal diversification and intra-tumour heterogeneity. In addition, we report a novel mechanism, loss-translocation-amplification (LTA) chromothripsis, which mediates rapid malignant transformation and punctuated evolution in about half of paediatric and adult high-grade osteosarcomas. Specifically, a single double-strand break triggers concomitant TP53 inactivation and segmental amplifications, often amplifying oncogenes to high copy numbers in extrachromosomal circular DNA elements through breakage-fusion-bridge cycles involving multiple chromosomes. LTA chromothripsis is detected at low frequency in soft-tissue sarcomas, but not in epithelial cancers, including those driven by TP53 mutation. Finally, we identify genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.
Task goals shape the relationship between decision and movement speed
Authors: Fievez Fanny , Cos Ignasi , Carsten Thomas , Derosiere Gerard , Zenon Alexandre , Duque Julie
Published: December 2023

The speed at which we move is linked to the speed at which we decide to make these movements. Yet, the principles guiding such relationship remain unclear: while some studies point towards a shared invigoration process boosting decision and movement speed jointly, others rather indicate a tradeoff between both levels of control, with slower movements accompanying faster decisions. Here, we aimed (1) at further investigating the existence of a shared invigoration process linking decision and movement and (2) at testing the hypothesis that such a link is masked when detrimental to the reward rate. To this aim, we tested 62 subjects who performed the tokens task in two experiments (separate sessions): Experiment 1 evaluated how changing decision speed affects movement speed while Experiment 2 assessed how changing movement speed affects decision speed. In the latter experiment, subjects were either encouraged to favor decision speed (fast decision group) or decision accuracy (slow decision group). Various mixed model analyses revealed a coregulation of decision (urgency) and movement speed in Experiment 1 and in the fast decision group of Experiment 2, but not in the slow decision group despite the fact that these same subjects displayed a coregulation effect in Experiment 1. Altogether, our findings support the idea that coregulation occurs as a default mode but that this form of control is diminished or supplanted by a tradeoff relationship, contingent on reward rate maximization. Drawing from these behavioral observations, we propose that multiple processes contribute to shaping the speed of decisions and movements.
Fluoxetine treatment during postnatal and juvenile temporal epochs evokes diametrically opposing changes in anxio-depressive behaviors, gene expression, mitochondrial function, and neuronal architecture in the medial prefrontal cortex
Authors: Ghai Utkarsha , Chachra Parul , Fanibunda Sashaina E. , Mendon Suchith , Bhaskaran Amogh , Sarkar Ambalika , Kukkemane Kowshik , Singh Vivek , Vaidya Vidita A.
Published: December 2023

Background

The selective serotonin reuptake inhibitor, fluoxetine is reported to evoke distinct effects on anxio-depressive behaviors based on the temporal window of administration. Here, we systematically addressed the influence of postnatal or juvenile fluoxetine treatment on anxio-depressive behavior, gene expression, mitochondrial biogenesis, and neuronal cytoarchitecture in adulthood.

Methods

Rat pups received postnatal fluoxetine (PNFlx) or juvenile fluoxetine (JFlx) treatment from postnatal day 2 (P2)-P21 or P28-48 respectively, and were assessed for changes in anxio-depressive behaviors, global gene expression, mitochondrial biogenesis/function, and dendritic cytoarchitecture in the medial prefrontal cortex (mPFC) in adulthood.

Results

PNFlx evoked long-lasting increases in anxio-depressive behaviors, whereas JFlx elicited persistent decreases in anxio-depressive behavior, accompanied by differential and minimally overlapping transcriptional changes in the mPFC in adulthood. We noted opposing changes in mitochondrial function and dendritic cytoarchitecture in the mPFC of PNFlx and JFlx animals, with a decline observed following PNFlx and an increase in response to JFlx treatment. Furthermore, the enhanced despair-like behavior in the PNFlx cohort was reversed by adult-onset treatment with nicotinamide, a precursor for NAD+which enhances mitochondrial bioenergetics.

Conclusions

Fluoxetine treatment in early postnatal versus juvenile windows evokes opposing and persistent effects on anxio-depressive behavior in adult male rats, along with differential effects on gene expression, mitochondrial function, and dendritic morphology in the mPFC. Collectively, our findings highlight two distinct temporal windows in which fluoxetine exposure programs starkly differing outcomes in mood-related behavior, and posits a role for altered bioenergetics within the mPFC in contributing to these distinctive changes in emotionality.
Single-molecule detection and super-resolution imaging with a portable and adaptable 3D-printed microscopy platform (Brick-MIC)
Authors: Moya Muñoz Gabriel G. , Brix Oliver , Klocke Philipp , Harris Paul D. , Luna Piedra Jorge R. , Wendler Nicolas D. , Lerner Eitan , Zijlstra Niels , Cordes Thorben
Published: December 2023

Over the past decades, single-molecule and super-resolution microscopy have advanced and represent essential tools for life science research. There is,however, a growing gap between the state-of-the-art and what is accessible to biologists, biochemists, medical researchers or labs with financial constraints. To bridge this gap, we introduce Brick-MIC, a versatile and affordable open-source 3D-printed micro-spectroscopy and imaging platform. Brick-MIC enables the integration of various fluorescence imaging techniques with single-molecule resolution within a single platform and exchange between different modalities within minutes. We here present variants of Brick-MIC that facilitate single-molecule fluorescence detection, fluorescence correlation spectroscopy and super-resolution imaging (STORM and PAINT). Detailed descriptions of the hardware and software components, as well as data analysis routines are provided, to allow non-optics specialist to operate their own Brick-MIC with minimal effort and investments. We foresee that our affordable, flexible, and open-source Brick-MIC platform will be a valuable tool for many laboratories worldwide.
Amygdala habituation during exposure is associated with failure to reduce phobic symptoms
Authors: Lor Cindy S. , Karner Alexander , Zhang Mengfan , Kostorz Kathrin , Sladky Ronald , Scharnowski Frank
Published: December 2023

Exposure therapy is an established treatment for anxiety disorders but the mechanisms underpinning its effectiveness remain unclear. Two theories offer contrasting perspectives: the traditional habituation model posits that a form of stimulus desensitization is required during exposure, while the inhibitory learning model emphasizes the formation of new non-fearful associations. Crucially, while the former may manifest as amygdala habituation, the latter may not. To distinguish between the two models, this study uses functional magnetic resonance imaging to examine the amygdala responses of spider-fearful participants during fear exposure. We hypothesized that intervention success might align with stable or even increased amygdala activation – an indicator of active engagement and re-learning as proposed by the inhibitory learning model. Conversely, decreasing amygdala activity might not be a sign of reduced fear memory as proposed by the habituation model, but could signal mental detachment, leading to suboptimal treatment outcomes. Our results corroborated our hypotheses: individuals with escalating amygdala responses during exposure exhibited better clinical progress, while those showing amygdala ‘habituation’ benefited less. Our results strengthen the case for the inhibitory learning model and highlight that therapy may not aim to diminish fear per se but rather to engage patients in active processing and association formation.
Identification of a Musashi2 translocation as a novel oncogene in myeloid leukemia
Authors: Spinler Kyle , Hamilton Michael , Bajaj Jeevisha , Shima Yutaka , Diaz Emily , Kritzik Marcie , Reya Tannishtha
Published: December 2023

Myeloid leukemias, diseases marked by aggressiveness and poor outcomes, are frequently triggered by oncogenic translocations. In the case of chronic myelogenous leukemia (CML) the BCR-ABL fusion initiates chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been transformative for CML, blast crisis CML remains relatively drug resistant. Here we show that MSI2-HOXA9, a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive diseasein vivowith decreased latency, increased lethality and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase Polrmt and augmenting mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first time that translocations involving the stem and developmental signal MSI2 can be oncogenic, and suggest that MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation across solid cancers.
The French flag problem revisited: Creating robust and tunable axial patterns without global signaling
Authors: Kremser Stephan , Vercelli Gabriel , Gerland Ulrich
Published: December 2023

Wolpert’s French flag problem conceptualizes the task of forming axial patterns with broad regions in multicellular systems. Wolpert described two different solutions to his problem, the balancing model and thresholding of a morphogen gradient, both of which require global, long-range signaling between cells. Since global signaling becomes challenging in large multicellular systems, we computationally explore alternative solutions, which use only local cell-cell signaling and are simple enough to potentially be implemented in natural or synthetic systems. We employ cellular automata rules to describe local signal processing logics, and search for rules capable of robust and tunable axial patterning with evolutionary algorithms. This yields large sets of successful rules, which however display only few types of behavior. We introduce a rule alignment and consensus procedure to identify patterning modules that are responsible for the different behaviors. With these modules as building blocks, we then construct local schemes for axial patterning, which function also in the presence of noise and growth, and for patterns with a larger number of different regions. The regulatory logic underlying these modules could therefore serve as the basis for the design of synthetic patterning systems, and as a conceptual framework for the interpretation of biological mechanisms.
Whole-brain modelling supports the use of serotonergic psychedelics for the treatment of disorders of consciousness
Authors: Mindlin I , Herzog R , Belloli L , Manasova D , Monge-Asensio M , Vohryzek J. , Escrichs A. , Alnagger N , Núñez P , Kringelbach ML , Deco G , Tagliazucchi E , Naccache L , Rohaut B , Sitt JD , Sanz Perl Y
Published: December 2023

Disorders of consciousness (DoC) are a challenging and complex group of neurological conditions characterised by absent or impaired awareness. The current range of therapeutic options for DoC patients is limited, offering few non-invasive pharmacological alternatives. This situation has sprung a growing interest in the development of novel treatments, such as the proposal to study the efficacy of 5HT2A receptor agonists (also known as psychedelics) to restore impaired consciousness. Given the ethical implications of exploring novel compounds in non-communicative individuals, we assessed in silico their effects in the whole-brain dynamics of DoC patients. We embedded the whole-brain activity of patients in a low-dimensional space, and then used this representation to visualise the effects of simulated neuromodulation across a range of receptors representing potential drug targets. Our findings show that activation of serotonergic and opioid receptors shifted brain dynamics of DoC patients towards patterns typically seen in conscious and awake individuals, and that this effect was mediated by the brain-wide density of activated receptors. These results showcase the role of whole-brain models in the discovery of novel pharmacological treatments for neuropsychiatric conditions, while also supporting the feasibility of accelerating the recovery of consciousness with serotonergic psychedelics.
Hyperoxia Induced Alteration of Chromatin Structure in Bone Marrow Derived Primary Mesenchymal Stromal Cells
Authors: Monroe Lauren A. , Kaonis Samantha , Calahan Natalie , Kabi Neda , Ghosh Soham
Published: December 2023

Chromatin is a highly dynamic entity of the eukaryotic cell nucleus. New evidence is emerging in support of the notion that chromatin can locally and globally rearrange itself to adapt with the cellular microenvironmental changes. Such changes include oxidative stress such as supraphysiological oxygen level, found in hyperoxia. Although it is known that hyperoxia can result in DNA damage and alterations in cell function, it is not well understood how the chromatin architecture changes under such a condition and what the functional significance of such change entails. In this work we developed an imaging-based technique to visualize and characterize nanoscale chromatin remodeling under hyperoxia, created via hydrogen peroxide treatment. We found high spatiotemporal variability of remodeling in different chromatin domains such as the euchromatin, heterochromatin and interchromatin. Chromatin remodeling was hindered by the GSK126 mediated inhibition of methyltransferase EZH2, which regulates the chromatin compaction. Epigenetic modifications and DNA damage under hyperoxia was investigated, which was found affected by the pretreatment of GSK126. The developed techniques and findings inform us with new mechanistic insights of chromatin remodeling which might lead to new intervention strategies to target genotoxic hyper-oxidative stress, which is common in degenerative diseases and aging, and for cell therapy in regenerative medicine.
Common Ancestry of theIdLocus: Chromosomal Rearrangement and Polygenic Possibilities
Authors: Sharma Ashutosh , Vijay Nagarjun
Published: December 2023

The diversity in dermal pigmentation and plumage color among domestic chickens is striking, with Black Bone Chickens (BBC) particularly notable for their intense melanin hyperpigmentation. This unique trait is driven by a complex chromosomal rearrangement on chromosome 20 at theFmlocus, resulting in the overexpression of theEDN3(a gene central to melanocyte regulation). In contrast, the inhibition of dermal pigmentation is regulated by theIdlocus. Although prior studies using genetic crosses, GWAS, and gene expression analysis have investigated the genetic underpinnings of theIdlocus, its precise location and functional details remain elusive. Our study aims to precisely locate theIdlocus, identify associated chromosomal rearrangements and candidate genes influencing dermal pigmentation, and examine the ancestral status of theIdlocus in BBC breeds. Using public genomic data from BBC and non-BBC breeds, we refined theIdlocus to a ∼1.6 Mb region that co-localizes with Z amplicon repeat units at the distal end of the q-arm of chromosome Z within a 10.36 Mb inversion in Silkie BBC. Phylogenetic and population structure analyses reveal that theIdlocus shares a common ancestry across all BBC breeds, much like theFmlocus. Selection signatures and highly differentiated BBC-specific SNPs within theMTAPgene position it as the prime candidate for theIdlocus withCCDC112and additional genes, suggesting a possible polygenic nature. Our results suggest that theIdlocus is shared among BBC breeds and may function as a supergene cluster in shank and dermal pigmentation variation.
Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion
Authors: Diaz Basabe Angelica , Lattanzi Georgia , Perillo Federica , Amoroso Chiara , Baeri Alberto , Farini Andrea , Torrente Yvan , Penna Giuseppe , Rescigno Maria , Ghidini Michele , Cassinotti Elisa , Baldari Ludovica , Boni Luigi , Vecchi Maurizio , Caprioli Flavio , Facciotti Federica , Strati Francesco
Published: December 2023

The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). Porphyromonas gingivalis is a keystone oral pathogen associated with CRC. The oral pathobiont Fusobacterium nucleatum influences the anti-tumour functions of CRC-infiltrating iNKT cells. However, the impact of other oral bacteria, like P. gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumour microenvironment in CRC. Mechanistically, in vivo and in vitro experiments show that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery though increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing iNKT cells to upregulate CHI3L1, thus impairing iNKT cell cytotoxicity and promoting host tumour immune evasion.
C5aR Expression in Kidney Tubules, Macrophages and Fibrosis
Authors: Dunlap Carolyn , Zhao Niky , Ertl Linda S , Schall Thomas J , Sullivan Kathleen
Published: December 2023

The anaphylatoxin C5a and its receptor C5aR (CD88) are complement pathway effectors implicated in renal diseases, including ANCA-associated vasculitis. We investigated the kidney expression of C5aR and a second C5a receptor C5L2 by using immunohistochemistry and in situ hybridization on formalin-fixed, paraffin-embedded human and mouse kidney. C5aR was detected on interstitial macrophages and in multiple tubular regions, both distal and proximal; C5L2 had a similar expression pattern. The 5/6 nephrectomy model of chronic kidney injury exhibited increased C5aR expression by infiltrating cells within the fibrotic regions. Functional assessment of myeloid C5aR in vitro revealed that C5a induced the expression of chemokines and remodeling factors by macrophages, including CCL-3/-4/-7,-20, MMP-1/-3/-8/-12, and F3, and promoted survival by blocking neutrophil apoptosis. C5a activity was C5aR dependent, as demonstrated by reversal with the C5aR inhibitor avacopan. Collectively, these results suggest that myeloid C5aR may induce excessive inflammation in the kidney via immune cell recruitment, extracellular matrix destruction, and remodeling, resulting in fibrotic tissue deposition.
Investigation of Biomedical Cell Image Cryptography Based on RC4 Technique
Authors: Jiang Song , Kumar Ela
Published: December 2023

Enormous data permeates various facets of social life, including public administration, community services, and scientific research, owing to the advent of new technologies. With the escalation of data transportation concerns, its significance in our daily lives has magnified. Particularly in the medical field, preserving information integrity during data transit has become an urgent priority. For instance, safeguarding massive electronic medical files like MRI images from cyberattacks and data loss poses a formidable challenge. Encryption and decryption techniques are employed as a solution. While numerous image types have undergone testing using cryptography techniques, biomedical images have received limited attention. In this article, We implemented RC4, pixel shuffling, and steganography to encrypt and decrypt cell images. Evaluating the encryption and decryption performance of these cell images involved testing cell viability, live/dead ratio, and morphology.
Cyclo(Pro-Tyr) elicits conserved cellular damage in fungi by targeting the [H+]ATPase Pma1 in plasma membrane domains
Authors: Vela-Corcia David , Hierrezuelo Jesus , Perez-Lorente Alicia Isabel , Stincone Paolo , Pakkir Shah Abzer Kelminal , Grelard Axelle , de Vicente Antonio , Perez-Garcia Alejandro , Loquet Antoine , Petras Daniel , Romero Diego
Published: December 2023

Bioactive metabolites play a crucial role in shaping interactions among diverse organisms. In this study, we identified cyclo(Pro-Tyr), a metabolite produced by Bacillus velezensis, as a potent inhibitor of Botrytis cinerea and Caenorhabditis elegans, two potential cohabitant eukaryotic organisms. Based on our investigation, cyclo(Pro-Tyr) disrupts plasma membrane polarization, induces oxidative stress and increases membrane fluidity, which compromises fungal membrane integrity. These cytological and physiological changes induced by cyclo(Pro-Tyr) may be triggered by the destabilization of membrane microdomains containing the [H+]ATPase Pma1. In response to cyclo(Pro-Tyr) stress, fungal cells activate a transcriptomic and metabolomic response, which primarily involves lipid metabolism and Reactive Oxygen Species (ROS) detoxification, to mitigate membrane damage. This similar response occurs in the nematode C. elegans, suggesting that cyclo(Pro-Tyr) universally targets eukaryotic cellular membranes.
Identification of the potassium binding site in serotonin transporter SERT
Authors: Hellsberg Eva , Boytsov Danila , Chen Qingyang , Niello Marco , Freissmuth Michael , Rudnick Gary , Zhang Yuan-Wei , Sandtner Walter , Forrest Lucy Rachel
Published: December 2023

Clearance of serotonin (5-hydroxytryptamine, 5-HT) from the synaptic cleft after neuronal signaling is mediated by serotonin transporter SERT, which couples this process to the movement of a Na+ion down its chemical gradient. After release of 5-HT and Na+into the cytoplasm, the transporter faces a rate-limiting challenge of resetting its conformation to be primed again for 5-HT and Na+binding. Early studies of vesicles containing native SERT revealed that K+gradients can provide an additional driving force, via K+antiport. Moreover, under appropriate conditions, a H+ion can replace K+. Intracellular K+accelerates the resetting step. Structural studies of SERT have identified two binding sites for Na+ions, but the K+site remains enigmatic. Here, we show that K+antiport can drive substrate accumulation into vesicles containing SERT extracted from a heterologous expression system, allowing us to study the residues responsible for K+binding. To identify candidate binding residues, we examine many cation binding configurations using molecular dynamics simulations, predicting that K+binds to the so-called Na2+site. Site directed mutagenesis of residues in this site can eliminate the ability of both K+and H+to drive 5-HT accumulation into vesicles and, in patch clamp recordings, prevent the acceleration of turnover rates and the formation of a channel-like state by K+or H+. In conclusion, the Na2+site plays a pivotal role in orchestrating the sequential binding of Na+and then K+(or H+) ions to facilitate 5-HT uptake in SERT.
Calcyphosine is a microtubule-associated protein required for spindle formation and function
Authors: Setu Bipul , Nie Qian , Echele Grace , Spencer Susan A.
Published: December 2023

Calcyphosine (CAPS) is a highly conserved but little explored calcium-binding protein that shows elevated expression in many forms of human cancer. Here we uncover a role for CAPS in spindle formation during mitosis. Our experiments suggest that CAPS is a microtubule-binding, spindle-associated protein that helps create the kinetochore fibers that bind and segregate chromosomes. Knockdown of CAPS causes a variety of defects during mitosis, including uncongressed chromosomes and multi-polar spindles, as well as high levels of apoptosis and a reduced mitotic index. We find that CAPS promotes microtubule bundling, both in vitro and in cells, and knockdown of CAPS leads to reduction of thick k-fibers in the mitotic spindle. The high level of CAPS observed in many forms of cancer suggests that CAPS may promote cell proliferation, but our results indicate that CAPS overexpression has little effect on the cell cycle. This suggests that the high level of CAPS expression may be a consequence of cancer, rather than a driving force for cell proliferation.
Small-molecule degraders reduce Aβ production through CAPRIN1-mediated lysosomal degradation of APP in Alzheimer iPSC-derived neurons
Authors: Jung Sunghan , Jaiswal Nancy , Rai Ratan Kumar , Takagi Yuichiro , Lo Ho-Yin , Gao Cen , Zeng Lifan , Wang Xu , Wohlford Reagan K , Higgins Ryan , Bellail Anita C , Hao Chunhai
Published: December 2023

INTRODUCTION: The amyloid cascade of amyloid β (Aβ) production from amyloid precursor protein (APP) plays a key role in the pathogenesis of Alzheimer disease (AD). However, disease-modifying therapies to disrupt this amyloid cascade remain an unmet challenge. METHODS: Using neurons and organoids differentiated from induced pluripotent stem cells (iPSCs) derived from sporadic and familiar AD patients, we identified small-molecule degraders that reduce Aβ through screening of our library of cytoplasmic activation/proliferation-associate protein 1 (CAPRIN1)-targeted small-molecules. RESULTS: The small-molecule degraders act as molecular glues that bind CAPRIN1 and APP and enhance the protein-protein interaction. Tracking CAPRIN1 and APP in neurons revealed that the degraders induce CAPRIN1-mediated APP degradation through the endosomal-lysosomal pathway and thus reduce Abeta; peptide production in AD iPSC neurons and extracellular deposition in AD iPSC organoids. DISCUSSION: The small-molecule degraders provide new therapeutics through targeted protein degradation of APP and disruption of the amyloid cascade in AD brain.
Nucleocytoplasmic transport rates are regulated by cellular processes that modulate GTP availability
Authors: Scott Kelsey L. , Halfmann Charles T. , Hoefakker Allison D. , Purkayastha Purboja , Wang Ting Ching , Lele Tanmay P. , Roux Kyle J.
Published: December 2023

Nucleocytoplasmic transport (NCT), the facilitated diffusion of cargo molecules between the nucleus and cytoplasm through nuclear pore complexes (NPCs), enables numerous fundamental eukaryotic cellular processes. Ran GTPase uses cellular energy in the direct form of GTP to create a gradient across the nuclear envelope (NE) that drives the majority of NCT. We report here that changes in GTP availability resulting from altered cellular physiology modulate the rate of NCT, as monitored using synthetic and natural cargo, and the dynamics of Ran itself. Cell migration, cell spreading and/or modulation of the cytoskeleton or its connection to the nucleus alter GTP availability and thus rates of NCT, regulating RNA export and protein synthesis. These findings support a model in which changes in cellular physiology that alter GTP availability can regulate the rate of NCT, impacting fundamental cellular processes that extensively utilize NCT.

Changes in the availability of cellular GTP resulting from physiologically relevant processes, including cell migration and cell spreading, alter the rates of Ran-dependent nuclear import and export. Altered rates of nucleocytoplasmic transport regulate RNA localization and protein synthesis.
Chloroplast Genome Data ofTecticornia indica, a Hygrohalophytic C4 Plant Species
Authors: Sharpe Richard M. , Williamson-Benavides Bruce , Edwards Gerald E. , Dhingra Amit
Published: December 2023

Tecticornia indicais a hygrohalophytic, NAD-malic enzyme-type C4 plant species with near-aphyllous photosynthetic shoots. Total cellular DNA was extracted from the aphyllous shoots and branches ofTecticornia indicafor subsequent High Throughput Sequencing (HTS). Illumina HiSeq 2000 technology produced a total of 91,825,666 reads. Reads were trimmed and filtered to retain base calls corresponding to a 99.9% base call accuracy. Ade novoassembly produced 413,729 contigs and 45,238 scaffolds with a maximum length of 120,548 nucleotides, an N50of 881, and an average depth of coverage of 16.29 nucleotides. A subset of 2,196,299 reads were used for assembling the chloroplast genome at an average depth of coverage of 1,094 nucleotides. Sanger sequencing was performed to validate the LSC-IR-SSC junctions and to complete the missing regions of the chloroplast genome. The assembled chloroplast genome map andT. indicagenomic sequence is expected to facilitate genetics and genomic research focused on understanding function of genes involved in halophytic and drought tolerant traits.

SPECIFICATIONS TABLE

VALUE OF THE DATA

Genomic sequence information ofTecticornia indicaand its chloroplast map will be useful for genomics research.

Genomics and genetics scientists, bioinformatics and biotechnologists in the fields of photosynthesis, taxonomy and drought tolerance will benefit from these data.

These data can be used in developing molecular markers and quantitative trait loci in identification and selection of halophyte and drought tolerance, taxonomic resolution, and variables in photosynthetic genes.
Transcription promotes discrete long-range chromatin loops besides organizing cohesin-mediated DNA folding
Authors: Chapard Christophe , Bastié Nathalie , Cournac Axel , Gadal Olivier , Koszul Romain , Beckouët Frédéric
Published: December 2023

The multi-layered arrangement of eukaryotic genomes and chromosome spatial organization dynamics are of functional importance for gene expression, DNA replication and segregation. SMC complexes are essential instruments of chromosome folding by carrying out long range intra-chromatid DNA looping. Cohesin, in addition to tether sister chromatids, also ensures dynamic regulation of gene expression in mammals by promoting interaction between distal regulatory elements and promoters whereas transcription affects genome folding in numerous organisms and in multiple ways. Here, we comprehensively dissect the relative contributions of transcription and cohesin complexes, as well as their interplay, on the yeastS. cerevisiaegenome organization through DNA borders and loops. Transcription activation specifically induces appearance of DNA borders and loops, independently of SMC complexes, while also directly interfering in addition with cohesin-mediated loop expansion.