bluuebunny/crossref_metadata_2025 huggingface dataset:
Closure in the Visual Cortex: How do we sample?
Authors: Nisar Irfa , Elder James H.
Published: October 2023

Does the human visual system sample shapes at discrete points? During adaptation, when the neurons are fatigued, one observes the underlying principles that were once less prominent than the fatigued features. Operating under deficit, these less prominent features expose the original contributions from the fatigued neurons that are now absent. An underlying lower-order neural process is thus, now revealed. In this paper, we conduct experiments using a modified version of the circle-polygon illusion to reveal the brain’s sampling pattern. The circle-polygon illusion produces polygonal percepts during adaptation when a static dark outline circle is pulsed at 2 Hz alternating with a gradient luminance circle. We define sampling as the edge length of the emergent polygon. We develop a reconstruction function that defines the edge length based on psychophysical responses. We perform two experiments. In the first experiment, we present circles of size [2,4,8,16] deg presented at eccentricity [0,1,2,4,8] deg in a cross design. In the second experiment, we modify the method of Sakurai (2014) and display arc lengths that are 1/8, 1/4, 3/8, 1/2, 5/8, 3/4, 7/8 and 1 (whole) of a circle, of size 4 and 8 deg, presented centrally. The observers report the edge length. We find that the stimulus size and presentation eccentricity, taken together, best explain the edge length reported by the users. The users, as a random effect, do not influence the mean of the edge length reported when considering the best model reported (size and eccentricity together). However, the users do influence edge length reported only when using mean eccentricity or eccentricity as the parameter influencing edge length. Arc lengths of a circle produce the same or similar edge lengths. The length of the curve does not play a significant role signifying that biological neurophysiology at an eccentricity controls the edge length formation. Using the influences on edge length, we define sampling as a sum of qualitative influences and a sampling function derived from Taylors polynomial using sampling values along the eccentricity grid. As we use the sampled values directly to reconstruct the function, we remove the need for recording directly from neurons and instead rely on behavioural responses to build the reconstruction function.
Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer
Authors: Angarola Brittany L. , Sharma Siddhartha , Katiyar Neerja , Kang Hyeon Gu , Nehar-Belaid Djamel , Park SungHee , Gott Rachel , Eryilmaz Giray N. , LaBarge Mark A. , Palucka Karolina , Chuang Jeffrey H. , Korstanje Ron , Ucar Duygu , Anczukow Olga
Published: October 2023

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. We investigate how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory, or cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveal co-localization of aged immune and epithelial cellsin situ. Lastly, transcriptional signatures of aging mammary cells are found in human breast tumors, suggesting mechanistic links between aging and cancer. Together, these data uncover that epithelial, immune, and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment, and neoplasia risk.
Discovery of a locus associated with susceptibility to esca dieback in grapevine
Authors: Guillaume Arnold , Emilce Prado , Vincent Dumas , Gisèle Butterlin , Eric Duchêne , Komlan Avia , Didier Merdinoglu
Published: October 2023

Esca is the most destructive and predominant grapevine trunk diseases. The chronic infections and vine mortality caused by esca syndrome lead to huge economic losses and threatens the sustainability of vineyards worldwide. Although shown as associated with the presence of wood fungi, the etiology of esca remains still unclear and putatively involves multifactorial causes, which makes the development of effective control methods challenging. As differences in esca susceptibility had already been observed among grapevine varieties, we investigated in a biparental population the presence of genetic factors that can explain theses variations. Thanks to the destructive phenotyping of a 16-year-old vineyard plot, we discovered that the Gewurztraminer variety carries on chromosome 1 a locus linked to variations in trunk necrosis associated with esca, which we have namedENS1. Our study also suggests that there is a partial link between trunk vigor and necrosis due to esca. To our best knowledge,ENS1is the first instance of genetic factor identified as involved in the limitation of necrosis associated to grapevine esca. While the identification ofENS1alone may not provide a complete resolution of the esca issue, this discovery represents nonetheless a first step towards a genetic solution and paves the way for broader genetic investigations in the future.
Support Vector Machine based prediction models for drug repurposing and designing novel drugs for colorectal cancer
Authors: Sengupta Avik , Kumar Rahul
Published: October 2023

Colorectal cancer (CRC) has witnessed a concerning increase in incidence and poses a significant therapeutic challenge due to its poor prognosis. There is a pressing demand to identify novel drug therapies to combat CRC. In this study, we addressed this need by utilizing the library of CRC pharmacological profiles of anticancer drugs and developed QSAR models for prediction of alternative and promiscuous anti-cancer compounds for CRC treatment. Our QSAR models demonstrated their robustness by achieving high correlation of determination (R2) after 10-fold cross validation. For 12 CRC cell lines, R2ranges from 0.609-0.827. Highest performance was achieved for SW1417 and GP5d cell lines with R2, 0.827 and 0.786, respectively. Further, we listed the most common descriptors in the drug profiles of the CRC cell lines and we also checked the correlation of the descriptors with the drug activity. The KRFP314 fingerprint was the predominantly occurring descriptor, with the KRFPC314 fingerprint following closely in prevalence within the drug profiles of the CRC cell lines. Beyond predictive modeling, we also successfully validated drug-to-oncogene relationship viain-silicomethods and identified FDA-approved drugs which could be used as potential anti-CRC drugs, paving the way for subsequentin vitroorin vivoexperiments to validate their efficacy. To provide easy accessibility and utility of our research findings, we have incorporated these models into a free-to-use user-friendly prediction webserver named, “ColoRecPred” hosted on project.iith.ac.in/cgntlab/colorecpred. This web-based tool can be used to screen for potential anti-cancer compounds for CRC.
LAVASET: Latent Variable Stochastic Ensemble of Trees. A novel ensemble method for correlated datasets
Authors: Kasapi Melpomeni , Xu Kexin , Ebbels Timothy M.D. , O’Regan Declan P. , Ware James S. , Posma Joram M.
Published: October 2023

Motivation

Random Forests (RFs) can deal with a large number of variables, achieve reasonable prediction scores, and yield highly interpretable feature importance values. As such, RFs are appropriate models for feature selection and further dimension reduction (DR). However, RFs are often not appropriate for correlated datasets due to their mode of selecting individual features for splitting. Addressing correlation relationships in high dimensional datasets is imperative for reducing the number of variables that are assigned high importance, hence making the DR most efficient. Here, we propose the LAtent VAriable Stochastic Ensemble of Trees (LAVASET) method that derives latent variables based on the distance characteristics of each feature and aims to incorporate the correlation factor in the splitting step.

Results

Without compromising on performance in the majority of examples, LAVASET outperforms RF by accurately determining feature importance across all correlated variables and ensuring proper distribution of importance values. LAVASET yields mostly non-inferior prediction accuracies to traditional RFs when tested in simulated and real 1D datasets, as well as more complex and high-dimensional 3D datatypes. Unlike traditional RFs, LAVASET is unaffected by single ‘important’ noisy features (false positives), as it considers the local neighbourhood. LAVASET, therefore, highlights neighbourhoods of features, reflecting real signals that collectively impact the model’s predictive ability.

LAVASET is freely available as a standalone package fromhttps://github.com/melkasapi/LAVASET.
Effect of Soybean and Seaweed-based Diets on Growth Performance, Feed Utilization, and Gut Microbiota of Tilapia: A Systematic Review and Meta-analysis
Authors: Viagem Leonildo dos Anjo , Hakizimana Jean Nepomuscene , Rumisha Cyrus , Cerozi Brunno da Silva , Misinzo Gerald
Published: October 2023

Tilapia, a significant aquaculture species globally, relies heavily on feed for its production. While numerous studies have investigated the impact of soybean and seaweed-based diets on tilapia, a comprehensive understanding remains elusive. This review aimed at evaluating and synthesizing the existing literature on these diets’ effects, focusing on growth performance, feed utilization, and gut microbiota. A systematic search of databases was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a total of 57 studies were included in the qualitative analysis and 24 in the meta-analysis. The results indicated that soybean-based diets, at a 59.4% inclusion level improved the Specific Growth Rate (SGR) of tilapia with an effect size of -2.14 (95% CI: -2.92, -1.37;p< 0.00001;I2= 99%) and did not improve the feed conversion rate (FCR), as the effect size was 1.80 (95% CI: 0.72, 2.89;p= 0.001;I2= 100%). For seaweed-based diets, at a 15,9% inclusion level did not improve SGR, with an effect size of -0.74 (95% CI: -1.70, 0.22;p= 0.13;I2= 99%), and the FCR with an effect size of -0.70 (95% CI: -1.94, 0.54;p= 0.27;I2= 100%). Regarding the gut microbiota, was noted a lack of studies meeting the inclusion criteria for tilapia. However, findings from studies on other farmed fishes suggested that soybean and seaweed-based diets could have diverse effects on gut microbiota composition and promote the growth of beneficial microbiota. This study suggests that incorporating soybean-based diets at 59.4% inclusion can improve the SGR of tilapia. Seaweed-based diets, while not demonstrating improvement in the analyzed parameters with an inclusion level of 15.9%, have the potential to contribute to the sustainability of the aquaculture industry when incorporated at lower levels.
C-section and systemic inflammation synergize to disrupt the neonatal gut microbiota and brain development in a model of prematurity
Authors: Morin Cécile , Faure Flora , Guenoun David , Sautet Irvin , Diao Sihao , Faivre Valérie , Hua Jennifer , Schwendimann Leslie , Mokhtari Amazigh , Martin Rebeca , Chadi Sead , Demené Charlie , Delahaye-Duriez Andrée , Diaz-Heijtz Rochellys , Fleiss Bobbi , Matrot Boris , Auger Sandrine , Tanter Mickael , Van Steenwinckel Juliette , Gressens Pierre , Bokobza Cindy
Published: October 2023

Infants born very preterm (below 28 weeks of gestation) are at high risk of developing neurodevelopmental disorders, such as intellectual deficiency, autism spectrum disorders, and attention deficit. Preterm birth often occurs in the context of perinatal systemic inflammation due to chorioamnionitis and postnatal sepsis (Dammann, O. and Leviton, A.,Intermittent or sustained systemic inflammation and the preterm brain. Pediatr Res, 2014.75(3): p. 376-80). In addition, C-section is often performed for very preterm neonates to avoid hypoxia during a vaginal delivery (Luca, A.,et al.,Birth trauma in preterm spontaneous vaginal and cesarean section deliveries: A 10-years retrospective study.PloS one,2022, 17(10), e0275726.) We have developed and characterized a mouse model based on intraperitoneal injections of IL-1β between postnatal days one and five to reproduce perinatal systemic inflammation (Favrais, G.,et al.,Systemic inflammation disrupts the developmental program of white matter.Ann Neurol,2011.70(4): p. 550-65). This model replicates several neuropathological, brain imaging, and behavioral deficits observed in preterm infants. We hypothesized that C-sections could synergize with systemic inflammation to induce more severe brain abnormalities. We observed that C-sections significantly exacerbated the deleterious effects of IL-1β on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced functional connectivity in the brain relative to vaginal delivery plus intraperitoneal saline. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation on brain maldevelopment and malfunction, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders.

Significance Statement

In a well-established mouse model of the encephalopathy of prematurity, we observed that C-section exacerbates the deleterious effects of neonatal systemic inflammation (intraperitoneal injections of IL-1β between postnatal days one and five) on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced brain functional connectivity. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders.
Identification of NanoLuciferase Substrates Transported by Human ABCB1 and ABCG2 and their Zebrafish Homologs at the Blood-Brain Barrier
Authors: Inglut Collin T. , Quinlan John A. , Robey Robert W. , Thomas Joanna R. , Walker Joel R. , Zhou Wenhui , Huang Huang-Chiao , Gottesman Michael M.
Published: October 2023

ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier (BBB) impede delivery of therapeutic agents to the brain, including agents to treat neurodegenerative diseases and primary and metastatic brain cancers. Two transporters, P-glycoprotein (P-gp, ABCB1) and ABCG2, are highly expressed at the BBB and are responsible for the efflux of numerous clinically useful chemotherapeutic agents, including irinotecan, paclitaxel, and doxorubicin. Based on a previous mouse model, we have generated transgenic zebrafish in which expression of NanoLuciferase (NanoLuc) is controlled by the promoter of glial fibrillary acidic protein, leading to expression in zebrafish glia. To identify agents that disrupt the BBB, including inhibitors of ABCB1 and ABCG2, we identified NanoLuc substrates that are also transported by P-gp, ABCG2, and their zebrafish homologs. These substrates will elevate the amount of bioluminescent light produced in the transgenic zebrafish with BBB disruption. We transfected HEK293 cells with NanoLuc and either human ABCB1, ABCG2, or their zebrafish homologs Abcb4 or Abcg2a, respectively, and expressed at the zebrafish BBB. We evaluated the luminescence of ten NanoLuc substrates, then screened the eight brightest to determine which are most efficiently effluxed by the ABC transporters. We identified one substrate efficiently pumped out by ABCB1, two by Abcb4, six by ABCG2, and four by Abcg2a. These data will aid in the development of a transgenic zebrafish model of the BBB to identify novel BBB disruptors and should prove useful in the development of other animal models that use NanoLuc as a reporter.

Significance Statement

The ATP-Binding Cassette (ABC) transporters ABCB1 and ABCG2 at the blood-brain barrier (BBB) hinder pharmacological treatment of brain-related diseases. Consequently, there is a need for tools to identify BBB disruptors. We conducted a screen of ten NanoLuciferase substrates, identifying the brightest and those that were transported by human and zebrafish ABC transporters at the BBB. This work supports and complements our development of a transgenic zebrafish model, in which NanoLuciferase is expressed within glial cells, enabling detection of BBB disruption.
Insect Pollinators: The Time is Now for Identifying Species of Greatest Conservation Need
Authors: deMaynadier Phillip , Schlesinger Matthew D. , Hardy Spencer P. , McFarland Kent P. , Saucier Laura , White Erin L. , Zarrillo Tracy A. , Young Bruce E.
Published: October 2023

Severe declines in the abundance of insects, including economically and ecologically important pollinators are alarming conservationists and the public. Yet despite these increasingly well documented declines, relatively few pollinating insects other than some butterflies and bumble bees have appeared as Species of Greatest Conservation Need (SGCN) in State Wildlife Action Plans, decadal-scale blueprints for wildlife conservation efforts across the United States that require updating in 2025. Species absent from SGCN lists are ineligible for congressionally appropriated State Wildlife Grants that direct millions of dollars annually for their conservation. In the past, knowledge about the distribution and abundance of many insect pollinators was too poor to identify those meeting state guidelines for inclusion as SGCN. Using case studies from 4 northeastern states, we demonstrate that sufficient conservation status data now exists for many pollinators, including bees, butterflies, moths, beetles, and flower flies, to identify at-risk species meriting inclusion on SGCN lists in many states. Doing so will increase funding available for surveys, habitat protection and enhancement, and other conservation activities that will benefit this vitally important guild.
Origins and Evolution of NovelBacteroidesin Captive Apes
Authors: Nishida Alexandra H. , Ochman Howard
Published: October 2023

Bacterial strains evolve in response to the gut environment of their hosts, with genomic changes that influence their interactions with hosts as well as with other members of the gut community. Great apes in captivity have acquired strains ofBacteroides xylanisolvens, which are common within gut microbiome of humans but not typically found other apes, thereby enabling characterization of strain evolution following colonization. Here, we isolate, sequence and reconstruct the history of gene gain and loss events in numerous captive-ape-associated strains since their divergence from their closest human-associated strains. We show that multiple captive-ape-associatedB. xylanisolvenslineages have independently acquired gene complexes that encode functions related to host mucin metabolism. Our results support the finding of high genome fluidity inBacteroides, in that several strains, in moving from humans to captive apes, have rapidly gained large genomic regions that augment metabolic properties not previously present in their relatives.

Significance statement

Chronicling the changes that occur in bacterial genomes after a host-switch event is normally difficult due to age of most bacteria-host associations, which renders uncertainties about the bacterial ancestor (and ancestral genome) prior to colonization of the new host. However, the gut microbiomes of great apes in captivity contain bacterial strains that are unique to humans, allowing fine-scale assessment and reconstruction of the genomic changes that follow colonization. By sequencing and comparing closely related strains ofBacteroidesthat are restricted both to human and to captive great apes, we found that multiple bacterial lineages convergently acquired sets of genes involved in the metabolism of dietary polysaccharides. These results show that over relatively short timescales, the incorporation of strains into microbiomes involves large-scale genomic events that correspond to characteristics of the new host environment.
Experimental exposure to winter thaws reveals tipping point in yellow birch bud mortality and phenology in the northern temperate forest of Québec, Canada
Authors: Marquis Benjamin , Lajoie Geneviève
Published: October 2023

Climate change is expected to increase the frequency and intensity of winter thaws, which could have two contrasting effects on leaf phenology. Phenology could either be advanced through the acceleration of forcing accumulation or chilling completion, or be postponed through a reduction in chilling associated with warming air temperature. We tested the influence of winter thaws on budburst phenology by exposing 300 tree cuttings of sugar maple and yellow birch trees to five different frequencies and durations of winter thaws in the lab. In spring, half of the cuttings were exposed to air temperature in two cities representing an air temperature gradient of + 2.0 °C to mimic the ongoing climate warming and bud phenology was monitored three times a week. Irrespective of thaw treatment, yellow birch phenology occurred earlier in the warmer city, showing the importance of spring temperature in triggering budburst. The treatment with the highest frequency and duration of thawing increased bud mortality and delayed the onset of spring phenology whereas low frequency treatments did not, thereby identifying a tipping point in the impact of winter thaws on bud phenology. Past this point, winter thaws could slow the acceleration of bud phenology induced by warmer spring temperature and limit carbon uptake by delaying the closure of the canopy. Climate change simulations projected by the CMIP6 Canadian downscaled climate scenario show that winter thaws will increase in frequency. Hence the expected advance in the spring phenology associated with warmer spring is not necessarily as straightforward as previously thought.

Graphical abstract
Cell Chirality of Micropatterned Endometrial Microvascular Endothelial Cells
Authors: Zambuto Samantha G. , Jain Ishita , Theriault Hannah S. , Underhill Gregory H. , Harley Brendan A.C.
Published: October 2023

Chirality is an intrinsic cellular property that describes cell polarization biases along the left-right axis, apicobasal axis, or front-rear axes. Cell chirality plays a significant role in the arrangement of organs in the body as well as the orientation of organelles, cytoskeletons, and cells. Vascular networks within the endometrium, the mucosal inner lining of the uterus, commonly display spiral architectures that rapidly form across the menstrual cycle. Herein, we systematically examine the role of endometrial-relevant extracellular matrix stiffness, composition, and soluble signals on endometrial endothelial cell chirality using a high-throughput microarray. Endometrial endothelial cells display marked patterns of chirality as individual cells and as cohorts in response to substrate stiffness and environmental cues. Vascular networks formed from endometrial endothelial cells also display shifts in chirality as a function of exogenous hormones. Changes in cellular-scale chirality correlate with changes in vascular network parameters, suggesting a critical role for cellular chirality in directing endometrial vessel network organization.
Meta-Analysis Reveals That Explore-Exploit Decisions are Dissociable by Activation in the Dorsal Lateral Prefrontal Cortex, Anterior Insula, and the Anterior Cingulate Cortex
Authors: Sazhin Daniel , Dachs Abraham , Smith David V.
Published: October 2023

Explore-exploit research faces challenges in generalizability due to a limited theoretical basis for exploration and exploitation. Neuroimaging can help identify whether explore-exploit decisions involve an opponent processing system to address this issue. Thus, we conducted a coordinate-based meta-analysis (N=23 studies) finding activation in the dorsal lateral prefrontal cortex, anterior insula, and anterior cingulate cortex during exploration versus exploitation, which provides some evidence for opponent processing. However, the conjunction of explore-exploit decisions was associated with activation in the dorsal anterior cingulate cortex and dorsal medial prefrontal cortex, suggesting that these brain regions do not engage in opponent processing. Furthermore, exploratory analyses revealed heterogeneity in brain responses between task types during exploration and exploitation respectively. Coupled with results suggesting that activation during exploration and exploitation decisions is generally more similar than it is different suggests, there remain significant challenges in characterizing explore-exploit decision making. Nonetheless, dlPFC, AI, and ACC activation differentiate explore and exploit decisions and identifying these responses can aid in targeted interventions aimed at manipulating these decisions.
CONE: COntext-specific Network Embedding via Contextualized Graph Attention
Authors: Liu Renming , Yuan Hao , Johnson Kayla A , Krishnan Arjun
Published: October 2023

Human gene interaction networks, commonly known as interactomes, encode genes’ functional relationships, which are invaluable knowledge for translational medical research and the mechanistic understanding of complex human diseases. Meanwhile, the advancement of network embedding techniques has inspired recent efforts to identify novel human disease-associated genes using canonical interac-tome embeddings. However, one pivotal challenge that persists stems from the fact that many complex diseases manifest in specific biological contexts, such as tissues or cell types, and many existing interactomes do not encapsulate such information. Here, we propose CONE3, a versatile approach to generate context-specific embeddings from a context-free interactome. The core component of CONE consists of a graph attention network with contextual conditioning, and it is trained in a noise contrastive fashion using contextualized interactome random walks localized around contextual genes. We demonstrate the strong performance of CONE embeddings in identifying disease-associated genes when using known associated biological contexts to the diseases. Furthermore, our approach offers insights into understanding the biological contexts associated with human diseases.
Evaluation of the cross reactivity of neutralising antibody response in vaccinated human and convalescent hamster sera against SARS-CoV-2 variants up to and including JN.1 using an authentic virus neutralisation assay
Authors: Coombes Naomi S. , Bewley Kevin R. , Le Duff Yann , Alami-Rahmouni Nassim , Ryan Kathryn A. , Kempster Sarah , Ferguson Deborah , Davies Elizabeth R. , Weldon Thomas M. , Cross Eleanor S. , Smith Lauren , Norris Conner , Rogers-Broadway Karly Rai , Lewandowski Kuiama , Treagus Samantha , Everall Isobel , Pullan Steven T. , Hallis Bassam , Charlton Sue , Hall Yper , Funnell Simon G. P.
Published: October 2023

New vaccines, therapeutics and immunity elicited by natural infection create evolutionary pressure on SARS-CoV-2 to evolve and adapt to evade vaccine-induced and infection-elicited immunity. Vaccine and therapeutics developers thus find themselves in an “arms race” with the virus. The ongoing assessment of emerging SARS-CoV-2 variants remains essential as the global community transitions from an emergency response to a long-term management plan. Here, we describe how an authentic virus neutralisation assay using low passage clinical virus isolates has been employed to monitor resistance of emerging virus variants to neutralising antibodies from humans and experimentally infected hamsters. Sera and plasma from people who received three doses of a vaccine as well as those who received a bivalent booster were assessed against SARS-CoV-2 variants, up to and including JN.1. Contemporary or recent virus variants showed substantial resistance to neutralisation by antibodies from those who had received three doses of an ancestral vaccine but were still effectively neutralised by antibodies from individuals who had received a bivalent booster (ancestral/BA.1). In our recent studies, however, the JN.1 VOI was found to be significantly more resistant to neutralisation by antibodies from those who had received the ancestral/BA.1 bivalent boost. Convalescent sera from hamsters that had been experimentally infected with one of seven virus variants (ancestral, BA.1, BA.4, BA.5.2.1, XBB.1.5, XBB.1.16, XBB.2.3) were also tested here. The recent contemporary variant, BA.2.86, was effectively neutralised by sera from hamsters infected with XBB.1.5 and XBB.1.16 but it was not neutralised by sera from those infected with BA.5.2.1. These data support the recommendations given by the WHO that a new vaccine was required and should consist of an XBB sub-lineage antigen.
Parietal stimulation reverses age-related decline in exploration, learning, and decision-making
Authors: Hwang Eun Jung , Korde Sayli , Han Ying , Sambangi Jaydeep , Lian Bowen , Owusu-Ofori Ama , Diasamidze Megi , Wong Lea M. , Pickering Nadine , Begin Sam
Published: October 2023

Aging can compromise decision-making and learning, potentially due to reduced exploratory behaviors crucial for novel problem-solving. We posit that invigorating exploration could mitigate these declines. Supporting this hypothesis, we found that older mice mirrored human aging, displaying less exploration and learning during decision-making, but optogenetic stimulation of their posterior parietal cortex boosted initial exploration, subsequently improving learning. Thus, enhancing exploration-driven learning could be a key to countering cognitive aging.
Molecular dynamic investigation for ROCO-4 kinase inhibitor as treatment options for parkinsonism
Authors: Datta Kankana , Ravi Lokesh
Published: October 2023

Parkinson’s disease (PD) is a neurodegenerative condition that degenerates dopaminergic neurons and is characterized by motor disabilities like rigidity, bradykinesia, postural instability, and resting tremors. Although the etiology of PD remains uncertain, familial and sporadic forms of PD are known to be predominately caused by the G2019S mutation present in the kinase domain of LRRK2. Therefore, it might be possible to treat Parkinson’s by inhibiting the kinase action of the mutated LRRK2 protein. In order to find possible inhibitors, 3069 phytochemicals were examined for their ability to bind ROCO4 kinase, which has structural and functional similarities to the LRRK2 protein. Open-source bioinformatics tools were used to determine the binding affinities of phytochemicals to the native and mutant variants of the protein. Mongolicain-A exhibited high specificity and selectivity towards the G2019S mutation of the ROCO4 protein with -12.3 Kcal/mol binding affinity, whereas Bacoside-A displayed high affinity (11.4 Kcal/mol) for the target protein, but lacked specificity towards the mutant form of the protein. Based on molecular simulation studies., RMSD, RMSF, SASA, potential energy, and hydrogen bond analysis, it was suggested that Mongolicain-A may be an effective inhibitor of the G2019S mutation and a promising drug molecule to address PD.
Microfluidic antibody profiling after repeated SARS-CoV-2 vaccination links antibody affinity and concentration to impaired immunity and variant escape in patients on anti-CD-20 therapy
Authors: Priddey Ashley , Chen-Xu Michael Xin Hua , Cooper Daniel James , MacMillan Serena , Meisl Georg , Xu Catherine K , Hosmillo Myra , Goodfellow Ian G. , Kollyfas Rafael , Doffinger Rainer , Bradley John R , Mohorianu Irina I , Jones Rachel , Knowles Tuomas P.J. , Smith Rona , Kosmoliaptsis V
Published: October 2023

Background

Patients with autoimmune/inflammatory conditions on anti-CD20 therapies, such as Rituximab, have suboptimal humoral responses to vaccination and are vulnerable to poorer clinical outcomes following SARS-CoV-2 infection. We aimed to examine how the fundamental parameters of antibody responses, namely affinity and concentration, shape the quality of humoral immunity after vaccination in these patients.

Methods

We performed in depth antibody characterisation in sera collected four to six weeks after each of three vaccine doses to wild-type (WT) SARS-CoV-2 in Rituximab-treated primary vasculitis patients (n=14) using Luminex and pseudovirus neutralisation assays, whereas a novel microfluidic-based immunoassay was used to quantify polyclonal antibody affinity and concentration against both WT and Omicron (B.1.1.529) variants. Comparative antibody profiling was performed at equivalent time points in healthy individuals after three antigenic exposures to WT SARS-CoV-2 (one infection and two vaccinations; n=15) and in convalescent patients after WT SARS-CoV-2 infection (n=30).

Results

Rituximab-treated patients had lower antibody levels and neutralisation titres against both WT and Omicron SARS-CoV-2 variants compared to healthy individuals. Neutralisation capacity was weaker against Omicron versus WT both in Rituximab-treated patients and in healthy individuals. In the Rituximab cohort, this was driven by lower antibody affinity against Omicron versus WT (median [range] KD: 21.6 [9.7-38.8] nM vs 4.6 [2.3-44.8] nM, p=0.0004). By contrast, healthy individuals with hybrid immunity produced a broader antibody response, a subset of which recognised Omicron with higher affinity than antibodies in Rituximab-treated patients (median [range] KD: 1.05 [0.45-1.84] nM vs 20.25 [13.2-38.8] nM, p=0.0002), underpinning the stronger serum neutralisation capacity against Omicron in the former group. Rituximab-treated patients had similar anti-WT antibody levels and neutralisation titres to unvaccinated convalescent individuals, despite two more exposures to SARS-CoV-2 antigen. Temporal profiling of the antibody response showed evidence of affinity maturation in healthy convalescent patients after a single SARS-CoV-2 infection which was not observed in Rituximab-treated patients, despite repeated vaccination.

Discussion

Our results enrich previous observations of impaired humoral immune responses to SARS-CoV-2 in Rituximab-treated patients and highlight the significance of quantitative assessment of serum antibody affinity and concentration in monitoring anti-viral immunity, viral escape, and the evolution of the humoral response.
Missense mutations in Myc Box I influence MYC cellular localization, mRNA partitioning and turnover to promote leukemogenesis
Authors: Arthur Nancy BJ , Christensen Keegan A , Mannino Kathleen , Ruzinova Marianna B. , Kumar Ashutosh , Gruszczynska Agata , Day Ryan B. , Erdmann-Gilmore Petra , Mi Yiling , Sprung Robert , York Conner R. , Reid Townsend R , Spencer David H. , Sykes Stephen M. , Ferraro Francesca
Published: October 2023

Somatic missense mutations in the phosphodegron domain of theMYCgene (MYC Box I) are detected in the dominant clones of a subset of acute myeloid leukemia (AML) patients, but the mechanisms by which they contribute to AML are unknown. To unveil unique proprieties of MBI MYC mutant proteins, we systematically compared the cellular and molecular consequences of expressing similar oncogenic levels of wild type and MBI mutant MYC. We found that MBI MYC mutants can accelerate leukemia by driving unique transcriptional signatures in highly selected, myeloid progenitor subpopulations. Although these mutations increase MYC stability, they overall dampen MYC chromatin localization and lead to a cytoplasmic accumulation of the mutant proteins. This phenotype is coupled with increased translation of RNA binding proteins and nuclear export machinery, which results in altered RNA partitioning and accelerated decay of select transcripts encoding proapoptotic and proinflammatory genes. Heterozygous knockin mice harboring the germline MBI mutationMyc p.T73Nexhibit cytoplasmic MYC localization, myeloid progenitors’ expansion with similar transcriptional signatures to the overexpression model, and eventually develop hematological malignancies. This study uncovers that MBIMYCmutations alter MYC localization and disrupt mRNA subcellular distribution and turnover of select transcripts to accelerate tumor initiation and growth.
Hypothalamic control of noradrenergic neurons stabilizes sleep
Authors: Broglia Gianandrea , Corsi Giorgio , Bouvier Pierre-Hugues Prouvot , Vassalli Anne , Tafti Mehdi , Bandarabadi Mojtaba
Published: October 2023

Hypocretin/orexin neurons are essential to stabilize sleep, but the underlying mechanisms remain elusive. We report that hypocretin neurons of the perifornical hypothalamus are highly active during rapid eye movement sleep and show state-specific correlation with noradrenergic neurons. Deletion of hypocretin gene significantly increased periodic reactivations of locus coeruleus noradrenergic neurons during sleep and dysregulated their activity across transitions, suggesting a role for hypocretin neurons in mediating neuromodulation to stabilize sleep.
Body composition and blood pressure relationship among western-Kenya school children and adolescents
Authors: Magutah Karani , Mbuthia Grace Wambura , Meiring Rebecca M.
Published: October 2023

Kenyan studies relating body composition (BC) and blood pressure (BP) have focused on adults. Insight into this relationship among children and adolescents provides evidence for reduction of adulthood cardiovascular disease-risk development. We describe BC and BP correlation among Kenyan children and adolescents.

This cross-sectional study randomly sampled 389 school-going participants. Weight, height, BP, waist circumference (WC) and hip circumference were measured. Waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and body-mass-index (BMI) were calculated. Relationships between BP and WC, WHR, WHtR and BMI were determined.

Males and females were 14.7±2.9 and 14.4±2.5 years old, respectively. Secondary and primary schools’ males had SBP 119.1±10.3 mmHg and 107.4±13.7 mmHg; females 111.2±11.8 mmHg and 106.7±11.7 mmHg respectively. The DBP in secondary and primary schools’ males was 69.2±7.8 mmHg and 65.7±8.6mmHg, and, 69.6±7.9 mmHg and 68.1±7.4 mmHg for females. Higher BMI, WC, and WHtR correlated with higher SBP in both sexes (Pearson’s “R” +0.3 to +0.5; p<0.05). In females, DBP correlated with BMI, WC and WHtR, and only with WC for males. In all schools, only WC correlated with SBP in both sexes, BMI, WHR and WHtR correlating only among females. For males, BMI in primary and WHtR and WHR in secondary schools additionally correlated with SBP. For females, BMI and WHtR had correlations across school levels. For private and public schools, BMI, WC and WHtR had +0.2 to +0.6 correlations with SBP. The DBP correlated with WC and WHtR among private schools’ males, and, with WHtR and BMI in both school sets for females.

For both sexes, WC had strongest and WHR weakest correlation with SBP. Only in secondary school females did DBP correlate some BC variables. In both sexes, BMI, WC and WHtR all fairly correlated with SBP in private and public schools, WHR appearing least applicable in predicting Kenyan children and adolescents’ BP.
Synaptic plasticity in the medial preoptic area of male mice encodes social experiences with female and regulates behavior toward young
Authors: Ito Kazuki , Sato Keiichiro , Tsuneoka Yousuke , Maejima Takashi , Okuno Hiroyuki , Hamasaki Yumi , Murakawa Shunsaku , Takabayashi Yuzu , Yoshihara Chihiro , Shindo Sayaka , Uki Haruka , Herlitze Stefan , Seki Masahide , Suzuki Yutaka , Sakurai Takeshi , Kuroda Kumi O , Minami Masabumi , Amano Taiju
Published: October 2023

A dramatic shift from aggressive infanticidal to paternal behaviors is an essential event for male mice after mating. While the central part of the medial preoptic area (cMPOA) has been shown to critically mediate the paternal behaviors in mice, how this brain region becomes activated by mating and subsequent interaction with pups has not been investigated. Here, we demonstrate that the reduction in inhibitory synaptic strength towards the cMPOA provided by posterior-dorsal medial amygdala (MePD) neurons is a key event for the post-mating behavioral shift in males. Consistent with this, we found optogenetic disinhibition of MeCartptto the cMPOA synapses reduces male aggression towards pups. The cMPOA of paternal mice mediated pup-induced neural plastic changes in the bed nucleus of the stria terminalis. These findings provide possible functions of cMPOA neural circuits required for the reception to young in male mice.
Heterogeneous dual-metal control ofSalmonellainfection
Authors: Roche Béatrice , Cunrath Olivier , Bleck Christopher , Claudi Beatrice , Antelo Varela Minia , Li Jiagui , Bumann Dirk
Published: October 2023

Iron controls bacterial infections through diverse pathogen and host mechanisms that remain challenging to disentangle. Here, we determined how individualSalmonellacells access iron in infected mice. Our results showed that the iron transporter SLC11A1 restricted iron availability. However, manySalmonellabypassed this restriction by targeting macrophage endosomes that contained remnants of iron-rich red blood cells. These iron-replete bacteria dominated overallSalmonellagrowth and masked the relieve of iron-starved bacteria under iron overload. These data, combined with our previous discovery of magnesium deprivation as a primary mechanism for controllingSalmonella, reveal a heterogeneous dual-metal mechanism of nutritional immunity, and highlight the power of single-cell analyses under physiological in-vivo conditions to unravel complex anti-bacterial host mechanisms.

One sentence summary

Iron and magnesium limitations control distinctSalmonellasubsets during infection.
MUSE-XAE: MUtational Signature Extraction with eXplainable AutoEncoder enhances tumour type classification
Authors: Pancotti Corrado , Rollo Cesare , Birolo Giovanni , Fariselli Piero , Sanavia Tiziana
Published: October 2023

Mutational signatures are a critical component in deciphering the genetic alterations that underlie cancer development and have become a valuable resource for understanding the genomic changes that occur during tumorigenesis. In this paper, we present MUSE-XAE, a novel method for mutational signature extraction from cancer genomes using an explainable Auto-Encoder. Our approach employs a hybrid architecture consisting of a nonlinear encoder that can capture nonlinear interactions and a linear decoder, ensuring the interpretability of the active signatures in cancer genomes. We evaluated and compared MUSE-XAE with other available tools on synthetic and experimental cancer datasets and demonstrated that it achieves very accurate extraction capabilities while enhancing tumour-type classification. Our findings indicate that the use of Auto-Encoders is feasible and effective. This approach could facilitate further research in this area, with neural network-based models playing a critical role in advancing our understanding of cancer genomics
Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia
Authors: Boncompagni Gioia , Tatangelo Vanessa , Lopresti Ludovica , Ulivieri Cristina , Capitani Nagaja , Tangredi Carmela , Finetti Francesca , Marotta Giuseppe , Frezzato Federica , Visentin Andrea , Ciofini Sara , Gozzetti Alessandro , Bocchia Monica , Calzada-Fraile Diego , Cofreces Noa B. Martin , Trentin Livio , Patrussi Laura , Baldari Cosima T.
Published: October 2023

The tumor microenvironment (TME) plays a central role in the pathogenesis of chronic lymphocytic leukemia (CLL), contributing to disease progression and chemoresistance. Leukemic cells shape the TME into a pro-survival and immunosuppressive niche through contact-dependent and contact-independent interactions with the cellular components of the TME. Immune synapse (IS) formation is defective in CLL. Here we asked whether soluble factors released by CLL cells contribute to their protection from cytotoxic T cell (CTL)-mediated killing by interfering with this process. We found that healthy CTLs cultured in media conditioned by leukemic cells from CLL patients or Eμ-TCL1 mice upregulate the exhaustion marker PD-1 and become unable to form functional ISs and kill target cells. These defects were more pronounced when media were conditioned by leukemic cells lacking p66Shc, a proapoptotic adaptor whose deficiency has been implicated in disease aggressiveness both in CLL and in the Eμ-TCL1 mouse model. Multiplex ELISA assays showed that leukemic cells from Eμ-TCL1 mice secrete abnormally elevated amounts of CCL22, CCL24, IL-9 and IL-10, which are further upregulated in the absence of p66Shc. Among these, IL-9 and IL-10 were also overexpressed in leukemic cells from CLL patients, where they inversely correlated with residual p66Shc. Using neutralizing antibodies or the recombinant cytokines we show that IL-9, but not IL-10, mediates both the enhancement in PD-1 expression and the suppression of effector functions in healthy CTLs. Our results demonstrate that IL-9 secreted by leukemic cells negatively modulates the anti-tumor immune abilities of CTLs, highlighting a new suppressive mechanism and a novel potential therapeutical target in CLL.
Refined movement analysis in the Staircase test reveals differential motor deficits in mouse models of stroke
Authors: Skrobot Matej , Sa Rafael De , Walter Josefine , Vogt Arend , Paulat Raik , Lips Janet , Mosch Larissa , Mueller Susanne , Dominiak Sina , Sachdev Robert , Böhm-Sturm Philipp , Dirnagl Ulrich , Endres Matthias , Harms Christoph , Wenger Nikolaus
Published: October 2023

Accurate assessment of post-stroke deficits is vital in translational research. Recent advances in machine learning provide unprecedented precision in quantifying rodent motor behavior post-stroke. However, the extent to which these tools can detect lesion-specific upper extremity deficits remains unclear. Using proximal middle cerebral artery occlusion (MCAO) and cortical photothrombosis (PT), we assessed post-stroke impairments in mice through the Staircase test. Lesion locations were identified using 7T-MRI. Machine learning was applied to reconstruct kinematic trajectories usingMouseReach, a data-processing toolbox. This yielded 30 refined outcome parameters effectively capturing motor deficits. Lesion reconstructions located ischemic centers in the striatum (MCAO) and sensorimotor cortex (PT). Pellet retrieval was altered in both cases but did not correlate with stroke volume or ischemia extent. Instead, cortical ischemia was characterized by increased hand slips and modified reaching success. Striatal ischemia led to progressively prolonged reach durations, mirroring delayed symptom onset in basal ganglia strokes. In summary, refined machine learning-based movement analysis revealed specific deficits in mice after cortical and striatal ischemia. These findings emphasize the importance of thorough behavioral profiling in preclinical stroke research to increase translational validity of behavioral assessments.