bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving Structural Plausibility in 3D Molecule Generation via Property-Conditioned Training with Distorted Molecules
Authors: Vost Lucy , Chenthamarakshan Vijil , Das Payel , Deane Charlotte M.
Published: September 2024

Traditional drug design methods are costly and time-consuming due to their reliance on trial-and-error processes. As a result, computational methods, including diffusion models, designed for molecule generation tasks have gained significant traction. Despite their potential, they have faced criticism for producing physically implausible outputs. We alleviate this problem by conditionally training a diffusion model capable of generating molecules of varying and controllable levels of structural plausibility. This is achieved by adding distorted molecules to training datasets, and then annotating each molecule with a label representing the extent of its distortion, and hence its quality. By training the model to distinguish between favourable and unfavourable molecular conformations alongside the standard molecule generation training process, we can selectively sample molecules from the high-quality region of learned space, resulting in improvements in the validity of generated molecules. In addition to the standard two datasets used by molecule generation methods (QM9 and GEOM), we also test our method on a druglike dataset derived from ZINC. We use our conditional method with EDM, the first E(3) equivariant diffusion model for molecule generation, as well as two further models—a more recent diffusion model and a flow matching model—which were built off EDM. We demonstrate improvements in validity as assessed by RD-Kit parsability and the PoseBusters test suite; more broadly, though, our findings highlight the effectiveness of conditioning methods on low-quality data to improve the sampling of high-quality data.
Characterizing human CMV-specific CD8+T cells using multi-layer single-cell omics
Authors: Gemünd Ioanna , Bonaguro Lorenzo , Becker Matthias , Müller Sophie , Joos Clemens , De Domenico Elena , Aschenbrenner Anna C , Schultze Joachim L , Moosmann Andreas , Beyer Marc D
Published: September 2024

In this study we established a comprehensive workflow to collect multi-omics single-cell data using a commercially available micro-well based platform. This included whole transcriptome, cell surface markers (targeted sequencing-based cell surface proteomics), T cell specificities, adaptive immune receptor repertoire (AIRR) profiles and sample multiplexing. With this technique we identified novel paired T cell receptor sequences for three prominent human CMV epitopes. In addition, we review the ability of dCODE dextramers to detect antigen-specific T cells at low frequencies by estimating sensitivities and specificities when used as reagents for single-cell multi-omics.

Motivation

In this study, we report the first five-layer multi-omics dataset using the BD Rhapsody single-cell platform for the characterization of human antigen-specific T cells. Modalities include whole transcriptome, T cell receptor (TCR) sequences, T cell antigen specificity measured by dCODE dextramers, surface marker proteins and combinatorial sample multiplexing combining two distinct hashing approaches.
Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer’s disease
Authors: Davis Miyah R. , Robinson Edward , Koronyo Yosef , Salobrar-Garcia Elena , Rentsendorj Altan , Gaire Bhakta P. , Mirzaei Nazanin , Kayed Rakez , Sadun Alfredo A. , Ljubimov Alexander V. , Schneider Lon S. , Hawes Debra , Black Keith L. , Fuchs Dieu-Trang , Koronyo-Hamaoui Maya
Published: September 2024

Accumulation of pathological tau isoforms, especially hyperphosphorylated tau at serine 396 (pS396-tau) and tau oligomers, has been demonstrated in the retinas of patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Previous studies have noted a decrease in retinal ganglion cells (RGCs) in AD patients, but the presence and impact of pathological tau isoforms in RGCs and RGC integrity, particularly in early AD stages, have not been explored. To investigate this, we examined retinal superior temporal cross-sections from 25 patients with MCI (due to AD) or AD dementia and 16 cognitively normal (CN) controls, matched for age and gender. We utilized the RGC marker ribonucleic acid binding protein with multiple splicing (RBPMS) and Nissl staining to assess neuronal density in the ganglion cell layer (GCL). Our study found that hypertrophic RGCs containing pS396-tau and T22-positive tau oligomers were more frequently observed in MCI and AD patients compared to CN subjects. Quantitative analyses indicated a decline in RGC integrity, with 46-55% and 55-56% reductions of RBPMS+RGCs (P<0.01) and Nissl+GCL neurons (P<0.01-0.001), respectively, in MCI and AD patients. This decrease in RGC count was accompanied by increases in necroptotic-like morphology and the cleaved caspase-3 apoptotic marker in RGCs of AD patients. Furthermore, there was a 2.1 to 3.1-fold increase (P<0.05-0.0001) in pS396-tau-laden RGCs in MCI and AD patients, with a greater abundance observed in individuals with higher Braak stages (V-VI), more severe clinical dementia ratings (CDR=3), and lower mini-mental state examination (MMSE) scores. Strong correlations were noted between the decline in RGCs and the total amount of retinal pS396-tau and pS396-tau+RGCs, with pS396-tau+RGC counts correlating significantly with brain neurofibrillary tangle scores (r= 0.71, P= 0.0001), Braak stage (r= 0.65, P= 0.0009), and MMSE scores (r= -0.76, P= 0.0004). These findings suggest that retinal tauopathy, characterized by pS396-tau and oligomeric tau in hypertrophic RGCs, is associated with and may contribute to RGC degeneration in AD. Future research should validate these findings in larger cohorts and explore noninvasive retinal imaging techniques that target tau pathology in RGCs to improve AD detection and monitor disease progression.
CCR2 limits inflammatory functions of CD8 TRM cells that impair recognition memory during recovery from WNV encephalitis
Authors: Ai Shenjian , Arutyunov Artem , Liu Joshua , Hill Jeremy D. , Jiang Xiaoping , Klein Robyn S.
Published: September 2024

Central nervous system (CNS) resident memory CD8 T cells (TRM) that express IFN-γ contribute to neurodegenerative processes, including synapse loss, leading to memory impairments. Here, we show that CCR2 signalling in CD8 TRMthat persist within the hippocampus after recovery from CNS infection with West Nile virus (WNV) significantly prevents the development of memory impairments. Using CCR2-deficient mice, we determined that CCR2 expression is not essential for CNS T cell recruitment or virologic control during acute WNV infection. However, transcriptomic analyses of forebrain CCR2+versus CCR2-CD8 TRMduring WNV recovery reveal that CCR2 signalling significantly regulates hippocampal CD8 TRMphenotype and function via extrinsic and intrinsic effects, decreasing the expression of CD103 and granzyme A and IFN-γ, respectively. Consistent with this, WNV-recoveredCd8acreCcr2fl/flmice exhibit decreased recognition memory. Our findings highlight a neuroprotective role for CCR2 in limiting CD8 T cell-mediated neuroinflammation and cognitive deficits, providing insights into potential therapeutic targets for CNS infections.
Vapor pressure deficit dominates the spatiotemporal variations in ecosystem photosynthetic quantum yield
Authors: Yu Liyao , Luo Xiangzhong , Zhao Ruiying , Satriawan Tin W. , Tian Jiaqi
Published: September 2024

The quantum yield (α) of photosynthesis represents the maximum efficiency of light use as indicated by the initial slope of photosynthetic light response curves. Understandingαis crucial for accurate modeling of photosynthesis and terrestrial carbon cycle. Despite its importance, the spatial and temporal variations inαat large scales remain largely elusive.

We leveraged long-term eddy-covariance observations from 90 sites globally and examined the spatiotemporal variations inαdue to climatic drivers, using statistical and machine learning approaches.

We found significant spatial variability inαacross and within biomes, primarily driven by atmospheric vapor pressure deficit and soil moisture variations. Meanwhile, the temporal changes inαare mainly driven by the negative effect of vapor pressure deficit, which weakens the positive effects of elevated CO2and leaf area index.

Our results highlight the dominant role of vapor pressure deficit in controlling the spatiotemporal variations ofαas well as the unneglectable impacts of soil water content, CO2, and leaf area onα. Those new results provide insights for improving the representation ofαin ecosystem photosynthesis models.
Bolero: a dedicated workflow to decipher Hepatitis B virus transcriptome from long-reads sequencing method coupled to 5’RACE amplification of transcripts
Authors: Grand Xavier , Giraud Guillaume , Rifki Alia , Paturel Alexia , Bousquet Delphine , Roca Suarez Armando Andres , Bourgeois Cyril , Levrero Massimo , Zoulim Fabien , Testoni Barbara
Published: September 2024

Hepatitis B virus (HBV) represents a major health burden, as it affects close to 290 million people worldwide. Although prophylactic vaccines are available, current therapeutic compounds do not usually achieve HBV eradication due to the persistence of the covalently closed circular (ccc)DNA that serves as viral reservoir. Thus, novel biomarkers that reliably reflect intrahepatic cccDNA transcriptional activity would be highly relevant for the monitoring of infected individuals, as well as the evaluation of new treatments targeting HBV. In this context, the development of 5’ rapid amplification of complementary DNA ends (5’RACE) as a strategy to capture and amplify full-length HBV RNAs, coupled with long-read and full-length sequencing approaches (e.g., Oxford Nanopore Technology), has recently enabled the detailed characterization of these molecules. The analysis of such data requires a dedicated bioinformatics pipeline due to the highly condensed nature of the HBV genome, which is characterized by the production of multiple transcripts and spliced variants that overlap each other. Here, we present Bolero, a computational method and built-in workflow designed to handle HBV sequencing data and evaluate the relative expression of viral RNAs and their spliced variants. The analysis of HBV-infected cell lines demonstrates that our bioinformatics pipeline is efficient for the identification and quantification of individual HBV mRNAs. Thus, Bolero represents a useful tool to study cccDNA transcriptional activity and the heterogeneity of HBV RNA spliced variants.

Author summary

Transcriptomic analyses have brought comprehensive insights in the mechanisms controlling gene expression. Moreover, with the recent advances in sequencing technologies and computational methods, researchers can nowadays not only quantify gene expression, but also study alternative splicing, polyadenylation, transcription initiation, and even rare phenomena such as distant gene fusions. However, conventional analysis tools still rely heavily on the assumption of linear genomes with minimal overlap between open reading frames, rendering them insufficient for studying complex viruses such as hepatitis B virus (HBV).

Unlike typical linear genomes, HBV genome consists in a circular DNA molecule, which results in an extensive sequence overlap between its transcripts. To tackle these challenges, we developed an innovative approach coupling 5’ rapid amplification of complementary DNA ends (5’RACE) and long-read sequencing to comprehensively explore the HBV transcriptome. Furthermore, we developed Bolero, a computational method designed to handle the peculiarities of HBV sequencing data, which allows a detailed characterization of the HBV transcriptome.
Origin of Cellular Senescence in Ciliates
Authors: Mitteldorf Josh
Published: September 2024

Mixing and sharing of genes is essential for population diversity, which contributes to the resilience and, ultimately, the survival of animal and plant communities. However, sharing of genes is antithetical to individual fitness; hence gene mixing is threatened with extinction if selection rewards selfish (clonal) reproduction. To address this dilemma, mechanisms have evolved to enforce a mandate for gene sharing. In most metazoa, the functions of sex and reproduction are tightly entwined, presumably for the purpose of compelling the sharing of genes. In protists, the functions of sex (conjugation) and reproduction (amitosis) are separate. The mandate for gene sharing is enforced, instead, by a form of cellular senescence. Ciliates can reproduce clonally a few hundred times before they senesce and die. Conjugation resets their biological clock, restarting the cycle of clonal reproduction. The question how reproduction in metazoa came to be linked to sex has been explored in the past, but a fully satisfying account in terms of evolutionary ecology is lacking. The question how senescence in protozoa came to be linked to sex has not been addressed, and is the topic of the current study. I present herein two numerical simulations (IBMs) for the evolution of cellular senescence in ciliates. The results shed light not only on the evolution of senescence in higher life forms, but on more general questions concerning the plausibility of group selection.
The coevolution of encephalization and manual dexterity in hominins and other primates
Authors: Baker Joanna , Barton Robert A. , Venditti Chris
Published: September 2024

The human hand is one of our most remarkable features. We have long, opposable thumbs and a suite of other features argued to be adaptations for interacting with and manipulating our environment, literally extending the reach of our cognitive powers. Consequently, enhanced manipulative dexterity, tool use and increased brain size are considered key features of how our ancestors evolved. This hypothesis predicts that anatomical dexterity and brain size co-evolved, and that this should be evident in the morphology of the hand. To test this hypothesis and to understand how hominin evolution may have deviated from any general primate trend, we collected a dataset of finger length, thumb length, and brain size across 94 extinct and extant species of primates. Using phylogenetic comparative methods, we reveal a strong primate-wide association between brain size and relative thumb length. We further demonstrate that this general association accurately predicts the co-evolution of these traits in hominins. Whilst hominins have significantly long thumbs compared to other primates, we infer that they have arisen from the same underlying evolutionary process acting across the whole primate order: increasing manipulative ability associated with specialized neural control processes. The relationships we recover are consistent with positive feedback between manipulation, tool use and cognition and therefore may go some way towards explaining evolutionary trends towards larger brain sizes among primates, and particularly in hominins. Our results emphasize the role of manipulative abilities in cognitive evolution and emphasize how neural and bodily adaptations are interconnected.
The MAASWERP study: An international, comparative case study on measuring biomechanics of the aged murine aorta
Authors: Neutel Cédric H.G. , van der Laan Koen W.F. , Wesley Callan D. , Krüger Dustin N. , Pencheva Margarita G. , Schalkwijk Casper G. , De Meyer Guido R.Y. , Martinet Wim , Delhaas Tammo , Reesink Koen D. , Giudici Alessandro , Guns Pieter-Jan , Spronck Bart
Published: September 2024

Arterial stiffening is a hallmark of vascular ageing, and unravelling its underlying mechanisms has become a central theme in the field of cardiovascular disease. While various techniques and experimental setups are accessible for investigating biomechanics of blood vessels bothin vivoandex vivo, comparing findings across diverse methodologies is challenging. In the present study, we aimed to compare arterial stiffness measurements of two distinctex vivosetups for measuring aortic mechanics. First, we measured arterial stiffness in the aorta of adult (5 months) and aged (24 months) wild-type C57Bl/6J micein vivo, after whichex vivobiomechanical evaluation was performed using the Rodent Oscillatory Tension Setup to study Arterial Compliance (ROTSAC; University of Antwerp, Belgium) and the DynamX setup (Maastricht University, The Netherlands). Measurements in both setups were conducted in parallel with matched protocols and identical buffers and chemicals. Overall, both methods revealed age-related increased stiffness, although parameters of aortic mechanics showed different numerical values, suggesting that results are not directly interchangeable between methods. Surprisingly, smooth muscle cell contraction had opposing effects between the setups. Indeed, smooth muscle cell contraction increased arterial stiffness in the ROTSAC but decreased stiffness in the DynamX. These opposing effects could be attributed to how the two setups differentially load the collagen fibres in the arterial wall,ex vivo. In conclusion, the observed differences between the twoex vivosetups highlight the necessity to report findings on (altered) aortic mechanics in the context of the used methodology.
Physiologically based demographic model/GIS analyses of thirteen invasive species in Africa: why the biology matters
Authors: Gutierrez Andrew Paul , Ponti Luigi , Neteler Markus , Cure Jose Ricardo , Kenmore Peter E. , Simmons George
Published: September 2024

Globally, research and policy groups often lack the expertise to develop appropriate models to analyze agroecological and invasive species problems holistically to inform management and quarantine policy development under extant and climate change over wide geographic landscapes. Off-the-shelf species distribution models (SDM) correlate weather and other variables to records of species presence and have become the mainstay for predicting the geographic distribution and favorability of invasive species (Elith 2017). However, SDM analyses lack the capacity to examine the underpinning dynamics of agroecosystems required to inform policy and develop management strategies. We propose that age-structured physiologically based demographic models (PBDMs) can solve important aspects of this challenge as they can be used to examine prospectively species dynamics locally as well as their potential geographic distribution and relative abundance across vast areas independent of presence records. PBDMs fall under the ambit of time-varying life tables (TVLTs; cf. Gilbertet al. 1976) and capture the weather driven biology, dynamics, and interactions of species, and can be used to examine the system from the perspective of any of the interacting species. Here, we use the PBDM structure to examine the dynamics across Africa of thirteen invasive species from various taxa having diverse biology and trophic interactions (see Gutierrez 1996, Gutierrez and Ponti 2013a). PBDMs are perceived to be difficult to develop, hence theraison d’êtreis to show this is not the case and illustrate their utility invasive and endemic agricultural and medical/veterinary pest species at the local and the large geographic scale of Africa. We note that PBDMs provide a structure for continued model improvements.

The development of open access software is proposed to facilitate PBDM development by non-experts emphasizing the crucial role of sound biological data on species responses to weather and to other species in a multi-trophic, interactions, and provide a guide for collecting the appropriate biological data. While the emphasis is on plant/arthropod interactions, models of diseases can be accommodated. The Supplemental Materials summarizes a large array of heritage PBDMs reported in the literature based on the methods outline herein, noting that the same model structure can be used to analyze and manage non pest species.
DIFFERENTIAL ANTIPROLIFERATIVE EFFECTS OF CANNABIDIOL (CBD) IN THE CORE AND INFILTRATIVE BOUNDARY OF HUMAN GLIOBLASTOMA CELLS
Authors: Abassi-Rana Ghazala , Calle-Patino Yolanda , Molina-Holgado Francisco
Published: September 2024

Background

We have previously reported that the brain cannabinoid signalling pathways regulates in the isocitrade dehydrogenase-1 wild-type glioblastoma (GBM) core and infiltrative boundary tumor cell proliferation. To uncover the mechanism behind these effects we have investigated the possible antitumoral actions of cannabidiol (CBD) in the tumour core cells (U87) and the Glioma Invasive Margin cells (GIN-8), the latter representing a better proxy of post-surgical residual disease.

Methods

Monolayer of GBM cells cultures were treated with increasing concentrations of CBD, Temozolomide (TMZ), Carmustine (BCUN), Fluoxetine, Doxorubicine (DOX) or vehicle. After treatment, cell viability was assessed using an MTT kit assay to evaluate mitochondrial activity/cell proliferation, cytotoxicity was evaluated by LDH release. In addition, we have investigated the effects of the CBD alone or in combination with the above drugs on the autophagic cell death, unfold protein response (UPR) mitochondrial response and release of proinflammatory cytokines.

This study highlights the potential therapeutic relevance of CBD in combination with other FDA-approved drugs against glioblastoma. We observed strong synergism between CBD and TMZ, FX, and DOXO in reducing U87-MG cell viability in vitro, with even stronger synergy between CBD and TMZ in GIN-8 cells. Our preliminary data identify CBD as a potential anti-neoplastic drug in both core and invasive margin cells. Given the heterogeneity of glioblastoma, further studies will elucidate the molecular mechanisms underlying CBD observed anti-tumoral actions and determine whether it can potentially be used in the future as an addition to current therapies.
CDK4 inactivation balances resistance to apoptosis with heightened metabolic sensitivity in triple negative breast cancer cells
Authors: Ziegler Dorian V. , Leal-Esteban Lucia , Parashar Kanishka , Castro Wilson , Zanou Nadège , Huber Katharina , López-Alcalá Jaime , Berney Xavier Pascal , Malagón María M , Roger Catherine , Berger Marie-Agnès , Paone Giulia , Gallart-Ayala Hector , Ivanisevic Julijana , Rieusset Jennifer , Irving Melita , Fajas Lluis
Published: September 2024

The shift in the energetic demands of proliferating cells during tumorigenesis requires intense crosstalk between the cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism in normal tissues. However, in the context of cancer, where CDK4 is upregulated or stabilized, the metabolic role of CDK4 is barely understood. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduced triple-negative breast cancer (TNBC) cell proliferation and allowed tumor formationin vivo. Furthermore, proapoptotic stimuli failed to induce appropriate cell death in TNBC cells with CDK4 depletion or long-term CDK4/6 inhibitor treatment. Mechanistically, CDK4 enhances mitochondria-ER contact (MERC) formation, thus promoting mitochondrial fission and ER-mitochondrial calcium signaling. Phosphoproteomic analysis also revealed a role for CDK4 in regulating PKA activity at MERCs to sustain ER-mitochondrial calcium signaling. This proper CDK4-mediated mitochondrial calcium signaling is then required for metabolic flexibility of TNBC cells. Taken together, these results demonstrate that CDK4 inhibition leads to cell death resistance, inhibiting mitochondrial apoptosis and functions through attenuated MERCs formation and ER-mitochondrial calcium signaling in TNBC. Overall, this study provides new insights into the mechanisms of TNBC resistance to CDK4/6i therapy and paves the way to explore potential synergistic therapeutic targeting MERCs-associated metabolic shifts.

Graphical Abstract
Truncated Complement Factor H Y402 Gene Therapy Cures C3 Glomerulonephritis
Authors: Chew Lindsey A. , Grigsby Daniel , Hester C. Garren , Amason Joshua , McPherson W. Kyle , Flynn Edward J. , Visel Meike , Flannery John G. , Rickman Catherine Bowes
Published: September 2024

Patients with both age-related macular degeneration (AMD) and C3 glomerulonephritis (C3G) are challenged by the absence of effective therapies to reverse and eliminate their disease burden. Capitalizing on complement dysregulation as both a significant risk factor for AMD and the known pathophysiology of C3G, we investigated the potential for adeno-associated virus (AAV) delivery of complement factor H (CFH) to rescue C3G in aCfh-/-mouse model of C3G. While past efforts to treat C3G using exogenous human CFH resulted in limited success before immune rejection led to a foreign protein response, our findings demonstrate the capacity for long-term AAV-mediated delivery of truncated CFH (tCFH) to restore inhibition of the alternative pathway of complement and ultimately reverse C3G without immune rejection. Comparing results from the administration of several tCFH vectors also revealed significant differences in their relative efficiency and efficacy. These discoveries pave the way for subsequent development of AAV-mediated tCFH replacement therapy for patients with C3G, while simultaneously demonstrating proof of concept for a parallel AAV-mediated tCFH gene augmentation therapy for patients with AMD.
Identification and structural characterization of pseudogenes inFusarium graminearum
Authors: Rau Domenico , Posadinu Chiara Maria , Murgia Maria Leonarda , Fois Davide , Porceddu Andrea
Published: September 2024

Pseudogenes provide valuable insight into the evolutionary history of genomes which can be challenging to ascertain through the examination of functional loci alone. This study presents the findings of a comprehensive, two-step genome-wide survey for the identification and characterization of pseudogenes inFusarium graminearum,the primary causal agent of wheat head blight.

By analysing the sequence homology between non-coding regions of the genome and predicted protein sequences, we identified regions with homology to putative paralogous functional sequences. These regions were characterised in terms of their matching sequence structure and position. Most identified pseudogenes were mapped within the fast-evolving genomic compartment and were derived from transposition events. The number of processed and putatively retroposed pseudogenes was found to be comparable. The number of identified pseudogenes was low, which is consistent with the low number of gene duplicates inF. graminearum. No compelling evidence was found to suggest that pseudogene formation can be explained by evolutionary accidents during gene family expansion or as caused by RIP-associated mutagenic events. Notably, about one-third (144/436) of the pseudogenes were found to overlap with untranslated or intron sequences of functional loci, indicating the potential to be transcribed. UsingFusariumcomparative genomics, we identified genomic regions with homology to genes lacking functional orthologs inF. graminearum. These were investigated as putative unitary pseudogenes and, in some cases, their original functions were completely lost after the radiation ofF. graminearum.

Interestingly, the paters of 18 loss-of-function pseudogenes showed homology to domains previously identified in proteins involved in pathogenesis.
Quantitative proteomics reveals differential extracellular vesicle cargo from M1 and M2 monocyte-derived human macrophages
Authors: Pantazi Paschalia , Clements Toby , Parsons Harriet T , Kaforou Myrsini , Heesom Kate J , Bennett Phillip R , Guller Seth , Abrahams Vikki M , Holder Beth
Published: September 2024

Extracellular vesicles (EVs) mediate intercellular communication by carrying molecular cargo that facilitate diverse physiological processes. Macrophages, playing central roles in immune responses, release EVs that modulate various cellular functions. Given the distinct roles of M1 and M2 macrophage states, understanding the proteomic profiles of their EVs is important for elucidation of EV-mediated signalling and identifying potential biomarkers for diseases involving macrophage polarisation. We employed quantitative proteomics combined with bioinformatics to characterise the proteomic profile of EVs released by M1 and M2 monocyte-derived macrophages. We identified 1,731 proteins in M1/M2 EVs, 132 of which were significantly differentially between M1 and M2. Proteomic data, together with pathway analysis, found that M1/M2 macrophage EV cargo relate to cellular source, and may play roles in shaping immune responses, with M1 EV cargo associated with promotion of pro-inflammatory and antiviral functions, while M2 EV cargo associated with immune regulation and tissue repair. M1 EV cargo was associated with cytokine/chemokine signalling pathways, DNA damage, methylation, and oxidative stress. M2 EV cargo were associated with macrophage alternative-activation signalling pathways, antigen presentation, and lipid metabolism. We also report that macrophage EVs carry metallothioneins, and other related proteins involved in response to metals and oxidative stress.
Bovine dendritic-cell subsets in lymphoid and non-lymphoid tissues: work in progress
Authors: Talker SC , Barut GT , Summerfield A
Published: September 2024

Bovine dendritic-cell subsets can be readily identified in flow cytometry by staining for Flt3, CD4 and CD13. While this gating strategy could be confirmed by bulk RNA-seq of subsets sorted from peripheral blood mononuclear cells, it remains to be determined if the same gating strategy can be applied to gate on cDC1, cDC2 and pDC within lymphoid and non-lymphoid tissues. With this preprint we aim to inform on the current status of phenotyping experiments performed on Flt3+cells in mesenteric lymph nodes, spleen and lung of cattle. Distinct DC subsets can be gated in all tissues based on CD4 and CD13, with high frequencies of Flt3+CD13+cells (putative cDC1) detected in the lung. Further phenotyping performed on lymph node cells (in particular CADM1, CD26 and CD123) support the subset classification analogous to blood, with pDC being Flt3+CD4+CD13-and cDC1 being Flt3+CD4-CD13+. Heterogeneous expression of CADM1 and CD26 on Flt3+CD4-CD13-putative cDC2 warrants further investigations.
Longitudinal analysis of glioblastoma response to oncolytic HSV1 guides PLX3397 combination for enhanced viral permissiveness
Authors: Ito Hirotaka , Shono Naoyuki , Zagami Claudia , Kim Min J , Quazim Alayo A. , McLaughlin Eric , Goins William F. , Fernandez Soledad , Chiocca E. Antonio , Nakashima Hiroshi
Published: September 2024

Clinical trial data underscores the need to improve oncolytic virus (OV) distribution within tumors, a challenge compounded by the lack of predictive biomarkers and limited opportunities for post-treatment analysis. To decipher the factors influencing treatment outcomes, we employed multimodal bioluminescence imaging (MM-BLI) in conjunction with magnetic resonance imaging (MRI) to monitor OV infection, replication, and tumor viability in orthotopic brain glioma mouse models. This approach revealed two distinct therapeutic responses: “Responders” with tumor regression and “Non-Responders” with tumor progression. In-depth analysis of individual brains from both groups uncovered dynamic interactions between the OV and the tumor microenvironment, highlighting the involvement of Iba-1+ microglia and tumor necrosis in hindering OV distribution within the tumor. To address this, we incorporated a CSF-1 receptor inhibitor (PLX3397), which improved tumor control by enhancing OV’s direct cytopathic effects and reducing microglial interference. Our findings highlight microglia as a significant barrier to effective OV therapy, suggesting that targeting brain-resident immune cells could enhance the therapeutic efficacy of OVs in resistant brain tumors.
Varying recombination landscapes between individuals are driven by polymorphic transposable elements
Authors: Huang Yuheng , Gao Yi , Ly Kayla , Lin Leila , Lambooij Jan Paul , King Elizabeth G. , Janssen Aniek , Wei Kevin H.-C. , Lee Yuh Chwen G.
Published: September 2024

Abstracts

Meiotic recombination is a prominent force shaping genome evolution, and understanding the causes for varying recombination landscapes within and between species has remained a central, though challenging, question. Recombination rates are widely observed to negatively associate with the abundance of transposable elements (TEs), selfish genetic elements that move between genomic locations. While such associations are usually interpreted as recombination influencing the efficacy of selection at removing TEs, accumulating findings suggest that TEs could instead be the cause rather than the consequence. To test this prediction, we formally investigated the influence of polymorphic, putatively active TEs on recombination rates. We developed and benchmarked a novel approach that uses PacBio long-read sequencing to efficiently, accurately, and cost-effectively identify crossovers (COs), a key recombination product, among large numbers of pooled recombinant individuals. By applying this approach to Drosophila strains with distinct TE insertion profiles, we found that polymorphic TEs, especially RNA-based TEs and TEs with local enrichment of repressive marks, reduce the occurrence of COs. Such an effect leads to different CO frequencies between homologous sequences with and without TEs, contributing to varying CO maps between individuals. The suppressive effect of TEs on CO is further supported by two orthogonal approaches–analyzing the distributions of COs in panels of recombinant inbred lines in relation to TE polymorphism and applying marker-assisted estimations of CO frequencies to isogenic strains with and without transgenically inserted TEs. Our investigations reveal how the constantly changing mobilome can actively modify recombination landscapes, shaping genome evolution within and between species.
Glutamine availability regulates cDC subsets in tissue
Authors: Lobel Graham P. , Han Nanumi , Arocho William A. Molina , Silber Michal , Shoush Jason , Noji Michael C. , Jerrick To Tsun Ki , Zhai Li , Lesner Nicholas P. , Simon M. Celeste , Haldar Malay
Published: September 2024

Abstract

Proliferating tumor cells take up glutamine for anabolic processes engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDC) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets – cDC1 and cDC2, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on Glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mTOR signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.

One Sentence Summary

Type 1 conventional dendritic cells require glutamine to maintain their number in non-lymphoid tissue.

Significance

Immune evasion is a key hallmark of cancer; however, the underlying pathways are diverse, tumor-specific and not fully elucidated. Many tumor cells avidly import glutamine to support their anabolic needs, creating a glutamine-deficient tumor microenvironment (TME). Herein, using mouse models of soft tissue sarcomas, we show that glutamine depletion in TME leads to reduced type 1 conventional dendritic cells – a cell type that is critical for adaptive immune responses. This work is a paradigm for how tumor cell metabolism can regulate anti-tumor immune responses and will be foundational to future efforts targeting glutamine metabolism for cancer immunotherapy.
Cross-expression analysis reveals patterns of coordinated gene expression in spatial transcriptomics
Authors: Sarwar Ameer , Rue Mara , French Leon , Cross Helen , Chen Xiaoyin , Gillis Jesse
Published: September 2024

Spatial transcriptomics promises to transform our understanding of tissue biology by molecularly profiling individual cells in situ. A fundamental question they allow us to ask is how nearby cells orchestrate their gene expression. To investigate this, we introduce cross-expression, a novel framework for discovering gene pairs that coordinate their expression across neighboring cells. Just as co-expression quantifies synchronized gene expression within the same cells, cross-expression measures coordinated gene expression between spatially adjacent cells, allowing us to understand tissue gene expression programs with single cell resolution. Using this framework, we recover ligand-receptor partners and discover gene combinations marking anatomical regions. More generally, we create cross-expression networks to find gene modules with orchestrated expression patterns. Finally, we provide an efficient R package to facilitate cross-expression analysis, quantify effect sizes, and generate novel visualizations to better understand spatial gene expression programs.
Listening to music modulates visual perception of paintings during binocular rivalry
Authors: Jiang Xintong , Cheng Yuhui , Jiang Yi , Du Yi
Published: September 2024

Music, as a hierarchically organized art form, profoundly influences perception and mood through its rich information and intense emotion. While previous research has demonstrated that music can shape visual perception, its influences on visual awareness in aesthetic scenes remain largely unclear. In a series of five experiments involving 138 participants, we used the binocular rivalry paradigm to investigate how sad or lively Chinese folk music influences the perception of traditional Chinese paintings with varying aesthetic emotion (bleak vs. vivid). Paintings were presented in upright or inverted orientations or replaced by patches. Results revealed that sad music significantly increased both the average dominance duration and the predominance score of bleak paintings. Conversely, lively music with a faster tempo accelerated the switch rate of both paintings and patches. These effects were interdependent, exclusively for meaningful (upright) paintings, and correlated with individual sensitivity to musical reward. Our findings support the hierarchical predictive coding model of binocular rivalry, demonstrating that musical aesthetic emotion exerts top-down modulation, while musical tempo provides bottom-up entrainment, jointly shaping visual awareness of paintings.
High-dimensional Ageome Representations of Biological Aging across Functional Modules
Authors: Ying Kejun , Tyshkovskiy Alexander , Chen Qingwen , Latorre-Crespo Eric , Zhang Bohan , Liu Hanna , Matei-Dediu Benyamin , Poganik Jesse R. , Moqri Mahdi , Kirschne Kristina , Lasky-Su Jessica , Gladyshev Vadim N.
Published: September 2024

The aging process involves numerous molecular changes that lead to functional decline and increased disease and mortality risk. While epigenetic aging clocks have shown accuracy in predicting biological age, they typically provide single estimates for the samples and lack mechanistic insights. In this study, we challenge the paradigm that aging can be sufficiently described with a single biological age estimate. We describe Ageome, a computational framework for measuring the epigenetic age of thousands of molecular pathways simultaneously in mice and humans. Ageome is based on the premise that an organism’s overall biological age can be approximated by the collective ages of its functional modules, which may age at different rates and have different biological ages. We show that, unlike conventional clocks, Ageome provides a high-dimensional representation of biological aging across cellular functions, enabling comprehensive assessment of aging dynamics within an individual, in a population, and across species. Application of Ageome to longevity intervention models revealed distinct patterns of pathway-specific age deceleration. Notably, cell reprogramming, while rejuvenating cells, also accelerated aging of some functional modules. When applied to human cohorts, Ageome demonstrated heterogeneity in predictive power for mortality risk, and some modules showed better performance in predicting the onset of age-related diseases, especially cancer, compared to existing clocks. Together, the Ageome framework offers a comprehensive and interpretable approach for assessing aging, providing insights into mechanisms and targets for intervention.
A human homolog of SIR2 antiphage proteins mediates immunity via the TLR pathway
Authors: Bonhomme Delphine , Vaysset Hugo , Ednacot Eirene Marie Q. , Rodrigues Vasco , Cury Jean , Trejo Veronica Hernandez , Benaroch Philippe , Morehouse Benjamin R. , Bernheim Aude , Poirier Enzo Z.
Published: September 2024

The full extent of immune system conservation between prokaryotes and eukaryotes is unknown. However, recent research supports that a subset of bacterial antiphage proteins is conserved in eukaryotes and likely gave rise to key actors of mammalian immunity. Here, we show that the SIR2 protein domain, present in bacterial antiphage systems, plays a role in eukaryotic innate immunity. Through phylogenetic analysis, we identify SIRanc, a human protein with a SIRim domain (subtype of SIR2). We demonstrate that SIRanc plays a pivotal role in the animal toll-like receptor (TLR) pathway of innate immunity by mediating the transcriptional upregulation of proinflammatory genes downstream of TLR stimulation. This depends on the enzymatic activity of SIRanc, which degrades NAD+, a central cellular metabolite. Finally, we show that proteins with a SIRim domain are diverse and widespread, detected in 19% of eukaryotic genomes, with SIRanc representing one of the five sirim lineages. This work opens avenues of research on the potential role of eukaryotic SIRim proteins in immunity, as well as on the involvement of SIRanc in human pathology.
A neural network model for the evolution of reconstructive social learning
Authors: Chisausky Jacob , Daras Inès Marguerite , Weissing Franz J. , Kozielska Magdalena
Published: September 2024

Learning from others is an important adaptation. However, the evolution of social learning and its role in the spread of socially transmitted information are not well understood. Few models of social learning account for the fact that socially transmitted information must be reconstructed by the learner, based on the learner’s previous knowledge and cognition. To represent the reconstructive nature of social learning, we present a modelling framework that incorporates the evolution of a neural network and a simple yet biologically realistic learning mechanism. The framework encompasses various forms of individual and social learning and allows the investigation of their interplay. Individual-based simulations reveal that an effective neural network structure rapidly evolves, leading to adaptive inborn behaviour in static environments, pure individual learning in highly variable environments, and a combination of individual and social learning in environments of intermediate stability. However, the evolutionary outcome depends strongly on the type of social learning (social guidance versus social instruction) and the order of individual and social learning. Moreover, the evolutionary dynamics of social learning can be surprisingly complex, with replicate simulations converging to alternative outcomes. We discuss the relevance of our modelling framework for cultural evolution and suggest future avenues of research.
Nucleus accumbens astrocytes bidirectionally modulate social behavior
Authors: VanRyzin Jonathan W , Reissner Kathryn J
Published: September 2024

Social behaviors are critical for survival and fitness of a species, and maladaptive social behaviors are frequently associated with neurodevelopmental and psychiatric disorders. As such, the neural circuits and cellular mechanisms driving social behaviors inform critical processes contributing to both health and disease. In particular, the nucleus accumbens (NAc) is a key hub for the integration of both social and non-social information required for successful social interactions and reward motivated behaviors. While astrocytes within the NAc have a recognized role in modulating neural activity, their influence over social behavior is yet undefined. To address this question, we manipulated NAc astrocyte signaling and determined effects on social interactions. NAc core astrocytes bidirectionally influenced social behavior in rats; agonism of astrocyte-specific hM3D(Gq) DREADD receptors increased social interaction time in the social interaction test and increased social preference in the 3-chamber test. Conversely, decreasing intracellular calcium signaling in astrocytes with viral expression of hPMCA reduced both social interaction and social preference in these tests. These results suggest that NAc astrocytes actively participate in the regulation of social behavior and highlight a putative role for astrocytes in disorders characterized by social dysfunction.
T-cell receptors identified by a personalized antigen-agnostic screening approach target shared neoantigen KRAS Q61H
Authors: Lennerz Volker , Doppler Christoph , Fatho Martina , Dröge Anja , Schaper Sigrid , Gennermann Kristin , Genzel Nadine , Plassmann Stephanie , Weismann David , Lukowski Samuel W. , Bents Dominik , Beushausen Christina , Kriese Karen , Herbst Hermann , Seitz Volkhard , Hammer Rudolf , Adam Paul J. , Eggeling Stephan , Wölfel Catherine , Wölfel Thomas , Hennig Steffen
Published: September 2024

Adoptive cell therapy (ACT) with TCR-engineered T-cells represents a promising alternative to TIL- or CAR-T therapies for patients with advanced solid cancers. Currently, selection of therapeutic TCRs critically depends on knowing the target antigens, a condition excluding most patients from treatment. Direct antigen-agnostic identification of tumor-specific T-cell clonotypes and TCR-T manufacturing using their TCRs can advance ACT for patients with aggressive solid cancers. We present a method to identify tumor-specific clonotypes from surgical specimens by comparing TCRβ-chain repertoires of TILs and adjacent tissue-resident lymphocytes. In seven NSCLC-patients, tumor-specific clonotypes were selected based on TIL-abundance and high tumor-to-nontumor frequency ratios. In two of the patients, we demonstrate that predicted tumor-specific clonotypes reacted against autologous tumors. In a third patient, we engineered TCR T-cells with four candidate tumor-specific TCRs that showed reactivity against the patient’s tumor and HLA-matched NSCLC cell lines. The TCR-T cells were then used to screen for candidate neoantigens and aberrantly expressed antigens. Three TCRs recognized recurrent driver-mutation KRAS Q61H-peptide ILDTAGHEEY presented by HLA-A*01:01. The TCRs were also dominant in a tumor relapse, one was found in cell free DNA. The finding of homologous TCRs in independent KRAS Q61H-positive cancers suggests a therapeutic opportunity for HLA-matched patients with KRAS Q61H-expressing tumors.