bluuebunny/crossref_metadata_2025 huggingface dataset:
Restoration of retinal regenerative potential of Müller glia by disrupting intercellular Prox1 transfer
Authors: Lee Eun Jung , Kim Museong , Park Sooyeon , Shim Ji Hyeon , Cho Hyun-Ju , Park Jung Ah , Park Kihyun , Lee Dongeun , Kim Jeong Hwan , Jeong Haen , Matsuzaki Fumio , Kim Seon-Young , Kim Jaehoon , Yang Hanseul , Lee Jeong-Soo , Kim Jin Woo
Published: April 2024

Individuals with retinal degenerative diseases face significant obstacles in restoring normal vision due to the inability to regenerate degenerated retinal cells. While retinal neurons can be regenerated from Müller glia (MG) in cold-blooded vertebrates, this regenerative ability is lacking in mammals, indicating the limited competence of mammalian MG for retinal regeneration. In this study, we elucidate the role of prospero-related homeobox 1 (Prox1) in rendering the mammalian retina incompetent for MG-derived regeneration. Prox1 accumulates in MG in the degenerating human and mouse retinas but not in those in the regenerating zebrafish retina. Strikingly, Prox1 in mouse MG originated from neighboring retinal neurons through intercellular protein transfer. Consequently, inhibition of Prox1 transfer to MG enables the reprogramming of MG into proliferative retinal progenitor cells in injured mouse retinas. Furthermore, we succeeded in regenerating retinal neurons and delaying vision loss in retinitis pigmentosa disease model in mice by adenoassociated viral gene delivery of an anti-Prox1 antibody that sequesters extracellular Prox1 in the mouse retina. Taken together, our findings highlight the therapeutic potential of anti-Prox1 therapy in restoring the regenerative potential of the mammalian retina.
Membrane permeability selection drove the stereochemistry of life
Authors: Goode Olivia , Łapińska Urszula , Glover Georgina , Milner David S. , Santoro Alyson E. , Pagliara Stefano , Richards Thomas A.
Published: April 2024

Early in the evolution of life a proto-metabolic network was encapsulated within a membrane compartment. The permeability characteristics of the membrane determined several key functions of this network by determining which compounds could enter the compartment and which compounds could not. One key feature of known life is the utilisation of right-handed D- ribose and deoxyribose sugars and left-handed L- amino acid stereochemical isomers (enantiomers), however, it is not clear why life adopted this specific chirality. We previously demonstrated that an archaeal and an intermediate membrane mimic, bearing a mixture of bacterial and archaeal lipid characteristics (a ‘hybrid’ membrane), display increased permeability compared to bacterial-like membranes. Here, we investigate if these membranes can drive stereochemical selection on pentose sugars, hexose sugars and amino acids. Using permeability assays of homogenous unilamellar vesicles, we demonstrate that both membranes select for D- ribose and deoxyribose sugars while the hybrid membrane uniquely selects for a reduced alphabet of L- facing amino acids. This repertoire includes alanine, the plausible first L- amino acid utilised. We conclude such compartments could provide stereochemical compound selection thereby demonstrating a solution to the chirality problem during the evolution of life.
Transcriptional regulators ensuring specific gene expression and decision making at high TGFβ doses
Authors: Hartmann Laura , Kristofori Panajot , Li Congxin , Becker Kolja , Hexemer Lorenz , Bohn Stefan , Lenhardt Sonja , Weiss Sylvia , Voss Björn , Loewer Alexander , Legewie Stefan
Published: April 2024

TGFβ-signaling regulates cancer progression by controlling cell division, migration and death. These outcomes are mediated by gene expression changes, but the mechanisms of decision making towards specific fates remain unclear. Here, we combine SMAD transcription factor imaging, genome-wide RNA sequencing and morphological assays to quantitatively link signaling, gene expression and fate decisions in mammary epithelial cells. Fitting genome-wide kinetic models to our time-resolved data, we find that the majority of TGFβ target genes can be explained as direct targets of SMAD transcription factors, whereas the remainder show signs of complex regulation, involving delayed regulation and strong amplification at high TGFβ doses. Knockdown experiments followed by global RNA sequencing revealed transcription factors interacting with SMADs in feedforward loops to control delayed and dose-discriminating target genes, thereby reinforcing the specific epithelial-to-mesenchymal transition at high TGFβ doses. We identified early repressors, preventing premature activation, and a late activator, boosting gene expression responses for a sufficiently strong TGFβ stimulus. Taken together, we present a global view of TGFβ-dependent gene regulation and describe specificity mechanisms reinforcing cellular decision making.
An AI-informed NMR structure reveals a LETM1 F-EF-hand for two-way mitochondrial calcium regulation.
Authors: Lin Qi Tong , Colussi Danielle M. , Lake Taylor , Stathopulos Peter
Published: April 2024

AlphaFold2 can accurately predict high-resolution protein structure from sequence but does not account for solvent conditions, ligands, post-translational modifications, lowly populated states or rare folds. Human leucine zipper EF-hand transmembrane protein-1 (LETM1) has one sequence-identifiable EF-hand but whether and how calcium (Ca2+) binding affects structure and function remains enigmatic. Here, we developed an approach that used highly confident AlphaFold2 Calpha positions to guide nuclear Overhauser effect (NOE) assignments and structure calculation of the LETM1 EF-hand in the presence of Ca2+. The resultant NMR structure exposes pairing between a partial loop-helix and full helix-loop-helix, forming an unprecedented F-EF-hand domain with non-canonical Ca2+ coordination but enhanced hydrophobicity for protein interactions compared to calmodulin. The structure also reveals the basis for pH sensing by His662, linking the canonical and partial EF-hands. Functionally, mutations that augmented or weakened Ca2+ binding led to increased and decreased matrix Ca2+ levels, respectively, establishing F-EF as a two-way mitochondrial Ca2+ potentiator. Collectively, we show how AlphaFold2 can be synergized with NMR data to produce solution-specific structures, revealing here an extraordinary LETM1 F-EF-hand sensor.
Comparative analysis of Pearson and Canonical correlation-based functional connectivity matrices for neuroimaging classification tasks
Authors: Antipushina Ekaterina , Zubrikhina Maria , Kalimullin Ruslan , Kotoyants Nikolay , Sharaev Maxim
Published: April 2024

Machine learning (ML) methodologies offer significant potential for addressing the intricate challenges inherent in the analysis of neuroimaging data within the realm of neurological research. Nonetheless, the effective application of these techniques is markedly contingent upon the particular task and dataset under examination, and the absence of standardized methodologies poses impediments to cross-study result comparisons. This study contributes substantively to the collective endeavor by conducting a comprehensive evaluation and comparative analysis of ML models in the context of predicting schizophrenia and autism spectrum disorder (ASD) utilizing distinct functional Magnetic Resonance Imaging (fMRI) datasets. In this research, we introduce Canonical Correlation Analysis (CCA) as an innovative modality to augment the classification of these multifaceted neurological conditions. By elucidating the efficacy of CCA in ameliorating classification accuracy within the framework of Support Vector Machines (SVM), our study endeavors to propel the domain of neuroimaging and deepen our understanding of these intricate neurological disorders.
A proposed workflow to analyze bacterial transcripts in RNAseq from blood extracellular vesicles of people with Multiple Sclerosis
Authors: Ascensión Alex M. , Gorostidi-Aicua Miriam , Otaegui-Chivite Ane , Alberro Ainhoa , Bravo-Miana Rocio del Carmen , Castillo-Trivino Tamara , Moles Laura , Otaegui David
Published: April 2024

Motivation

The taxonomical characterisation of bacterial species derived from genetic material blood, including reads derived from bacterial extracellular vesicles (bEVs) poses certain challenges, such as the proper discrimination of “true” reads from contaminating reads. This is a common issue in taxa profiling and can lead to the false discovery of species that are present in the sample. To avoid such biases a careful approximation to taxa profiling is necessary.

Results

In this work we propose a workflow to analyze the presence of bacterial transcripts as indicative of putative bEVs circulating in the blood of people with MS (pwMS). The workflow includes several reference mapping steps against the host genome and a consensus selection of genera based on different taxa profilers. The consensus selection is performed with a flagging system that removes species with low abundance or with high variation across profilers. Additionally, the inclusion of biological samples from known cultured species as well as the generation of artificial reads constitute two key aspects of this workflow.

Availability

The workflow is available at the following repository:https://github.com/NanoNeuro/EV_taxprofiling.

Contact

davidangel.otaeguibichot@osakidetza.eus
Single cell sequencing of zebrafish kidney marrows reveals AHR2-dependent endogenous regulation of hematopoiesis
Authors: Dasgupta Subham , Goodale Britton , Tanguay Robyn
Published: April 2024

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates a wide range of biological and toxicological responses. While largely studied in ligand-activated toxicant responses, AHR also plays important roles in endogenous physiological processes. We leveraged single cell sequencing and an AHR2 knockout zebrafish line to investigate the role of AHR2 in regulating hematopoiesis (production and differentiation of red and white blood cells from hematopoietic stem cells). Our objectives were to determine if absence of AHR2-1) alters proportions of immune cell populations and/or 2) impacts gene expression within individual immune cell types. We dissected kidney marrow (organ of hematopoiesis in zebrafish) from adult wildtype and AHR2 knockout zebrafish (N=3/genotype), isolated single cells and sequenced ∼ 5000 cells/sample (10X Genomics). We identified 14 cell clusters representing the expected major blood (erythrocytes, thrombocytes), immune (B cells, macrophages, lymphoid cells, granulocytes, etc), progenitors and kidney cell populations. We focused our analyses only on the progenitor and mature immune cell types. While there were no genotype-specific differences in proportion of individual cell types, gene expression differences were observed within several cell types. For known genes, such asrrm2, changes were up to 2000-fold, signifying their importance in AHR2-hematopoesis interaction. Several of the known genes are also identified as markers of carcinoma cells for an array of cancer types. However, many of the dysregulated genes are poorly annotated, limiting our ability to examine biological processes and pathways dysregulated on AHR2 mutation. Nevertheless, our study indicates that AHR2 plays an important endogenous role in hematopoiesis. Future work will focus on better characterizing anatomy of dysregulated genes and their functions in hematopoiesis.
Genome Report: Pseudomolecule-scale genome assemblies ofDrepanocaryum sewerzowiiandMarmoritis complanata
Authors: Smit Samuel J. , Whitehead Caragh , James Sally R. , Jeffares Daniel C. , Godden Grant , Peng Deli , Sun Hang , Lichman Benjamin R.
Published: April 2024

The Nepetoideae, a subfamily of Lamiaceae (mint family), is rich in aromatic plants, many of which are sought after for their use as flavours and fragrances or for their medicinal properties. Here we present genome assemblies for two species in Nepetiodeae:Drepanocaruym sewerzowiiandMarmoritis complanata. Both assemblies were generated using Oxford Nanopore Q20+ reads with contigs anchored to nine pseudomolecules that resulted in 335 Mb and 305 Mb assemblies, respectively, and BUSCO scores above 95% for both the assembly and annotation. We furthermore provide a species tree for the Lamiaceae using only genome derived gene models, complementing existing transcriptome and marker-based phylogenies.
Copper acquisition is essential for plant colonization and virulence in a root-infecting vascular wilt fungus
Authors: Palos-Fernández Rafael , Aguilar-Pontes María Victoria , Puebla-Planas Gema , Berger Harald , Studt-Reinhold Lena , Strauss Joseph , Di Pietro Antonio , López-Berges Manuel Sánchez
Published: April 2024

Phytopathogenic fungi provoke devastating agricultural losses and are difficult to control. How fungal pathogens adapt to the plant environment to cause disease and complete their life cycle on the host remains poorly understood. Here we show that efficient acquisition of copper, mediated by the transcriptional regulator Mac1, is crucial for plant colonization and virulence inFusarium oxysporum,a soilborne ascomycete that causes vascular wilt on more than 150 different crops. RNA-seq and ChIP-seq establish a direct role of Mac1 in activation of copper deficiency response genes, many of which are induced during plant infection. Loss of Mac1 impairs growth ofF. oxysporumunder copper-limiting condition as well as vascular colonization and virulence on tomato plants. Importantly, Mac1-independent overexpression of a copper reductase and a copper transporter restores growth under copper limitation and virulence in themac1null mutant background. These findings establish a key role for copper acquisition in fungal pathogenicity on plants and reveal new ways to protect crops from phytopathogens.
Blind source separation of event-related potentials using a recurrent neural network
Authors: O’Reilly Jamie A. , Sunthornwiriya-Amon Hassapong , Aparprasith Naradith , Kittichalao Pannapa , Chairojwong Pornnaphas , Klai-on Thanabodee , Lannon Edward W.
Published: April 2024

Event-related potentials (ERPs) are a superposition of electric potential differences generated by neurophysiological activity associated with psychophysical events. Spatiotemporal dissociation of these signal sources can supplement conventional ERP analysis and improve source localization. However, results from established source separation methods applied to ERPs can be challenging to interpret. Hence, we have developed a recurrent neural network (RNN) method for blind source separation. The RNN transforms input step pulse signals representing events into corresponding ERP difference waveforms. Source waveforms are obtained from penultimate layer units and scalp maps are obtained from feed-forward output layer weights that project these source waveforms onto EEG electrode amplitudes. An interpretable, sparse source representation is achieved by incorporating L1 regularization of signals obtained from the penultimate layer of the network during training. This RNN method was applied to four ERP difference waveforms (MMN, N170, N400, P3) from the open-access ERP CORE database, and independent component analysis (ICA) was applied to the same data for comparison. The RNN decomposed these ERPs into eleven spatially and temporally separate sources that were less noisy, tended to be more ERP-specific, and were less similar to each other than ICA-derived sources. The RNN sources also had less ambiguity between source waveform amplitude, scalp potential polarity, and equivalent current dipole orientation than ICA sources. In conclusion, the proposed RNN blind source separation method can be effectively applied to grand-average ERP difference waves and holds promise for further development as a computational model of event-related neural signals.
Availability of an inflammatory macrophage niche drives phenotypic and functional alterations in Kupffer cells
Authors: Huang Han-Ying , Chen Yan-Zhou , Zheng Xin-Nan , Yue Jia-Xing , Ju Huai-Qiang , Shi Yan-Xia , Tian Lin
Published: April 2024

Inflammatory signals lead to recruitment of circulating monocytes and induce their differentiation into disease-associated macrophages1–3. Therefore, whether blocking inflammatory monocytes can mitigate disease progression is being actively evaluated4. Here, we employed multiple lineage tracing models and confirmed that monocyte-derived macrophages (mo-macs) are the major population of liver metastasis-associated macrophages (LMAMs), while the population of Kupffer cells (KCs), liver-resident macrophages, is diminished in liver metastatic nodules. Paradoxically, genetic ablation of mo-macs resulted in only a marginal decrease in LMAMs. Using a proliferation recording system and a KC tracing model in a monocyte-deficient background, we found that LMAMs can be replenished either via increased local macrophage proliferation or by promoting KC infiltration. After occupying macrophage niches left vacant by monocyte depletion, KCs exhibit substantial phenotypic and functional alterations through epigenetic reprogramming. These data suggest that dual blockade of monocytes and macrophages could be used to effectively target immunosuppressive myelopoiesis and to reprogram the microenvironment towards an immunostimulatory state.
Linking phenology, harvest index and genetics to improve chickpea grain yield
Authors: Gimenez R. , Lake L. , Cossani M. C. , Ortega Martinez R. , Hayes J. E. , Dreccer M. F. , French R. , Weller J. L. , Sadras V. O.
Published: April 2024

Phenology is critical to crop adaptation. We grew 24 chickpea genotypes in 12 environments to analyse: the environmental and genotypic drivers of phenology; associations between phenology and yield; and phenotypes associated with allelic variants of three flowering related candidate loci:CaELF3a; a cluster of threeFTgenes on chromosome 3; and a region on chromosome 4 with an orthologue of the floral promoterGIGANTEA. A simple model with 3 genotype-specific parameters explained the differences in flowering response to daylength. Environmental factors causing flower abortion, such as low temperature and radiation and high humidity, led to a longer flowering-to-podding interval. Late podding associated with poor partition to grain, limiting yield in favourable environments. Sonali, carrying the early allele ofCaelf3a(elf3a), was generally the earliest to set pod, had low biomass but the highest harvest index. Genotypes combining the early variants ofGIGANTEAandFTorthologuesFTdel, where a deletion in the intergenic region ofFTa1-FTa2was associated with slow development, usually featured early reproduction and high harvest index, returning high yield in favourable environments. We emphasise the importance of pod set, rather than flowering, as a target for breeding, agronomic, and modelling applications.

Highlight

This paper analyses the environmental and genetic controls of chickpea phenology and its effects on grain yield, in a multi-environment trial including 24 genotypes with varying combinations of flowering related genes.
Co-infection with two iflaviruses (deformed wing virus and sacbrood virus) affects viral and immune dynamics and synergistically increases honey bee mortality
Authors: Durand Tristan , Dubois Eric , Bonjour-Dalmon Anne
Published: April 2024

The honey bee microbiome includes a wide variety of viruses. While most of them usually remain commensal, some can become pathogenic in specific contexts. Of these, one is that of deformed wing virus (DWV) and another, sacbrood virus (SBV). Although co-infection is the norm rather than the exception, most of the time these viruses have been studied independently. When investigated as co-infections, past studies have focused on their effects on the honey bee brood. In this study, we co-inoculated adult honey bees at emergence with DWV by injection and SBV orally (acting as the viral transmission byVarroa destructorand by trophallaxis or food, respectively), either simultaneously or sequentially. Using optical counters, we were able to track the survival and behaviour of these honey bees within colonies. Through regular in-hive sampling, we monitored the evolution of their viral loads as well as the expression of eight immune genes involved in honey bee anti-viral immunity. Here, we show that co-inoculations of DWV and SBV synergistically increase the virulence of DWV and conditionally promote the replication of both viruses. Finally, our results show that immune responses in adult honey bees depend on DWV genotypes and whether replication originates from a superinfecting virus or a virus already present in bees.

Author Summary

Honey bees are highly social pollinators that live in crowded colonies. Their population density and the high frequency of interactions between individuals favours disease transmission and makes colonies susceptible to pathogen outbreaks. Many viruses commonly infect honey bees, however, they are often studied as single infections. As an effort to better understand interactions between honey bees and multiple viral populations, we co-inoculated young bees with two common honey bee viruses (deformed wing virus and sacbrood virus), released them in colonies and monitored their health and behaviour. Our findings show evidence of synergies between both viruses, as we show that a virus seemingly harmless for adult bees (sacbrood virus) may actually increase the virulence of another virus (deformed wing virus). These results highlight the importance of monitoring and studying multiple pathogens at once for a better understanding of the threat they represent to colony health and survival.
Surface lipids influence developmental and species- specific chemical signalling in nematodes
Authors: Kotowska Anna M. , Hiramatsu Fumie , Alexander Morgan R. , Scurr David J. , Lightfoot James W. , Chauhan Veeren M.
Published: April 2024

ABSTRACT/SUMMARY

Chemical signalling facilitates organismal communication and coordinates physiological and behavioural processes. In nematodes, signalling has predominantly focused on secreted molecules leaving the surface’s communicative potential unexplored. By utilising 3D-OrbiSIMS, an advanced surface-sensitive mass spectrometry method, we directly characterised the molecular composition of the outermost regions (50 nm in depth) ofCaenorhabditis elegansandPristionchus pacificusto improve the understanding of surface-mediated chemical communication. We found that nematode surfaces consist of a lipid-dominated landscape (> 81 %C. elegansand > 69 %P. pacificusof all surveyed chemistries) with distinct compositions, which enrich in granularity and complexity through development. The surface-anchored lipids are also species-specific, reflecting evolutionary and ecological adaptations to their environmental niches. By exploring the effect of mutations on lipid production we found the peroxisomal fatty acid β-oxidation componentdaf-22is essential for defining the surface molecular fingerprint. This pathway is conserved across species in producing distinct chemical profiles, indicating its fundamental role in lipid metabolism and for maintaining surface integrity and function. Furthermore, we discovered that variations in surface-anchored lipids ofC. elegans daf-22larvae contribute to significantly increased susceptibility to predation byP. pacificus. Therefore, our findings reveal that the nematode surface is not just a passive boundary but a dynamic signalling platform with evolved, species-specific signatures. These molecular mechanisms are pivotal in shaping identity and communication strategies, providing new insights into the evolutionary and ecological dynamics of chemical signalling across organisms.

HIGHLIGHTS

Nematode surfaces are lipid-rich, changing with development.

Surface lipids are species-specific, reflecting adaptations.

Thedaf-22gene is key in shaping the surface lipid profile.

Surface lipids mediate predator-prey interactions in nematodes.
The reindeer circadian clock is rhythmic and temperature-compensated but shows evidence of weak coupling between the secondary and core molecular clock loops
Authors: Appenroth Daniel , Ravuri Chandra S , Torppa Sara K , Wood Shona H , Hazlerigg David G , West Alexander C
Published: April 2024

Circadian rhythms synchronize the internal physiology of animals allowing them to anticipate daily changes in their environment. Arctic habitats may diminish the selective advantages of circadian rhythmicity by relaxing daily rhythmic environmental constraints, presenting a valuable opportunity to study the evolution of circadian rhythms. In reindeer, circadian control of locomotor activity and melatonin release is weak or absent, and the molecular clockwork is reportedly non-functional. Here we present new evidence that the circadian clock in cultured reindeer fibroblasts is rhythmic and temperature-compensated. Compared to mouse fibroblasts, however, reindeer fibroblasts have a short free-running period, and temperature cycles have an atypical impact on clock gene regulation. In reindeer cells,Per2andBmal1reporters show rapid responses to temperature cycles, with a disintegration of their normal antiphasic relationship. The antiphasicPer2-Bmal1relationship re-emerges immediately after release from temperature cycles, but without complete temperature entrainment and with a marked decline in circadian amplitude. Experiments usingBmal1promoter reporters with mutated RORE sites showed that a reindeer-like response to temperature cycles can be mimicked in mouse or human cell lines by decouplingBmal1reporter activity from ROR / REV-ERB dependent transcriptional regulation. We suggest that weak coupling between core and secondary circadian feedback loops accounts for the observed behaviour of reindeer fibroblastsin vitro. Our findings highlight diversity in how the thermal environment affects the temporal organisation of mammals living under different thermoenergetic constraints.
Virological characteristics of the SARS-CoV-2 KP.2 variant
Authors: Kaku Yu , Uriu Keiya , Kosugi Yusuke , Okumura Kaho , Yamasoba Daichi , Uwamino Yoshifumi , Kuramochi Jin , Sadamasu Kenji , Yoshimura Kazuhisa , Asakura Hiroyuki , Nagashima Mami ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ito Jumpei , Sato Kei
Published: April 2024

The JN.1 variant (BA.2.86.1.1), arising from BA.2.86(.1) with the S:L455S substitution, exhibited increased fitness and outcompeted the previous dominant XBB lineage by the biggening of 2024. JN.1 subsequently diversified, leading to the emergence of descendants with spike (S) protein substitutions such as S:R346T and S:F456L. Particularly, the KP.2 (JN.1.11.1.2) variant, a descendant of JN.1 bearing both S:R346T and S:F456L, is rapidly spreading in multiple regions as of April 2024. Here, we investigated the virological properties of KP.2. KP.2 has three substitutions in the S protein including the two above and additional one substitution in non-S protein compared with JN.1. We estimated the relative effective reproduction number (Re) of KP.2 based on the genome surveillance data from the USA, United Kingdom, and Canada where >30 sequences of KP.2 has been reported, using a Bayesian multinomial logistic model. The Reof KP.2 is 1.22-, 1.32-, and 1.26-times higher than that of JN.1 in USA, United Kingdom, and Canada, respectively. These results suggest that KP.2 has higher viral fitness and potentially becomes the predominant lineage worldwide. Indeed, as of the beginning of April 2024, the estimated variant frequency of KP.2 has already reached 20% in United Kingdom.

The pseudovirus assay showed that the infectivity of KP.2 is significantly (10.5-fold) lower than that of JN.1. We then performed a neutralization assay using monovalent XBB.1.5 vaccine sera and breakthrough infection (BTI) sera with XBB.1.5, EG.5, HK.3 and JN.1 infections. In all cases, the 50% neutralization titer (NT50) against KP.2 was significantly lower than that against JN.1. Particularly, KP.2 shows the most significant resistance to the sera of monovalent XBB.1.5 vaccinee without infection (3.1-fold) as well as those who with infection (1.8-fold). Altogether, these results suggest that the increased immune resistance ability of KP.2 partially contributes to the higher Remore than previous variants including JN.1.
Post-mortem evidence for a reciprocal relationship between genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies
Authors: Koss David J. , Todd Olivia , Menon Hariharan , Anderson Zoe , Yang Tamsin , Attems Johannes , LeBeau Fiona E. , Erskine Daniel , Outeiro Tiago F.
Published: April 2024

DNA damage and DNA damage repair (DDR) dysfunction are insults with broad implications on cellular physiology, including in proteostasis, and have been recently implicated in many neurodegenerative diseases. Alpha-synuclein (aSyn), a pre-synaptic and nuclear protein associated with neurodegenerative disorders known as synucleinopathies, has been implicated in DNA double strand break (DSB) repair function. Consistently, DSB induction has been demonstrated in cell and animal models of synucleinopathy. Nevertheless, the types of DNA damage and the contribution of DNA damage towards Lewy body (LB) formation in synucleinopathies are unknown. Here, we demonstrate the increase of DSB in neuronal and non-neuronal cellular populations of post-mortem temporal cortex tissue from dementia with Lewy body (DLB) patients and demonstrate increases in DSBs early at a presymptomatic age of aSyn transgenic mice. Strikingly, in postmortem DLB tissue, DNA damage-derived ectopic cytoplasmic genomic material (eCGM) was evident within the majority of LBs examined. The observed cellular pathology was consistent with nucleoproteasomal upregulation of associated DNA damage repair proteins, particularly in base excision repair and DSB repair pathways. Collectively our study demonstrates the early occurrence of DNA damage and associated nucleoproteasomal changes in response to nuclear aSyn pathology. Furthermore, the data suggests a potential involvement for DNA damage derived eCGM for the facilitation of cytoplasmic aSyn aggregates. Ultimately, uncovering pathological mechanisms underlying DNA damage in DLB sheds light into novel disease mechanisms and opens novel possibilities for diagnosing and treating synucleinopathies.
Angiotensin Converting Enzyme (ACE) expression in microglia reduces amyloid β deposition and neurodegeneration by increasing SYK signaling and endolysosomal trafficking
Authors: Gomez Andrew R. , Byun Hyae Ran , Wu Shaogen , Muhammad AKM Ghulam , Ikbariyeh Jasmine , Chen Jaelin , Muro Alek , Li Lin , Bernstein Kenneth E. , Ainsworth Richard , Tourtellotte Warren G.
Published: April 2024

Genome-wide association studies (GWAS) have identified many gene polymorphisms associated with an increased risk of developing Late Onset Alzheimer’s Disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing microglia innate immune responses and lipid metabolism. Angiotensin Converting Enzyme (ACE), a GWAS LOAD risk-associated gene best known for its role in regulating systemic blood pressure, also enhances innate immunity and lipid processing in peripheral myeloid cells, but a role for ACE in modulating the function of myeloid-derived microglia remains unexplored. Using novel mice engineered to express ACE in microglia and CNS associated macrophages (CAMs), we find that ACE expression in microglia reduces Aβ plaque load, preserves vulnerable neurons and excitatory synapses, and greatly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of Alzheimer’s Disease (AD). ACE-expressing microglia show enhanced Aβ phagocytosis and endolysosomal trafficking, increased clustering around amyloid plaques, and increased SYK tyrosine kinase activation downstream of the major Aβ receptors, TREM2 and CLEC7A. Single microglia sequencing and digital spatial profiling identifies downstream SYK signaling modules that are expressed by ACE expression in microglia that mediate endolysosomal biogenesis and trafficking, mTOR and PI3K/AKT signaling, and increased oxidative phosphorylation, while gene silencing or pharmacologic inhibition of SYK activity in ACE-expressing microglia abrogates the potentiated Aβ engulfment and endolysosomal trafficking. These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing microglia as a cell-based therapy to augment endogenous microglial responses to Aβ in AD.
Pseudomonas aeruginosa-infected Myeloid-derived suppressor cells (MDSC) down-regulate lymphocyte activity and improves mice survival, followingin vivolung transfer
Authors: Born-Bony Maëlys , Cornu Clémentine , Villeret Bérengère , Voulhoux Romé , Sallenave Jean-Michel
Published: April 2024

Pseudomonas aeruginosa(P.a.) is a pathogenic opportunistic bacterium, classified as a priority by the WHO for the research of new treatments. As this bacterium is harmful trough the inflammation and tissue damage it causes, we investigated the role of Myeloid Derived Suppressor Cells (MDSC) inP.a.infections and their potential as a therapeutic target. We found that uponP.a.exposure, MDSC activity is increased and gain contact-independent properties. Interestingly, this activation is dependent onP.a.mobility but not its flagellin nor TLR5-MyD88 pathway. We also show that MDSC adoptive transfer increases mice survival inP.a.acute lung infection both in therapeutic and prophylactic set ups. Finally, usingan in vitroscratch assay model, we suggest that MDSC acts directly on lung epithelium to stimulate its repair. Together, we highlight a potential beneficial role of MDSC inP.a.infection response. We believe that the unique properties of MDSC make them attractive potential new therapeutic tools for patients with acute or chronic inflammatory diseases, where inflammation has to be kept in check.
Heterogenous transcriptomes ofNicotiana tabacumBY-2 suspension cell lines adapted to various osmoticum
Authors: Skrzypczak Tomasz , Wojtaszek Przemysław , Kasprowicz-Maluśki Anna
Published: April 2024

Plants abiotic stress response and adaptation belong to the most important subjects in plants biology. Here, we presentNicotiana tabacumsuspension cell lines adapted during long term cultures to high concentrations of NaCl, KCl, mannitol and sorbitol. Obtained lines differ in osmotic stress agents and final media osmolarities. RNA-seq analysis revealed similarities, as well as differences in adapted lines transcriptomes. Presented here BY-2 cells lines form a good model to reveal molecular mechanisms of plants adaptations to salt and osmotic stress on cellular level.
DeepGene: An Efficient Foundation Model for Genomics based on Pan-genome Graph Transformer
Authors: Zhang Xiang , Yang Mingjie , Yin Xunhang , Qian Yining , Sun Fei
Published: April 2024

Decoding the language of DNA sequences is a fundamental problem in genome research. Mainstream pre-trained models like DNABERT-2 and Nucleotide Transformer have demonstrated remarkable achievements across a spectrum of DNA analysis tasks. Yet, these models still face the pivotal challenge of (1) genetic language diversity, or the capability to capture genetic variations across individuals or populations in the foundation models; (2) model efficiency, specifically how to enhance performance at scalable costs for large-scale genetic foundational models; (3) length extrapolation, or the ability to accurately interpret sequences ranging from short to long within a unified model framework. In response, we introduce DeepGene, a model leveraging Pan-genome and Minigraph representations to encompass the broad diversity of genetic language. DeepGene employs the rotary position embedding to improve the length extrapolation in various genetic analysis tasks. On the 28 tasks in Genome Understanding Evaluation, DeepGene reaches the top position in 9 tasks, second in 5, and achieves the overall best score. DeepGene outperforms other cutting-edge models for its compact model size and superior efficiency in processing sequences of varying lengths. The datasets and source code of DeepGene are available at GitHub (https://github.com/wds-seu/DeepGene).
Combining EEG and Eye-Tracking in Virtual Reality - Obtaining Fixation-Onset ERPs and ERSPs
Authors: Nolte Debora , Vidal De Palol Marc , Keshava Ashima , Madrid-Carvajal John , Gert Anna L. , von Butler Eva-Marie , Kömürlüoğlu Pelin , König Peter
Published: April 2024

Extensive research conducted in controlled laboratory settings has prompted an inquiry into how results can be generalized to real-world situations influenced by the subjects’ actions. Virtual reality lends itself ideally to investigating complex situations but requires accurate classification of eye movements, especially when combining it with time-sensitive data such as EEG. We recorded eye-tracking data in virtual reality and classified it into gazes and saccades using a velocity-based classification algorithm, and we cut the continuous data into smaller segments to deal with varying noise levels, as introduced in the REMoDNav algorithm. Furthermore, we corrected for participants’ translational movement in virtual reality. Various measures, including visual inspection, event durations, and the velocity and dispersion distributions before and after gaze onset, indicate that we can accurately classify the continuous, free-exploration data. Combining the classified eye-tracking with the EEG data, we generated fixation-onset ERPs and ERSPs, providing further evidence for the quality of the eye movement classification and timing of the onset of events. Finally, investigating the correlation between single trials and the average ERP and ERSP identified that fixation-onset ERSPs are less time-sensitive, require fewer repetitions of the same behavior, and are potentially better suited to study EEG signatures in naturalistic settings. We modified, designed, and tested an algorithm that allows the combination of EEG and eye-tracking data recorded in virtual reality.
Clustering Electrophysiological Predisposition to Binge Drinking: An Unsupervised Machine Learning analysis
Authors: Uceta Marcos , del Cerro-León Alberto , Shpakivska-Bilán Danylyna , García-Moreno Luis M. , Maestú Fernando , Antón-Toro Luis Fernando
Published: April 2024

Background

The demand for fresh strategies to analyze intricate multidimensional data in neuroscience is increasingly evident. One of the most complex events during our neurodevelopment is adolescence, where our nervous system suffers constant changes, not only in neuroanatomical traits, but also in neurophysiological components. One of the most impactful factors we deal with during this time is our environment, especially when encountering external factors such as social behaviors or substance consumption. Binge Drinking (BD) has emerged as an extended pattern of alcohol consumption in teenagers, not only affecting their future lifestyle, but changing their neurodevelopment. Recent studies have changed their scope into finding predisposition factors that may lead adolescents into this kind of patterns of consumption.

Methods

In this article, using unsupervised machine learning (UML) algorithms, we analyze the relationship between electrophysiological activity of healthy teenagers and the levels of consumption they had two years later. We used hierarchical agglomerative UML techniques based on Ward’s minimum variance criterion to clusterize relations between power spectrum and functional connectivity and alcohol consumption, based on similarity in their correlations, in frequency bands from theta to gamma.

Results

We found that all frequency bands studied had a pattern of clusterization based on anatomical regions of interest related to neurodevelopment and cognitive and behavioral aspects of addiction, highlighting the dorsolateral and medial prefrontal, the sensorimotor, the medial posterior and the occipital cortices. All this patterns, of great cohesion and coherence, showed an abnormal electrophysiological activity, representing a dysregulation in the development of core resting-state networks. The clusters found maintained not only plausibility in nature, but robustness, making this a great example of the usage of UML in the analysis of electrophysiological activity, a new perspective into analysis that, while contributing to classical statistics, can clarify new characteristics of the variables of interest.
Assessing the impact of structural modifications in the construction of surveillance network for transboundary animal diseases: the role of backbone and sentinel nodes
Authors: Mesdour Asma , Ijoma Sandra , Bolajoko Muhammad-Bashir , Arsevska Elena , Ciss Mamadou , Cardinale Eric , Andraud Mathieu , Apolloni Andrea
Published: April 2024

Peste des Petits Ruminants (PPR) is a highly contagious disease that mainly affects sheep and goats and is transmitted through livestock movements. Because of its socio-economic impact, the Food and Agriculture Organisation (FAO) and the World Organization for Animal Health (WOAH) have set the goal to eradicate it by 2030, one of the key steps being the improvement of surveillance networks. The present study aimed to provide tools to identify areas that could serve assentinel nodes, i.e. areas that may be rapidly infected at the onset of epidemics. Using data from a market survey conducted in the Northern Region of Nigeria, we analyzed which nodes, under which conditions, could serve as sentinel nodes. We considered several modified networks to get around the problem of data only being available for part of the overall network structure and to account for potential errors made during the field study. For each configuration, we simulated the spread of PPR using a stochastic Susceptible-Infectious (SI) model based on animal movements to assess the epidemics’ extent and the presence of recurrent patterns to identify potentialsentinel nodes. We extracted the backbone of the reference network and checked for the presence of sentinel nodes within it. We then explored the possibility of using the backbone nodes as sentinel nodes. We investigated how the origin(seed)of the epidemics could affect the propagation pattern by comparing and grouping seeds based on their respective transmission paths. Results showed that the isolated backbone contains 45% sentinel nodes that remain stable or undergo only minor changes in 9 out of 11 configurations. On top of that, the characteristics of sentinel nodes identified in the backbone are not influenced by the severity of the disease. The H index, in-degree, and eigenvector are the most essential variables. This study provides an overview of the major axes of animal movements in Nigeria and the most vulnerable locations that should be prioritized for monitoring livestock diseases like PPR.
Uncovering critical transitions and molecule mechanisms in disease progressions using Gaussian graphical optimal transport
Authors: Hua Wenbo , Cui Ruixia , Yang Heran , Zhang Jingyao , Liu Chang , Sun Jian
Published: April 2024

Understanding disease progression is crucial for detecting critical transitions and finding trigger molecules, facilitating early diagnosis interventions. However, the high dimensionality of data and the lack of aligned samples across disease stages have posed challenges in addressing these tasks. We present a novel framework, Gaussian Graphical Optimal Transport (GGOT), for analyzing disease progressions. The proposed GGOT uses Gaussian graphical models, incorporating protein interaction networks, to characterize the data distributions at different disease stages. Then we use population-level optimal transport to calculate the Wasserstein distances and transport maps between stages, enabling us to detect critical transitions. By analyzing the per-molecule transport distance, we quantify the importance of each molecule and identify trigger molecules. Moreover, GGOT predicts the occurrence of critical transitions in unseen samples and visualizes the disease progression process. We apply GGOT to the simulation dataset and six disease datasets with varying disease progression rates, to show its effectiveness for detecting critical transitions and identifying trigger molecules.
Effect of alcohol on the speed of shifting endogenous and exogenous attention
Authors: Thiele Alexander , Heath Christopher , Pearson Jessica Kate , Sanjeev Sidharth , Read Jenny C. A.
Published: April 2024

The study aimed to investigate to what extent acute moderate doses of alcohol affect the speed of endogenous versus exogenous attentional shift times. Subjects viewed an array of 10 moving clocks and reported the time a clock indicated when cued. Target clocks were indicated by peripheral or central cues, including conditions of pre-cuing. This allowed assessing shift times when attention was pre-allocated, when peripheral cues triggered exogenous attention shifts, and when central cues triggered endogenous attention shifts. Each subject participated in 2 sessions (alcohol/placebo), whereby the order of drug intake was counterbalanced across subjects, and subjects were blinded to conditions. Confirming previous results, we show that pre-cuing resulted in the fastest shift times, followed by exogenous cuing, with endogenous attentional shifts being slowest. Alcohol increased attentional shift times across all 3 conditions compared to placebo. Thus, the detrimental effects of alcohol on attentional shift times did not depend on the type of attention probed.
2D MXene-DNA Hybrid Hydrogel for Thrombin Detection: A Versatile Approach for Biomedical Sensing
Authors: Morya Vinod , Bhatia Dhiraj , Ghoroi Chinmay
Published: April 2024

The delaminated MXene (2D MXene) and DNA hydrogel created enormous opportunities due to their versatility and ability to be tailored for specific applications. MXene offers high aspect ratio morphology and electrical conductivity, while DNA provides stimuli responsiveness and specificity in binding to ligands or complementary sequences. This synergy makes DNA an ideal actuator when combined with 2D MXenes. Present work makes the first effort to combine and exploit them for detecting the thrombin levels; a crucial proteolytic enzyme that plays a pivotal role in regulating blood clotting by cleaving fibrinogen into fibrin and plays a critical role in bleeding disorders such as Haemophilia and Von Willebrand disease. This study introduces a novel hybrid DNA hydrogel by leveraging the properties of 2D MXene with a thiol-modified thrombin binding aptamer (TBA) as a crosslinking agent. The TBA and its complementary DNA oligos are immobilized on 2D MXene sheets, forming a packed hydrogel. Upon thrombin binding, the TBA releases its complementary DNA, resulting in a loosened hydrogel and a change in resistance, which is used as a read-out for thrombin detection. The concept is successfully demonstrated, achieving 90-92% accuracy in detecting thrombin in artificial samples. This robust technique holds promise for biomedical sensing devices, allowing customization for the detection of various target molecules using specific aptamers.
Genetic gradual reduction of OGT activity unveils the essential role of O-GlcNAc in the mouse embryo
Authors: Formichetti Sara , Sadowska Agnieszka , Ascolani Michela , Hansen Julia , Ganter Kerstin , Lancrin Christophe , Humphreys Neil , Boulard Mathieu
Published: April 2024

The reversible glycosylation of nuclear and cytoplasmic proteins (O-GlcNAcylation) is catalyzed by a single enzyme, namely O-GlcNAc transferase (OGT). The mammalianOgtgene is X-linked and it is essential for embryonic development and for the viability of proliferating cells. We perturbed OGT’s functionin vivoby creating a murine allelic series of four single amino acid substitutions reducing OGT’s catalytic activity to a range of degrees. The severity of the embryonic lethality was proportional to the degree of impairment of OGT’s catalysis, demonstrating that the O-GlcNAc modification itself is required for early development. We identified milder hypomorphicOgtalleles that perturb O-GlcNAc homeostasis while being compatible with embryogenesis. The analysis of the transcriptomes of the mutant embryos at different stages suggested a sexually-dimorphic developmental delay caused by the decrease in O-GlcNAc. Furthermore, a mild reduction of OGT’s enzymatic activity was sufficient to loosen the silencing of endogenous retrovirusesin vivo.