bluuebunny/crossref_metadata_2025 huggingface dataset:
AtKC1 inhibitsAtAKT1 activation via its amino-terminal inhibitory domain
Authors: Zheng Zijie , Qu Yannan , Chen Jiexin , Tang Yuyue , Liu Dongliang , Huang Zhuo , Shen Huaizong
Published: December 2024

AKT1 is a plant Shaker-like, hyperpolarization-activated K+channel which plays a crucial role in K+absorption. Besides phosphorylation, AKT1 is subject to negative regulation byAtKC1, a silent channel of the same family. Previous structural studies unveiled that AKT1 andAtKC1 form 2:2 heterotetramer in purified samples. However, the structural analysis failed to offer more insight into the inhibition mechanism of AKT1 activation byAtKC1. Here, inspecting the complex structure of AKT1-AtKC1 reveals that a stable domain ofAtKC1 (residues 53 to 80), named inhibitory domain or I-domain, may inhibit AKT1 activation by stabilizing its depolarized, closed conformation. We confirmed this hypothesis with electrophysiological experiments. Interestingly, a single-point mutation (G315D) inAtKC1 has been reported to abolish its ability to inhibit AKT1. We solved the structure of AKT1-AtKC1(G315D) at a resolution of 2.8 Å which revealed an unexpected stoichiometry alteration between AKT1 andAtKC1 from 2:2 to 3:1. This stoichiometry change further supports the hypothesis as we reason that single I-domain ofAtKC1 in the channel complex is insufficient to effectively inhibit channel activation. Our findings reveal the inhibition mechanism ofAtKC1 on AKT1 and offer insight into the regulatory mechanisms of hyperpolarization-activated channels.
Ecological assembly dynamics of the seed-borne microbiome in cultivated and wild wheat
Authors: Özkurt Ezgi , Mariush Zaywa , Landermann-Habetha Doreen , Stukenbrock Eva H.
Published: December 2024

Background

Plants host diverse microbial communities that can significantly impact plant health. A portion of these communities is vertically transmitted to the next generation through seeds, influencing early plant development. While seed microbiota composition is known to be shaped by environmental, genetic, and stochastic factors, detailed insights into the factors that govern variation within and between plants of the same species remain limited. Furthermore, the dynamic of the vertically-transmitted microbes and their mode of host colonization are poorly understood.

Results

In this study, we characterized the bacterial communities of multiple seeds originating from the same spike of adult wheat plants and demonstrated a high extent of homogeneity in the composition of microorganisms. We propagated wheat seedlings under controlled conditions to monitor host colonization by these microorganisms. Intriguingly, in spite of a relatively homogeneous composition of bacteria in individual seeds, the microbes colonizing early-stage seedlings, particularly during their initial leaf development, vary extensively, even among seedlings of seeds from the same spike. Applying a neutral assembly model, we show that the transmission of microbiomes from seeds to seedlings is primarily governed by selective processes, whereas post-transmission microbial assembly in seedlings is governed by stochastic events.

Conclusions

Overall, this study introduces a novel experimental approach for investigating microbiome inheritance in plants. By leveraging high replication of seeds from the same wheat plant and field, we provide new insights into the stochastic nature of seed-associated microbiome composition and transmission in wheat.
Utilizing full-length 16S rRNA sequencing to assess the impact of diet formulation and age on targeted gut microbiome colonization in laboratory and mass-reared Mediterranean fruit flies
Authors: Mason Charles J. , Nelson Rosalie C. , Weaver Mikinley , Simmonds Tyler , Geib Scott , Shikano Ikkei
Published: December 2024

Insect gut microbiomes have important roles in overall host health and how hosts function in the environment. In laboratory and mass-reared insects, gut microbiomes can differ in composition and function compared to wild conspecifics. For fruit flies, like the Mediterranean fruit fly (medfly;Ceratitis capitata), these changes can influence male performance and behavior.

Overall, understanding factors that influence the ability of bacteria to colonize hosts is an important for the establishment of lost or novel microbiota into mass-reared insects. The goal of this study was to evaluate how host age and diet inoculation method influenced bacterial establishment in laboratory and mass-reared medfly. We used anEnterobacterstrain with antibiotic resistance and coupled it with full-length PacBio 16S rRNA sequencing to track the establishment of a specific isolates under different adult dietary conditions. We also used two longstanding reared lines of medfly in our study. Our results identified that diet had a strong interaction with age. Host medfly fed a liquid diet with the target bacteria were able to be colonized regardless of age, but those fed a slurry-based diet and separate water source were more resilient. This was consistent for both fly rearing lines used in the study. 16S rRNA sequencing corroborated the establishment of the specific strain, but also revealed some species/strain-level variation ofEnterobactersequences associated with the flies. Additionally, our study illustrates that long-read 16S rRNA sequencing may afford improved characterization of species- and strain-level distribution of Enterobacteriaceae in insects.

Importance:

Insects form intimate relationships with gut microorganisms that can help facilitate several important roles. The goals of our study were to evaluate factors that influence microbial establishment in lines of the Mediterranean fruit fly (medfly), an important pest species throughout the world. Mass-reared insects for sterile insect technique often possess gut microbiomes that substantially differ from wild flies, which can impact their performance in pest control contexts. Here, we show that liquid-based formulations can be utilized to manipulate the gut microbiota of mass-reared medfly. Furthermore, using near full-length 16S rRNA metabarcoding sequencing, we uncovered strain-level diversity of that was not immediately obvious using other approaches. This is a notable finding, as it suggests that full-length 16S rRNA approaches can have marked improvements for some taxa compared to fewer hypervariable regions at approximately the same cost. Our results provide new avenues for exploring and interrogating medfly-microbiome interactions.
Morphometric Identification of Parvalbumin-Positive Interneurons: A Data-Driven Approach
Authors: Panday Maheshwar , Monteiro Leanne , Daudi Ahad , Murphy Kathryn M.
Published: December 2024

Traditionally, anatomical studies of parvalbumin-positive (PV+) labelled interneurons describe them as a homogeneous population of neurons. In contrast, recent single-cell RNAseq studies have identified multiple transcriptomically distinct categories of PV+ cells. That difference between a single anatomical category of PV+ neurons and multiple transcriptomic categories presents a problem in understanding the role of these neurons in cortical function. One gap that might contribute to this discrepancy is that PV+ morphology is typically addressed using qualitative descriptions and simple quantifications, while single-cell RNAseq studies use big data and high dimensional analyses. PV+ neurons play critical roles in the experience-dependent development of the cortex and are often involved in disease-related changes associated with neurodegenerative and neuropsychiatric disorders. Here, we developed a modern data-driven analysis pipeline to quantify PV+ morphology. We quantified 97 morphometric features from 14274 PV+ neurons and applied unsupervised clustering that identified 13 different PV+ morphologies. We extended the analysis to compare PV+ dendritic arbour patterns and cell body morphologies. Finally, we compared the morphologies of PV+ neurons with the cell body morphologies of neurons expressing various genes associated with PV+ transcriptomic cell types. This approach identified a range of PV+ morphologies similar to the number of transcriptomic categories. It also found that the PV+ morphologies have cortical area, laminar, and transcriptomic biases that might contribute to cortical function.
Functional expression and sex dimorphism of the T-type Cav3.2 Calcium Channel in human DRG Neurons
Authors: Chemin Jean , Soubeyre Vanessa , Shiers Stephanie , François Amaury , Poulen Gaëtan , Lonjon Nicolas , Vachiery-Lahaye Florence , Bauchet Luc , Mery Pierre François , Price Theodore J , Bourinet Emmanuel
Published: December 2024

T-type/Cav3 calcium channels are key in neuronal excitability and pain processing with Cav3.2 being the prominent isoform in primary sensory neurons of the dorsal root ganglion (DRG). Its pharmacological inhibition or gene silencing induces analgesia in several preclinical models of inflammatory and neuropathic pain. However, the presence of Cav3.2, encoded by theCACNA1Hgene, in human DRG neurons remains unresolved. Using RNA in-situ hybridization and electrophysiological recordings, we show that human DRGs express Cav3.2 in a subset of neurons positive for the neurotrophic factor receptor TrkB (NTRK2gene). The Cav3.2 current exhibits typical biophysical and pharmacological properties, including inhibition by a low concentration of nickel and by Z944, a specific T-type calcium channel blocker in advanced clinical development. Conversely, ABT-639, a T-type calcium channel inhibitor that failed in Phase 2 trials for pain relief, does not inhibit Cav3.2 currents in human DRG neurons. Importantly, Cav3.2 currents are prominent in neurons from female organ donors, supporting the presence of sex differences in pain mechanisms in humans. These findings underscore the potential of continued exploration of Cav3.2 as a therapeutic target for pain treatment and highlight a specific subset of human neurons that likely rely on this channel to modulate their excitability.
Dominant Formation of DNA:RNA Hybrid G-Quadruplexes in the Genomes of Living Human and Mouse Cells
Authors: Tan Zheng
Published: December 2024

Guanine-rich nucleic acids can form four-stranded structures known as G-quadruplexes (G4s), which play critical roles in essential cellular activities. Putative G-quadruplex-forming sequences (PQSs) are abundant in the genomes of animal cells. To date, research on G4s has focused primarily on intramolecular G4s formed by four contiguous G-tracts from the same nucleic acid strand. However, our recent study indicates that a hybrid type of G4s, DNA:RNA hybrid G4s (hG4s), comprising G-tracts from both DNA and RNA, is, in fact, the most abundant G4 species found in the genomes of living yeast cells. Here, we demonstrate that hG4s also readily form and predominate in the genomes of living human and mouse cells, with an abundance several orders of magnitude greater than that of intramolecular DNA G4s (dG4s). Furthermore, each individual G-tract in a PQS tends to form an hG4 independent of adjacent G-tracts. This independence of DNA G-tracts is maintained even in PQSs containing four G-tracts, despite their potential to form intramolecular DNA G4s only by themselves. Collectively, our studies demonstrate that hG4s are the predominant physiological G4 structures in the genomes of eukaryotic organisms. Given that hG4s differ significantly from intramolecular dG4s in terms of structural form, formation mechanism, abundance, and association with transcription, there is a clear need for a comprehensive revision of our current understanding of genomic G4s and their functional roles. We hypothesize that hG4 formation may serve as a global sensing mechanism to monitor RNA levels in cells to maintain transcriptional homeostasis.

Abstract Figure
Tapetum specific TA29 promoter is regulated bycis- elements binding to positive and negative regulators
Authors: Sharma Preeti Apurve , Soni Kamlesh Kumar , Minhajuddin Bm , Yadava Satish Kumar , Burma Pradeep Kumar
Published: December 2024

The TA29 gene fromNicotiana tabacumwas one of the first tapetum-specific genes identified in 1990. Its promoter has been successfully used to developbarnase/barstargene-based male sterility and restorer transgenic lines for hybrid seed production in crops such as mustard. Despite its biotechnological significance, no major studies have been conducted to delineate the regulatory mechanisms of its promoter. The presented work identifies criticalcis-elements of the promoter, starting within-silicoanalysis followed by functional validation through mutational studies and promoter activity analysis in transgenic tobacco lines. This work led to the identification ofcis-elements that are putative binding sites for the transcription factors NtMYB12, NtGT-1a, NtNAG1, and NtLZ-HD. The binding sites for NtMYB12, NtGT-1a, and NtNAG1 act as positive regulators, whereas the binding site for NtLZ-HD functions as a negative regulator.
Global distribution of a land plant by means of oceanic dispersal
Authors: Vatanparast Mohammad , Takayama Koji , Tateishi Yoichi , Kajita Tadashi
Published: December 2024

The geographic range of species is one of the key indicators of their evolutionary success. Unlike animals, most plants are immobile and expand their range primarily through long-distance dispersal (LDD) of seeds. Seeds can be dispersed over very long distances, especially by ocean currents. However, little is understood about the role of ocean currents in LDD and the contribution of land barriers to genetic differentiation on a global scale. To investigate the outermost limits of LDD by ocean currents in land plants, we studiedCanavalia rosea(Sw.) DC. (Fabaceae), which is distributed throughout littoral areas of the tropics and subtropics around the world. Our results using DNA sequences from six chloroplast regions and two low-copy nuclear loci from 436 individuals in 37 populations revealed that ocean currents played a crucial role in the species’ range expansion and maintaining its global distribution despite the constraints by continental barriers. These suggest that the global distribution ofC. roseais the result of recent transoceanic dispersal within and between the Atlantic and Indo-Pacific oceans, while the Isthmus of Panama has prevented gene flow across the American continents. These results highlight the power of oceanic seed dispersal in shaping plant biogeography.
Mathematical Programming and Graph Neural Networks illuminate functional heterogeneity of pathways in disease
Authors: Triantafyllidis Charalampos P.
Published: December 2024

We employ a computationally intensive framework that integrates mathematical programming and graph neural networks to elucidate functional phenotypic heterogeneity in disease by classifying entire pathways under various conditions of interest. Our approach combines three distinct yet seamlessly integrated modelling schemes: i) we first leverage Prior-Knowledge Networks (PKNs) derived from comprehensive and established databases to reconstruct their topology using genomic and transcriptomic data via mathematical programming optimization, ii) we apply causal learning via Additive Noise Models (ANMs) to further prune the optimized networks, and iii) we apply tailored Graph Convolutional Networks (GCNs) to classify each network as a single data point atgraph-level, using Mode of Regulation (MoR) and gene activity profiles as node embeddings. These networks may vary in their biological or molecular annotations, which serves as a labelling scheme for their supervised classification. We demonstrate the framework in the DNA damage and repair pathway using theTP53regulon in a pancancer study, classifying Gene Regulatory Networks (GRNs) across differentTP53mutation types. This scalable approach enables the classification of diverse conditions while addressing the multifactorial nature of diseases. It disentangles their polygenic complexity and reveals new functional patterns through a causal representation.
Spatially informed phenotyping by cyclic-in-situ-hybridization identifies novel fibroblast populations and their pathogenic niches in systemic sclerosis
Authors: Li Yi-Nan , Filla Tim , Györfi Andrea-Hermina , Liang Minrui , Devakumar Veda , Micu Alexandru , Chai Hongtao , Bergmann Christina , Pecher Ann-Christin , Henes Jörg , Moinzadeh Pia , Krieg Thomas , Kreuter Alexander , Schett Georg , Homey Bernhard , Dietrich Sascha , Distler Jörg H.W. , Matei Alexandru-Emil
Published: December 2024

Spatially non-resolved transcriptomic data identified functionally distinct populations of fibroblasts in health and disease. However, in-depth transcriptional profilingin situat single-cell resolution has not been possible so far. Here, we studied fibroblast populations in the skin of SSc patients and healthy individuals using cyclic in situ hybridization (cISH) as a novel approach for spatially-resolved transcriptional phenotyping with subcellular resolution. cISH deconvoluted the heterogeneity of 20,979 cells including 3,764 fibroblasts (FB). BANKSY-based spatially-informed clustering identified nine FB subpopulations, with SFRP2+ RetD FB and CCL19+ nonPV FB as novel subpopulations that reside in specific cellular niches and display unique gene expression profiles. SFRP2+ RetD FB and CCL19+ nonPV FB as well as COL8A1+ FB, display altered frequencies in SSc skin and play specific, disease-promoting roles for extracellular matrix release and leukocyte recruitment as revealed by their transcriptional profile, their cellular interactions and ligand-receptor analyses. The frequencies of COL8A1+ FB and their interactions with monocytic cells and B cells are associated with progression of skin fibrosis in SSc. In summary, our spatially-resolved transcriptomic approach identified novel fibroblast subpopulations deregulated in SSc skin with specific pathogenic roles, some of which may potentially serve as biomarkers for progression of skin fibrosis.
Different hydrological conditions after permafrost thaw result in distinct microbial community compositions
Authors: Waqas Muhammad , Liebmann Patrick , Vogel Cordula , Varsadiya Milan , Wang Haitao , Shibistova Olga , Novák Milan , Urich Tim , Guggenberger Georg , Bárta Jiří
Published: December 2024

Permafrost degradation leads to the formation of contrasting hydrological conditions such as water-saturated anoxic and dry oxic soils, which significantly influence the bacterial community structure and abundance. To investigate the bacterial abundance and diversity under these hydrological conditions, we collected soil samples from different horizons of both dry and wet degraded permafrost soils and non-degraded intact permafrost soil for comparison. The bacterial alpha diversity, measured by the Observed and Chao1 indices, was significantly greater in wet degraded permafrost soil (wet site) and intact permafrost soil (intact site) than in dry degraded permafrost soils (dry site). Notably, the wet and intact sites exhibited similar levels of alpha diversity as well as shared greater number of zOTUs. The relative proportion of most bacterial taxa was significantly differed among the sites. At the class level, dry site was dominated mainly by K-strategic bacteria like aliphatic degraders (Thermoleophilia), acidophilic and cellulolytic (Acidobacteriae), while wet site was dominated by mainly r-strategic bacteria from class Gammaproteobacteria and anoxygenic aerobic phototrophs (Gemmatimonadetes). According to Spearman correlation analysis, the relative proportion of bacterial taxa in dry and wet sites showed significant correlation with soil physicochemical parameters, whereas fewer correlations were found in intact site. The relative proportion of Pseudomonadota classes and Acidobacteriota were positively correlated with SOC, N, and C:N ratio, but were negatively correlated with pH in both dry and wet sites. In contrast, anaerobic methylotrophs (Methylomirabilota), anoxygenic photoheterotrops (Chloroflexota), Gemmatimonadota and filamentous Actinobacteriota were negatively correlated with SOC, N, and C:N. Additionally, strong correlations were observed between bacterial taxa and extracellular enzyme activities, where Alphaproteobacteria, Gammaproteobacteria, and Acidobacteriota showed positive correlations with both hydrolytic and oxidative enzymes in dry and wet sites, except for PerOx in wet site where they showed negative correlation. Conversely, Gemmatimonadota and Actinobacteriota displayed negative correlations with enzymes in dry and wet site, except for the PerOx in wet site, where they showed positive correlation.
Temporary suspension of mineral phosphorus reduces mobilizable bone zinc in adult laying hens irrespective of the dietary zinc supply
Authors: Lucke Annegret , Weller Agnes , Pokorny Julia , Puntigam Reinhard , Slama Julia , Schedle Karl , Windisch Wilhelm , Brugger Daniel
Published: December 2024

This study examined the effects of short-term dietary zinc (Zn) and phosphorus (P) variations on the mobilizable bone Zn pool and overall Zn status in adult laying hens. Forty-eight hens (50% Lohmann Brown Classic, 50% Lohmann LSL Classic) were housed in pairs (one hen per breed per pen) across 24 pens. The pens were randomly assigned to one of two dietary P levels (0.37% or 0.84% in DM) using a high-protein corn-soybean diet (11.4 MJ AME/kg, 21.5% CP) during a 14-day acclimatization period. Following acclimatization, pens from both P groups were further randomized into four dietary treatments in a 2 × 2 factorial design, varying in P levels (low vs. high) and Zn supplementation (28 vs. 131 mg/kg) over an 8-day experimental feeding phase. Performance metrics, egg production and quality, and tissue mineral concentrations (plasma, liver, bone, and eggs) were measured. Statistical analyses were performed using linear mixed models in SAS 9.4, incorporating random effects of pen nested within treatment group and fixed effects of dietary P, dietary Zn, breed, and their interactions. Tukey-corrected 95% confidence intervals were used to estimate effect differences, with significance set at P < 0.05. Performance metrics, including egg production and body weight, were unaffected by dietary treatments (P > 0.1), indicating no clinical symptoms of Zn deficiency. However, hens on low-Zn diets exhibited significant reductions in plasma Zn concentration (-0.83 mg/L; P = 0.0008) and liver Zn concentration (-6.78 mg/kg DM; P = 0.01), confirming subclinical Zn deficiency. Low-Zn diets also increased the femoral molar Ca:P ratio by 0.15 (P = 0.01), irrespective of dietary P supply. Interestingly, low-P diets led to a significant reduction in femur Zn content (-0.46 mg; P = 0.0009), regardless of Zn supplementation, following 21 days of reduced P feeding. These findings highlight the higher susceptibility of laying hens to phytate antagonism compared to broilers, as evidenced by measurable subclinical Zn deficiency under short-term Zn deprivation. Additionally, a temporary suspension of mineral P supply appeared to impair the mobilizable bone Zn pool. The underlying functional mechanisms driving these interactions remain unclear and warrant further investigation.
Pelagic ecosystem responses to changes in seawater conditions during the Middle Pleistocene Transition in the Eastern Mediterranean
Authors: Agiadi Konstantina , Vasiliev Iuliana , Vite Antoine , Zarkogiannis Stergios , Fuster-Alonso Alba , Mestre-Tomás Jorge , Koskeridou Efterpi , Quillévéré Frédéric
Published: December 2024

We present a multiproxy, ecosystem-level assessment of paleoenvironmental change and its impacts on marine organisms in the Eastern Mediterranean during the Middle Pleistocene Transition, between 923 and 756 kyr B.P. (marine isotope stages MIS 23–18). This study combines analyses of organic biomarkers; organic matter content; carbon and oxygen stable isotopes on bulk sediment, surface-dwelling, deep-dwelling planktonic and benthic foraminifera, ostracods and fish otoliths; as well as foraminiferal, ostracod and sponge abundance estimates, with a statistical assessment of paleoenvironmental regime shifts and estimation of fish distribution depths in the past. Our results show that temperature and productivity played the most important role in driving ecosystem changes in the study area at different times: temperature was the primary driver during MIS 21 interglacial, whereas productivity became a dominant factor in MIS 19 interglacial. In addition, the responses of organisms throughout the water column varied. Both interglacials yielded relatively higher plankton and benthos biomasses. However, for fishes, the responses differed. The abrupt global warming that occurred in early MIS 21, which was also captured by our record, probably led to a reduction in diel vertical migration by mesopelagic fishes and consequently to the efficiency of the biological carbon pump. In contrast, increased productivity across trophic levels is attested for MIS 19 that subsequently dropped in MIS 18, affecting foraminifera, ostracod and sponge biomasses, but not inhibiting fish diel vertical migration. Therefore, we conclude that carbon sequestration during MIS 19 was likely enhanced.
Water-conducting roots responsible for nitrogen uptake in maize (Zea mays)
Authors: Jiang Yutong , Whalen Joann K.
Published: December 2024

Nitrate (NO3-) uptake is primarily driven by mass flow and varies among maize root types. The importance of embryonic and crown roots in acquiring NO3-was determined here in wet and dry soils. Maize was grown in a split-root pot that segregated the embryonic and crown roots. The soil was moistened to water potentials of either -5kPa or -30kPa. A partial N mass balance was made by destructively sampling shoots, roots, and soils after 0, 24, and 48 h following15N-KNO3injection at the V3 and V6 stages. Gross nitrification was assessed using a15N isotope dilution technique. At the V3 stage, crown roots had 202% more N uptake than embryonic roots in wet soil (-5 kPa). However, in dry soil (-30 kPa), N uptake was similar for embryonic and crown roots, possibly due to an 80% reduction of hydraulic conductance in crown roots. By the V6 stage, crown roots dominated N uptake, with embryonic roots supplying < 20% of N uptake. Soil gross nitrification rate was similar for root types. The present studies indicated that maize NO3-uptake depends primarily on the crown roots, due to their capacity to extract water and NO3-from soil, even under dry conditions.

Highlight

This study reveals how different maize root types contribute to nitrate uptake under varying soil moisture conditions, suggesting that soil water management is important to ensure optimal nitrogen uptake.
Hampered AMPK-ULK1 cascade in Alzheimer’s disease (AD) instigates mitochondria dysfunctions and AD-related alterations that are alleviated by metformin
Authors: Mary Arnaud , Barale Samantha , Eysert Fanny , Valverde Audrey , Lacas-Gervais Sandra , Bauer Charlotte , Eddarkaoui Sabiha , Buée Luc , Buée-Scherrer Valérie , Checler Frédéric , Chami Mounia
Published: December 2024

Background

Mitochondrial structure and function alterations are key pathological features in Alzheimer’s disease (AD) brains. The adenosine monophosphate-activated protein kinase (AMPK) and its downstream effector Unc-51 like autophagy activating kinase 1 (ULK1) represent a key node controlling mitochondria health, the alteration of which likely contribute to AD development.

Methods

We designed this study to investigate AMPK-ULK1 activation state in post-mortem human sporadic AD brains, in 3xTgAD mice that recapitulate most of human AD features, and in neuronal cells expressing the amyloid precursor protein with the familial Swedish mutation (APPswe). We examined the impact of the pharmacological and genetic modulation of AMPK-ULK1 cascade on mitochondria structure and functions in APPswe cells. We evaluated the potential beneficial impact of AMPK-ULK1 activation by Metformin (Met) on mitochondria defects, as well as on early- and late-stage AD-related alterationsin vivoandex vivo.

Results

At first, we show that AMPK-ULK1 cascade is defective in murine and human AD brains as well as in APPswe cells. We then report that Met administration to 3xTgAD mice alleviates the alterations of neuronal mitochondria structure and function and we consolidate these results in cells using both pharmacological and genetic tools to modulate AMPK-ULK1 cascade. In mice brains, Met reduces the early accumulation of APP C-terminal fragments (APP-CTFs) as well as the amyloid beta (Aβ) burden present in aged mice. Mechanistically, we show that Met increases the localization of APP-CTFs within cathepsin D-positive lysosomal compartmentsin vivoand enhances cathepsin D activityin vitro. The reduction of Aβ load by Met occurs through an increased recruitment of Iba1+cells to Aβ plaques and an enhancement of the phagocytic activity of microglia. Accordingly, in symptomatic 3xTgAD mice, Met alleviates microgliosis and astrogliosis, modulates microglia morphology, reduces peripheral proinflammatory cytokines levels, and regulates the expression of a set of inflammatory genes. In addition, Met normalizes dendritic spines shape in organotypic hippocampal slice cultures modeling AD and improves learning performance of 3xTgAD mice.

Conclusions

Our study demonstrates potential therapeutic benefits of targeting AMPK-ULK1 cascade to reverse both early and late AD-related alterations, deserving further investigation in fundamental research and in human clinical studies.
Benchmarking of Chromatin Immunoprecipitation (ChIP-Seq) methods in the Pacific oysterMagallana gigas
Authors: Dellong Amelie , Fallet Manon , Stenger Pierre-Louis , Chaparro Cristian , Vidal-Dupiol Jeremie , Clément Julie , Cosseau Céline , Grunau Christoph
Published: December 2024

Chromatin Immunoprecipitation sequencing (ChIP-seq) is the method of choice to generate chromatin landscapes across genomes. The scarcity of literature on ChIPseq and absence of a canonical “gold standard” method in mollusks and especially the pacific oysterMagallana gigas, prompted us to compare four ChIP-seq methodologies (Native-ChIP, Crosslink-ChIP, ChIPmentation and Cut & Tag) to find the most suitable method for this species. Our results show that Cut & Tag performs best and ChIPmentation worst. We hypothesize that the reason for this lies in a particularly fragile chromatin structure around genes in the oyster.
Habitat complexity defines global biological and societal landscapes
Authors: Cant James , Schiettekatte Nina , Madin Elizabeth M. P. , Madin Joshua S , Dornelas Maria
Published: December 2024

The three-dimensional structure of land- and seascapes sits at the boundary of biotic and abiotic geographies, linking geological processes to the configuration of localised weather patterns and oceanographic regimes and determines whether, and how, organisms access and use available resources. Evaluating the relationship between habitat complexity and biodiversity has long been a prominent feature of ecological research. However, inconsistencies in approaches used in defining and quantifying habitat complexity have so far precluded cross-system comparisons, preventing synthetic assessments into the ecological and evolutionary role of habitat complexity. Here we expand a framework developed for quantifying the structural complexity of coral reef environments to present a scalable solution for estimating the complexity of terrestrial and aquatic habitats globally. We present high-resolution (1.87 x 1.87 km pixel size) maps detailing global patterns in the geometric complexity measures of height range, rugosity, and fractal dimension, and illustrate how key differences in these characteristics across marine and terrestrial landscapes serve to delineate the configuration of different biomes and anthromes. Overall, this work refines understanding for the mechanisms through which habitat complexity defines the global configuration of society and nature and offers a platform for exploring these interactions at varying spatial scales.
PSGL-1 excludes HIV Env from virion surface through spatial hindrance involving structural folding of the decameric repeats (DR)
Authors: Tiwari Sameer , Delfing Bryan M. , Han Yang , Lockhart Christopher , Haikerwal Amrita , Waheed Abdul A. , Freed Eric O. , Jafri M. Saleet , Klimov Dmitri , Wu Yuntao
Published: December 2024

P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like surface glycoprotein, is primarily expressed on lymphoid and myeloid cells. PSGL-1 has recently been identified as an HIV restriction factor, blocking HIV infectivity mainly through virion incorporation that sterically hinders virion attachment to target cells. PSGL-1 also inhibits HIV Env incorporation into virions. However, the molecular mechanisms of PSGL-1-mediated Env exclusion remained unclear. Here, we investigated the role of PSGL-1’s extracellular (EC) and intracellular (IC) domains in Env exclusion. We demonstrate that both EC and IC are important for Env exclusion; when EC was deleted, PSGL-1 completely lost its ability to inhibit Env incorporation, whereas when IC was deleted, PSGL-1 partially lost this activity. In addition, when the decameric repeats (DR) were deleted from EC, PSGL-1 also lost its ability to inhibit Env incorporation. Sequential DR deletion mutagenesis further demonstrated that a minimum of 9 DRs is necessary for Env exclusion. Molecular modeling of the DR structure revealed that PSGL-1 mutants with 7 or fewer DRs pose as an extended “rod-like” structure, whereas those with 9 or more DRs collapse into a “coil-like” structure that spatially excludes Env. Our studies suggest a model in which Env exclusion involves Gag-mediated PSGL-1 targeting to the virion assembly site where DR-mediated spatial exclusion blocks Env incorporation.
Fluid intelligence relates to neural measures of cognitive map formation
Authors: Tenderra R.M. , Theves S.
Published: December 2024

Psychometric research on intelligence consistently identifies latent factors underlying performance correlations across cognitive tasks, with one general factor (g) explaining most variance and predicting general life outcomes. Their biological basis is yet unresolved, in particular with regard to the neural information processing mechanisms that may underlie intelligence. Here we test the hypothesis that interindividual differences in relational processing, supported by cognitive maps in the hippocampus, are related to fluid intelligence (gf), a statistical approximation of the general factor. Using standardized cognitive tests and fMRI of mnemonic tasks, we demonstrate a positive correlation specifically between gfand map-like relational encoding of task information. This relationship was neither present for non-relational mnemonic responses in the hippocampus nor for less g-related factors. These findings offer first empirical support for a link between neural mechanisms related to relational reasoning and general cognitive performance and probe the presumed relevance of hippocampal coding properties for cognition more broadly.
Biophysical boundaries for dormancy release in sunflower achenes
Authors: Arata Gonzalo Joaquín , Batlla Diego , Riveira-Rubin Mailén , Demkura Patricia Verónica , Mazzobre María Florencia , Rolandelli Guido , Buera María del Pilar , Rodríguez María Verónica
Published: December 2024

Reactions leading to dormancy release (DR) in “dry”, orthodox seeds are still poorly understood, as well as their dependence on moisture content and temperature. Sunflower achenes were used to explore the effects of MC combined with a wide range of storage temperatures (ST°) on DR dynamics, tested at 10 and 25°C. Embryo sensitivity to abscisic acid, oxygen uptake and ageing indicators were followed and complemented with predicted viability loss dynamics. Water status was addressed with sorption isotherms and the glass transition temperature (Tg). Small variations in MC and ST° had profound effects on achene dormancy and embryo responsiveness to ABA. Using a ‘temperature by humidity’ coordinate system we mapped three regions allowing DR within the glassy, rubbery and fluid states. Full DR (allowing germination at 10 and 25°C) occurred only in the rubbery state (aboveTg), and optimal ST° for full DR dropped from +30 to-18°C with MC increasing from 0.045 to 0.1 gH2O.gDW-1. Differently, under both glassy and fluid states, DR was incomplete (allowing germination at 25°C but not at 10°C) and required warm ST° which also promoted ageing.

Highlight

Sunflower achenes display diverse mechanisms for dormancy release in the “dry” state, depending on the physical state of water produced by different humidity and temperature combinations.
Single-cell analysis of the epigenome and 3D chromatin architecture in the human retina
Authors: Yuan Ying , Biswas Pooja , Zemke Nathan R. , Dang Kelsey , Wu Yue , D’Antonio Matteo , Xie Yang , Yang Qian , Dong Keyi , Lau Pik Ki , Li Daofeng , Seng Chad , Bartosik Weronika , Buchanan Justin , Lin Lin , Lancione Ryan , Wang Kangli , Lee Seoyeon , Gibbs Zane , Ecker Joseph , Frazer Kelly , Wang Ting , Preissl Sebastian , Wang Allen , Ayyagari Radha , Ren Bing
Published: December 2024

Most genetic risk variants linked to ocular diseases are non-protein coding and presumably contribute to disease through dysregulation of gene expression, however, deeper understanding of their mechanisms of action has been impeded by an incomplete annotation of the transcriptional regulatory elements across different retinal cell types. To address this knowledge gap, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome and 3D chromatin architecture in human retina, macula, and retinal pigment epithelium (RPE)/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 sub-classes of retinal cells. Comparative analysis of chromatin landscapes between human and mouse retina cells further revealed both evolutionarily conserved and divergent retinal gene-regulatory programs. Leveraging the rapid advancements in deep-learning techniques, we developed sequence-based predictors to interpret non-coding risk variants of retina diseases. Our study establishes retina-wide, single-cell transcriptome, epigenome, and 3D genome atlases, and provides a resource for studying the gene regulatory programs of the human retina and relevant diseases.
Motor unit mechanisms of speed control in mouse locomotion
Authors: Thomas Kyle , Gibbs Rhuna , Marques Hugo , Carey Megan R. , Sober Samuel J.
Published: December 2024

During locomotion, the coordinated activity of dozens of muscles shapes the kinematic features of each stride, including systematic changes in limb movement across walking speed. Motor units, each of which consists of a single motor neuron and the muscle fibers it innervates, contribute to the total activation of each muscle through their recruitment and firing rate when active. However, it remains unknown how the nervous system controls locomotor speed by changing the firing of individual motor units. To address this, we combined quantitative behavioral analysis of mouse locomotion with single motor unit recordings from the lateral and long heads of the triceps brachii, which drive monoarticular extension of the elbow and biarticular movements of the elbow and shoulder, respectively. In contrast to prior studies employing bulk EMG to examine muscle activity, our recordings revealed the diversity of spike patterning across motor units as well as systematic differences in motor unit activity across muscles and locomotor speeds. First, motor unit activity differed significantly across the lateral and long heads, suggesting differential control of these two closely apposed elbow extensor muscles. Second, we found that individual units were recruited probabilistically during only a subset of strides, showing that bulk EMG signals consistently present in every stride in fact reflect stochastically varying subsets of individual motor units. Finally, although recruitment probability and firing rate both increased at faster walking speeds, increases in recruitment were proportionally larger than rate changes, and recruitment of individual units accompanied changes in limb kinematics. Together, these results reveal how the firing of individual motor units varies systematically across muscles and walking speeds to produce flexible locomotor behavior.
Neural mechanisms of attention, not expectation, govern spatial selection by probabilistic cueing
Authors: Sunder Sricharan , Rajendran Kavya , Biswas Mainak , Sridharan Devarajan
Published: December 2024

Spatial probabilistic “Posner” cueing is widely employed in studies of endogenous spatial attention. Such cueing guides attention by providing prior knowledge about the likely spatial location of task-relevant events. Yet, it has been compellingly argued that such spatial priors also elicit expectation effects, rendering Posner cueing unsuitable for measuring attentional effects in isolation. We address this debate by combining signal detection theory models of behavior with concurrent electrophysiological recordings, and directly compare Posner cueing effects with those of attention and expectation cueing. Participants performed two tasks: a dual cueing task, with orthogonal relevance (attention) and probability (expectation) cues, as well as a Posner cueing task. Relevance and probability cueing independently modulated distinct behavioral parameters – perceptual sensitivity and decisional criterion, respectively – whereas Posner cueing modulated both sensitivity and criterion. However, only sensitivity modulations by Posner cueing were correlated with those of relevance cueing. Criterion modulations by Posner cueing were uncorrelated with those of probability cueing. Both Posner and relevance cueing, but not probability cueing, modulated various neural markers of spatial attention, including steady-state visually evoked potential (SSVEP) amplitude and alpha-band (8-12 Hz) oscillation power. Representational similarity analysis and cue-label prediction with deep convolutional neural networks revealed dissociable underpinnings of relevance and probability cueing, and identified Posner cueing’s neural representations with those of relevance cueing. Our results address a long-standing debate in the attention literature and clearly demonstrate that spatial selection by probabilistic cueing is governed by neural mechanisms of attention, not expectation.

Significance Statement

How does our brain select relevant information for accomplishing task goals? “Posner cueing” is a popular choice for studying brain mechanisms of goal-driven attention in the lab. Posner cues guide attention by providing advance information about the likely location of task-relevant events. Yet, Posner cueing has been criticized because it engages brain mechanisms not only of attention but of event expectation, as well. We address this critique by employing state-of-the-art neural decoding approaches, including deep convolutional neural networks, and show that behavioral and neural underpinnings of Posner cueing closely match those of attention, not expectation. The results address a long-standing debate in the attention literature and validate Posner cueing as a reliable method for measuring attention’s effects in the brain.
Threshold-dependent negative autoregulation of PIF4 gene expression optimizes growth and fitness in Arabidopsis
Authors: Das Sreya , Garhwal Vikas , Mondal Krishanu , Das Dipjyoti , Gangappa Sreeramaiah N.
Published: December 2024

PHYTOCHROME INTERACTING FACTOR 4 (PIF4) is a vital transcription factor that controls plant growth by integrating environmental signals like light and temperature. Though upstream regulators of PIF4 are known, transcriptional regulation ofPIF4is poorly understood. Here, we demonstrate that thePIF4undergoes negative autoregulation. We show thatPIF4promoter activity is more in thepif4mutant but significantly reduced inPIF4overexpression transgenic lines. Moreover, CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), which enhances PIF4 protein stability, promotes PIF4 autoinhibition. However, Phytochrome B (phyB), a photoreceptor that decreases PIF4 stability, inhibits autoinhibition. We further develop a network-based mathematical model incorporating the PIF4 autoinhibition and other key interactions. Our modeling and data analysis reveals that PIF4 autoregulation depends on a threshold of cellular PIF4 concentration. Our model also successfully predicts the hypocotyl growth andPIF4promoter activity in various light and temperature conditions. Moreover, we show that the transgenic lines with enhanced PIF4 function negatively influence biomass and yield, irrespective of photoperiod and temperature. Together, the negative feedback of PIF4 dampens its own function and restraints unregulated growth. Our study thus elucidates the mechanisms of how the phyB-COP1/DET1-PIF4 module controlsPIF4transcription in tune with the endogenous PIF4 level.
The (α, β)-kBoolean Signatures of Molecular Toxicity: Microcystin as a Case Study
Authors: Moscato Pablo , Jaeger-Honz Sabrina , Haque Mohammad Nazmul , Schreiber Falk
Published: December 2024

Background

The (α, β)-k-Feature Set Problem is a combinatorial problem, that has been proven as alternative to typical methods for reducing the dimensionality of large datasets without compromising the performance of machine learning classifiers.

Result

We present a case study that shows that solutions of the (α, β)-k-Feature Set Problem help to identify molecular substructures related to toxicity. The dataset investigated in this study is based on the inhibition of ser/thr-proteinphosphatases by Microcystin (MC) congeners. MC congeners are a class of structurally similar cyanobacterial toxins, which are critical to human consumption.

Conclusion

We show that it is possible to identify biologically meaningful toxicity signatures by applying the (α, β)-kfeature sets on extended connectivity fingerprint representations of MC congeners. Boolean rules were derived from the feature sets to classify toxicity and can be mapped on the chemical structure, leading to insights on the absence/presence of substructures that can explain toxicity. The presented method can be applied on any other molecular data set and is therefore transferrable to other use cases.
Predation on scyphozoan polyps and selective nematocyst incorporation dynamics in the aeolid,Caloria militaris
Authors: Dror Hila , Lotan Tamar , Angel Dror
Published: December 2024

Aeolid nudibranchs are known to prey on various cnidarians and incorporate nematocysts from their prey into their cerata (dorsal appendages) for self-defense. Nematocyst incorporation is selective, and is based on species, diet, prey availability, and predation pressure. This study investigated the interactions between two nudibranch species,Caloria militarisandFlabellina affinis, and scyphozoan polyps from common eastern Mediterranean jellyfish species, includingRhopilema nomadica,Cassiopea andromeda,Phyllorhiza punctata, andAureliasp. Laboratory experiments were used to assess whether these nudibranchs feed on scyphozoan polyps, and if they incorporate the prey nematocysts into the cerata. Results indicate that whileF. affinisavoids scyphozoan polyps,C. militarisconsumes all tested species, and can subsist on them for extended durations (up to 255 days). Predation rates varied among prey species tested, ranging from a mean of 8 to 43.3 polyps day-1. However,C. militarisdoes not store scyphozoan nematocysts. These findings contribute to understanding nudibranch feeding ecology and the potential roles these predators play in regulating jellyfish blooms. Identification of scyphozoan nematocysts in the cerata of predator aeolid nudibranchs is discussed as a means to locate cryptic scyphozoan polyps in the marine environment.