Miracle-dz/UniFAR-FTUs huggingface dataset:
A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease

Alzheimer’s Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution. Author Summary Cognitive decline in Alzheimer’s Disease (AD) correlates most strongly with dysfunction and loss of synapses in affected brain regions. While synaptic dysfunction is a well-established early symptom of AD, how impaired synaptic transmission may lead to progressive cognitive decline, remains subject to active research. In this study, we examine the effect of synapse loss on neuronal network function using a computational model of place cells in the hippocampal network. Place cells encode a cognitive map of an animal’s environment, enabling navigation and spatial memory. This provides a useful indicator of cognitive function, as place cell function is well characterized and abnormalities in place cell firing have been shown to underlie navigational deficits in rodents. We find that synapse loss in our network is sufficient to produce progressive impairments in place cell function, which resemble those observed in mouse models of the disease, supporting the hypothesis that synaptic dysfunction may underlie the cognitive impairment in AD. Furthermore, we observe that loss of excitatory and inhibitory synapses produce distinct spatial impairments. Future experiments investigating the relative contribution of different synaptic inputs may thus allow new insights into the neuronal network alterations in AD and potentially enable the identification of new therapeutic targets.
Postharvest handling induces changes in fruit DNA methylation status and is associated with alterations in fruit quality in tomato (Solanum lycopersicum L.)

Postharvest handling of tomato (Solanum lycopersicum L.), specifically low-temperature storage and early harvest are used to extend shelf life, but often reduce fruit quality. Recent work suggests that DNA methylation dynamics influences fruit ripening through the demethylase SlDML2 gene. However, the influence of postharvest handling on DNA methylation in relation to fruit quality is unclear. This work aimed to clarify these issues by analyzing DNA methylation using methyl-sensitive amplification polymorphism (MSAP), semi-quantitative transcriptional analysis of marker genes for fruit quality (RIN; RIPENING INHIBITOR) and DNA methylation (SlDML2; Solanum lycopersicum L. DNA demethylase 2), and, fruit biochemical quality biomarkers. Multivariate analysis of these data supported the view that DNA methylation of fruit was influenced more by postharvest handling than ripening stage, however, fruit quality was influenced mainly by ripening. Fruit chilled postharvest were distinct in their DNA methylation state and quality characteristics, which implied that these three phenomena i.e., chilling, methylation, and quality are highly connected. In addition, different postharvest handling methods modulated SlDML2 transcript levels but had little effect on the level of RIN transcripts in fruit that reached the Turning stage after early harvest, and cold storage. These data collectively helped to advance our interpretation of tomato fruit ripening. In conclusion, our findings revealed that postharvest-induced variation in fruit quality is in relation to DNA methylation. Long-term this work will help better connect physiological changes in tomato fruit to events happening at the molecular level.
A virulence associated siderophore importer causes antimicrobial efflux in Klebsiella pneumoniae

The accessory genome of many pathogenic bacteria includes ABC transporters that scavenge metal by siderophore uptake and ABC transporters that contribute to antimicrobial resistance by multidrug efflux. There are mechanistic and recently recognised structural similarities between siderophore importer proteins and efflux pumps. Here we investigated the influence of siderophore importer YbtPQ on antimicrobial resistance of Klebsiella pneumoniae. YbtPQ is encoded in the yersiniabactin cluster in a prevalent mobile genetic element ICEKp, and is also common in pathogenicity islands of Escherichia coli and Yersinia species, where yersiniabactin enhances virulence. Deletion of ICEKp increased the sensitivity of K. pneumoniae to all antimicrobials tested. The mechanism was dependent on the yersiniabactin importer YbtPQ and involved antimicrobial efflux, since it was affected by the inhibitor reserpine. The element ICEKp is naturally highly mobile, indeed the accessory genome of K. pneumoniae is recognised as a reservoir of genes for the emergence of hospital outbreak strains and for transfer to other Gram-negative pathogens. Introduction of ICEKp, or a plasmid encoding YbtPQ, to E. coli decreased its sensitivity to a broad range of antimicrobials. Thus, a confirmed siderophore importer, on a rapidly evolving and highly mobile element capable of interspecies transfer, may have a secondary function exporting antimicrobials.
The effects of starvation.

Ancel Keys, a professor of physiology at the University of Minnesota and a consultant to the War Department, wanted to study the effects of starvation, and find the best way to provide post-war rehabilitation to people who had experienced severe deprivation and emaciation during the war. This led Keys to conduct a study to observe the physical and mental effects of starvation on healthy men by studying them under normal conditions, subjecting them to semistarvation, and then following them through rehabilitation. The participants were healthy young men who were “World War II conscientious objectors” (refused to serve in the war).
Reconfigurable Filtering of Neuro-Spike Communications Using Synthetically Engineered Logic Circuits

High-frequency firing activity can be induced either naturally in a healthy brain as a result of the processing of sensory stimuli or as an uncontrolled synchronous activity characterizing epileptic seizures. As part of this work, we investigate how logic circuits that are engineered in neurons can be used to design spike filters, attenuating high-frequency activity in a neuronal network that can be used to minimize the effects of neurodegenerative disorders such as epilepsy. We propose a reconfigurable filter design built from small neuronal networks that behave as digital logic circuits. We developed a mathematical framework to obtain a transfer function derived from a linearization process of the Hodgkin-Huxley model. Our results suggest that individual gates working as the output of the logic circuits can be used as a reconfigurable filtering technique. Also, as part of the analysis, the analytical model showed similar levels of attenuation in the frequency domain when compared to computational simulations by fine-tuning the synaptic weight. The proposed approach can potentially lead to precise and tunable treatments for neurological conditions that are inspired by communication theory.
Deep-LUMEN Assay – Human lung epithelial spheroid classification from brightfield images using deep learning

Three-dimensional (3D) tissue models such as epithelial spheroids or organoids have become popular for pre-clinical drug studies. However, different from 2D monolayer culture, the characterization of 3D tissue models from non-invasive brightfield images is a significant challenge. To address this issue, here we report a Deep-Learning Uncovered Measurement of Epithelial Networks (Deep-LUMEN) assay. Deep-LUMEN is an object detection algorithm that has been fine-tuned to automatically uncover subtle differences in epithelial spheroid morphology from brightfield images. This algorithm can track changes in the luminal structure of tissue spheroids and distinguish between polarized and non-polarized lung epithelial spheroids. The Deep-LUMEN assay was validated by screening for changes in spheroid epithelial architecture in response to different extracellular matrices and drug treatments. Specifically, we found the dose-dependent toxicity of Cyclosporin can be underestimated if the effect of the drug on tissue morphology is not considered. Hence, Deep-LUMEN could be used to assess drug effects and capture morphological changes in 3D spheroid models in a non-invasive manner. Significance of the work Deep learning has been applied for the first time to autonomously detect subtle morphological changes in 3D multi-cellular spheroids, such as spheroid polarity, from brightfield images in a label-free manner. The technique has been validated by detecting changes in spheroid morphology in response to changes in extracellular matrices and drug treatments.
Identification of signaling pathways, matrix-digestion enzymes, and motility components controlling Vibrio cholerae biofilm dispersal

Bacteria alternate between being free-swimming and existing as members of sessile multicellular communities called biofilms. The biofilm lifecycle occurs in three stages: cell attachment, biofilm maturation, and biofilm dispersal. Vibrio cholerae biofilms are hyper-infectious and biofilm formation and dispersal are considered central to disease transmission. While biofilm formation is well-studied, almost nothing is known about biofilm dispersal. Here, we conduct an imaging screen for V. cholerae mutants that fail to disperse, revealing three classes of dispersal components: signal transduction proteins, matrix-degradation enzymes, and motility factors. Signaling proteins dominated the screen and among them, we focused on an uncharacterized two-component sensory system that we name DbfS/DbfR for Dispersal of Biofilm Sensor/Regulator. Phospho-DbfR represses biofilm dispersal. DbfS dephosphorylates and thereby inactivates DbfR, which permits dispersal. Matrix degradation requires two enzymes: LapG, which cleaves adhesins, and RbmB, which digests matrix polysaccharide. Reorientations in swimming direction, mediated by CheY3, are necessary for cells to escape from the porous biofilm matrix. We suggest that these components act sequentially: signaling launches dispersal by terminating matrix production and triggering matrix digestion and, subsequently, cell motility permits escape from biofilms. This study lays the groundwork for interventions that modulate V. cholerae biofilm dispersal to ameliorate disease. Significance statement The pathogen Vibrio cholerae alternates between the free-swimming state and existing in sessile multicellular communities known as biofilms. Transitioning between these lifestyles is key for disease transmission. V. cholerae biofilm formation is well studied, however, almost nothing is known about how V. cholerae cells disperse from biofilms, precluding understanding of a central pathogenicity step. Here, we conducted a high-content imaging screen for V. cholerae mutants that failed to disperse. Our screen revealed three classes of components required for dispersal: signal transduction, matrix degradation, and motility factors. We characterized these components to reveal the sequence of molecular events that choreograph V. cholerae biofilm dispersal. Our report provides a framework for developing strategies to modulate biofilm dispersal to prevent or treat disease.
Modeling Soil Responses to Nitrogen and Phosphorus Fertilization Along a Soil Phosphorus Stock Gradient

In this study, we investigate the responses of soil organic carbon (C) to nitrogen (N) and phosphorus (P) additions along a soil P stock gradient of five beech forest stands in Germany, using a modeling approach. Two different soil models with coupled C, N, and P cycles are used to simulate fertilization experiments conducted at the study sites. The first model, the stand-alone soil module of QUINCY (QUINCY-soil, Thum et al., 2019), is a conventional soil model that uses first-order kinetics to describe soil organic matter (SOM) turnover and represents microbial biomass only implicitly. The second model, the Jena Soil Model (JSM) (Yu et al., 2020), is a novel microbial soil model, which explicitly simulates microbial dynamics and describes the turnover of SOM as the consequence of several interactive processes, such as microbially mediated depolymerization of litter and SOM, organo-mineral association, and vertical transport. We applied both site-level models to five study sites and compared the modeled soil profile with observations. In addition, model scenarios were conducted to simulate the fertilization of N and P, and we further evaluate the effect of soil P stock, plant litter quality, and SOM CNP stoichiometry, on the responses of soil (heterotrophic) respiration (Rs) to nutrient addition. We found that the fitness between simulated and observed SOM profiles (defined as normalized root mean square ratios, Knrmsr) were generally better in JSM than in QUINCY-soil (Knrmsr larger by 0.03 ± 0.10 to 0.16 ± 0.06 for various soil measurements at all sites); The general pattern of observed Rs responses to nutrient fertilization, that N addition decreases Rs whereas P addition increases it, can be reproduced by JSM but not by QUINCY-soil. Our results indicated that a detailed explicit description of microbial processes and organo-mineral association is required to model plant-soil-microbial interactions, thus to better reproduce SOM profiles and their responses to nutrient additions. It highlights the need to better represent these processes in future model developments.
Phosphate Fertilizer in Soybean-Wheat Cropping System Under No-Till Management

Improvements in soybean (Glycine max [L.] Merrill) and wheat (Triticum aestivum L.) yields in cropping systems under no-till management (NTM) in the subtropics have been obtained through advances in phosphorus (P) utilization, cultivar selection, and planting and harvesting strategies. This fact, along with the P application in band application in consolidated planting, has resulted in adequate P utilization efficiency and small depleted soil P levels. The aim of this study was to evaluate the efficiency of P2O5 rates and application methods in soybean-wheat cropping under NTM during two growing seasons (2014–2016) in a Typical Eutrorthox. Four P2O5 rates (0, 30, 60, and 120 kg ha−1) of triple superphosphate (45% P2O5) were applied using two application methods (broadcast and band application at sowing) before the soybean and wheat crops were cultivated. Both P application methods resulted in a significant yield response to P2O5 rates for the soybean and wheat crops. Under NTM, broadcast P2O5 application was more effective than band application in soybean, and maximum grain yields were obtained with 129.3 and 88.1 kg P2O5 ha−1, respectively. Maximum wheat grain yields were obtained with 91.8 and 99.7 kg P2O5 ha−1 for broadcast and band application, respectively. Except for total P in leaves, nutrient uptake and yield components were not affected by the P application methods and rates. The results suggested that in soils with adequate available P levels of >15 mg kg−1 (Mehlich 1 extractant), the grain yield is equivalent or superior with broadcast P application as compared with band application for both soybean and wheat crops when cultivated in a Typical Eutrorthox under subtropical conditions. However, broadcast application is considered more effective for large areas of grain cultivation, where it is necessary to sow crops uniformly within the shortest possible time.
Biomineralization of Sr by the Cyanobacterium Pseudanabaena catenata Under Alkaline Conditions

A non-axenic culture of Pseudanabaena catenata, a close relative of the bloom-forming cyanobacterium found in the high pH First Generation Magnox Storage Pond at the Sellafield Nuclear Facility, was supplemented with 1 mM of SrCl2, to determine its effect on the fate of Sr. The addition of 1 mM Sr to the P. catenata culture resulted in ∼16% reduction in the overall growth of the culture (OD600nm) and a 21% reduction in the concentration of chlorophyll-a (Chl-a) compared to those without Sr. The fate of Sr was assessed using a multi-technique approach. Inductively coupled plasma atomic emission spectroscopy showed that virtually all of the Sr was removed from solution, while extracellular biomineral precipitates were analyzed using transmission electron microscopy analysis, and were shown to contain Sr, Ca, and S using energy-dispersive X-ray spectroscopy analysis. In addition, intracellular P-containing electron-dense features, likely to be polyphosphate bodies, were associated with the P. catenata cells and contained Sr. Bulk analysis of the cultures by X-ray diffraction showed the presence of Ca-containing strontianite whilst Extended X-ray Absorption Fine Structure analysis showed the presence of strontium phosphate minerals. The presence of Sr associated with intracellular polyphosphate was unexpected, and contrasts with other model photosynthetic systems in the literature that have highlighted carbonate biominerals as the dominant sink for Sr. Understanding the fate of Sr with microorganisms associated with the Spent Nuclear Fuel Ponds (SNFPs) is crucial to understanding the fate of radioactive 90Sr in such extreme environments, and could also suggest a potential remediation strategy for treatment of 90Sr contaminated waters from Spent Nuclear Fuel Ponds SNFPs and in contaminated aquatic systems.
Aging of the Immune System: Research Challenges to Enhance the Health Span of Older Adults

The world’s population is aging, which brings about huge scientific challenges. Since the biological process of aging is by far the greatest risk factor for most chronic diseases, understanding the molecular and cellular mechanisms by which aging leads to these conditions is of vital importance to increase the health span of older adults. One of the most prominent biological systems to face the impacts of aging is the immune system, with age-related changes in immunity being responsible for an increase in susceptibility to infectious diseases and a decrease in the effectiveness of vaccinations. In addition, the innate immune system is responsible for one of the main characteristics of aging, namely, the increase in low-grade inflammation known as inflammaging. Five research challenges present themselves: the origins and impact of age-related inflammation, the impact of senescence on immunity, age-related changes in immune function, the effects of decreased immune function on infection and vaccination, and strategies to overcome declining immunity. These are all especially important at this time, since aging is a major risk factor for the development of severe complications from infectious diseases such as COVID-19, influenza, and bacterial pneumonia.
Yes-Associated Protein 1: Role and Treatment Prospects in Orthopedic Degenerative Diseases

The Hippo/yes-associated protein 1 signaling pathway is an evolutionarily conserved signaling pathway. This signaling pathway is primarily involved in the regulation of stem cell self-renewal, organ size and tissue regeneration by regulating cell proliferation, differentiation and apoptosis. It plays an important role in embryonic development and tissue organ formation. Yes-associated protein 1 (YAP1) is a key transcription factor in the Hippo signaling pathway and is negatively regulated by this pathway. Changes in YAP1 expression levels affect the occurrence and development of a variety of tumors, but the specific mechanism associated with this phenomenon has not been thoroughly studied. Recently, several studies have described the role of YAP1 in osteoarthritis (OA). Indeed, YAP1 is involved in orthopedic degenerative diseases such as osteoporosis (OP) in addition to OA. In this review, we will summarize the significance of YAP1 in orthopedic degenerative diseases and discuss the potential of the targeted modulation of YAP1 for the treatment of these diseases.
Constraint-based modelling revealed changes in metabolic flux modes associated with the Kok effect

Constraint-based modelling was applied to provide a mechanistic understanding of the possible metabolic origins of the ‘Kok effect’ – the change in quantum yield of net photosynthesis at low light intensity. The well-known change in quantum yield near the light-compensation point (LCP) was predicted as an emergent behaviour from a purely stoichiometric model. From our modelling results, we discovered another subtle change in quantum yield at a light intensity lower than the LCP. Our model predicted a series of changes in metabolic flux modes in central carbon metabolism associated with the changes in quantum yields. We demonstrated that the Kok effect can be explained by changes in metabolic flux modes between catabolism and photorespiration. Changes in RuBisCO carboxylation to oxygenation ratio resulted in a change in quantum yield at light intensities above the LCP, but not below the LCP, indicating the role of photorespiration in producing the Kok effect. Cellular energy demand was predicted to have no impact on the quantum yield. Our model showed that the Kok method vastly overestimates day respiration – the CO2 released by non-photorespiratory processes in illuminated leaves. The theoretical maximum quantum yield at low light intensity was higher than typical measured values, suggesting that leaf metabolism at low light may not be regulated to optimise for energetic efficiency. Our model predictions gave insights into the set of energetically optimal changes in flux modes in low light as light intensity increases from darkness. One sentence summary The Kok effect can be explained by the changes in flux modes between catabolism and photorespiration.
Fetal innate immunity contributes to the induction of atypical behaviors in a mouse model of maternal immune activation

Maternal immune activation (MIA) increases likelihood of altered neurodevelopmental outcomes. Maternal cytokines are proposed to affect fetal brain development in mice; however, the contribution of fetal immunity to neurodevelopmental disorders is largely unexplored. Here, we show that MIA mediated by Toll-like receptor 3 (TLR3), but not other TLRs, induces a specific set of behavioral phenotypes including decreased sociability and increased restricted repetitive behavior in offspring. Accordingly, these behavioral phenotypes were absent when offspring were deficient for Trif, the downstream adapter molecule of TLR3. Using single-cell RNA sequencing, we identified clusters of border-associated macrophages that were significantly enriched in the fetal brain following TLR3-MIA, and these clusters were diminished in Trif−/− fetal brains.Moreover, we found that triggering TLR3-TRIF in offspring can occur through transplacental viral infection, resulting in altered behavioral phenotypes. Collectively, our data indicate that fetal innate immunity contributes to MIA-induced atypical behaviors in mice.