Miracle-dz/UniFAR-FTUs huggingface dataset:
Fasting reverses drug-resistance in hepatocellular carcinoma through p53-dependent metabolic synergism

Cancer cells voraciously consume nutrients to support their growth, exposing a metabolic vulnerability that can be therapeutically exploited. Here we show in hepatocellular carcinoma (HCC) cells, xenografts, and in patient-derived HCC organoids that fasting can synergistically sensitize resistant HCC to sorafenib. Mechanistically, sorafenib acts non-canonically as an inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR-signaling, prevents this Warburg shift. Regulating glucose transporter and pro-apoptotic protein expression, p53 is necessary and sufficient for the sorafenib-sensitizing effect of fasting. p53 is also crucial for fasting-mediated improvement of sorafenib efficacy in an orthotopic HCC mouse model. Together, our data suggest intermittent fasting and sorafenib as rational combination therapy for HCC with intact p53 signaling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies aimed at improving therapy response in advanced-stage, and possibly even early-stage, HCC. HIGHLIGHTS Fasting sensitizes resistant HCC xenografts and patient-derived organoids to sorafenib Sorafenib-mediated Warburg shift is prevented by glucose limitation upon fasting Fasting synergistically improves sorafenib efficacy in non-resistant models p53 is required for synergism by regulating glucose uptake and apoptosis GRAPHICAL ABSTRACT
Effects of physical, chemical, and biological ageing on the mineralization of pine wood biochar by a Streptomyces isolate

If biochar is to be used for carbon (C) management, we must understand how ageing affects biochar C mineralization. Here, we incubated aged and unaged eastern white pine wood biochar produced at 350 and 550 °C with a Streptomyces isolate, a putative biochar-decomposing microbe. Ageing was simulated via exposure to (a) alternating freeze-thaw and wet-dry cycles (physical ageing), (b) concentrated hydrogen peroxide (chemical ageing) and (c) nutrients and microorganisms (biological ageing). Elemental composition and surface chemistry (Fourier Transform Infrared spectroscopy) of biochar samples were compared before and after ageing. Ageing significantly increased biochar C mineralization in the case of physically aged 350 °C biochar (p < 0.001). Among 350 °C biochars, biochar C mineralization was positively correlated with an increase in O/C ratio (R2 = 0.78) and O-containing functional groups (R2 = 0.73) post-ageing, suggesting that surface oxidation during ageing enhanced biochar degradation by the isolate. However, in the case of 550 °C biochar, ageing did not result in a significant change in biochar C mineralization (p > 0.05), likely due to lower surface oxidation and high condensed aromatic C content. These results have implications for the use of biochar for long term C storage in soils. Synopsis This study highlights the impact of ageing on the microbial mineralization of biochar, which can affect its long-term C storage capacity. TOC Graphic
Prediction of adverse drug reactions associated with drug-drug interactions using hierarchical classification

Adverse drug reactions (ADRs) associated with drug-drug interactions (DDIs) represent a significant threat to public health. Unfortunately, most conventional methods for prediction of DDI-associated ADRs suffer from limited applicability and/or provide no mechanistic insight into DDIs. In this study, a hierarchical machine learning model was created to predict DDI-associated ADRs and pharmacological insight thereof for any drug pair. Briefly, the model takes drugs’ chemical structures as inputs to predict their target, enzyme, and transporter (TET) profiles, which are subsequently utilized to assess occurrences of ADRs, with an overall accuracy of ~91%. The robustness of the model for ADR classification was validated with DDIs involving three widely prescribed drugs. The model was then applied for interstitial lung disease (ILD) associated with DDIs involving atorvastatin, identifying the involvement of multiple targets, enzymes, and transporters in ILD. The model presented here is anticipated to serve as a versatile tool for enhancing drug safety.
Reconciling Inherent Interfacial Compatibility Conflict Enhances Adhesive Infiltration and Resolves Dentin Bonding Durability

Wet bonding is a basic technique used daily in clinics for tooth-restoration fixation. However, only 50% of the bonding lasts more than 5 years and thus patients must visit the dentists repeatedly. This is attributed to the limited infiltration of adhesives into the demineralized dentin (DD) matrix during wet-bonding. Herein, we show that reconciling interfacial compatibility conflict between the DD matrix and the critical hydrophobic adhesive molecules via hydrophobizing the DD matrix enables the adhesives to thoroughly infiltrate and uniformly distribute within the DD matrix. Thus, the bonding of the hydrophobic DD matrix using commercial dentin adhesives achieves the bonding strength 2-6 times higher than that of the non-treated DD matrix. When a hydrophobic adhesive is applied on the hydrophobic DD matrix, a flawless hybrid layer is produced as observed by nanoleakage investigation. A long-term bonding strength comes up to 7.3 fold that of the control group and very importantly, with no attenuation after 12 months. This study clarifies the basic cause of poor wet-bonding durability and demonstrates a paradigm in adhesive dentistry to overcome the long-existing bonding durability problem associated with inadequate adhesive infiltration into the DD matrix. This provides a new angle of view to resolve clinical dentin bonding durability problem and will significantly promote adhesive dentistry. Highlights Inherent interfacial compatibility conflict between demineralized dentin matrix and hydrophobic molecules of dentin adhesives is the basic cause for the dentin bonding durability problem. Reconciling the interfacial compatibility conflict markedly facilitates adhesive infiltration in the demineralized dentin matrix and greatly enhances bonding effectiveness. High interfacial compatibility produces a flawless hybrid layer and ideal bonding effectiveness and durability. Graphical Abstract For wet bonding, poor infiltration of adhesives within the DD matrix inevitably produces numerous defects throughout the hybrid layer, which always leads to the failure of restoration. Via hydrophobizing the DD matrix, reconciling interfacial compatibility conflict between the DD matrix and the hydrophobic adhesive monomers overcomes durability problems associated with the infiltration of adhesives into the DD matrix producing a flawless hybrid layer and providing ideal bonding effectiveness and durability.
Cholinergic signalling at the body wall neuromuscular junction couples to distal inhibition of feeding in C. elegans

Complex biological functions within organisms are frequently orchestrated by systemic communication between tissues. In the model organism C. elegans, the pharyngeal and body wall neuromuscular junctions are two discrete structures that control feeding and locomotion, respectively. These distinct tissues are controlled by separate, well-defined neural circuits. Nonetheless, the emergent behaviours, feeding and locomotion, are coordinated to guarantee the efficiency of food intake. We show that pharmacological hyperactivation of cholinergic transmission at the body wall muscle reduces the rate of pumping behaviour. This was evidenced by a systematic screening of the cholinesterase inhibitor aldicarb’s effect on the rate of pharyngeal pumping on food in mutant worms. The screening revealed that the key determinant of the inhibitory effect of aldicarb on pharyngeal pumping is the L-type nicotinic acetylcholine receptor expressed in body wall muscle. This idea was reinforced by the observation that selective hyperstimulation of the body wall muscle L-type receptor by the agonist levamisole inhibited pumping. Overall, our results reveal that body wall cholinergic transmission controls locomotion and simultaneously couples a distal inhibition of feeding.
Testing for parallel genomic and epigenomic footprints of adaptation to urban life in a passerine bird

Identifying the molecular mechanisms involved in rapid adaptation to novel environments and determining their predictability are central questions in Evolutionary Biology and pressing issues due to rapid global changes. Complementary to genetic responses to selection, faster epigenetic variations such as modifications of DNA methylation may play a substantial role in rapid adaptation. In the context of rampant urbanization, joint examinations of genomic and epigenomic mechanisms are still lacking. Here, we investigated genomic (SNP) and epigenomic (CpG methylation) responses to urban life in a passerine bird, the Great tit (Parus major). To test whether urban evolution is predictable (i.e parallel) or involves mostly non-parallel molecular processes among cities, we analysed three distinct pairs of city and forest Great tit populations across Europe. Results reveal a polygenic response to urban life, with both many genes putatively under weak divergent selection and multiple differentially methylated regions (DMRs) between forest and city great tits. DMRs mainly overlapped transcription start sites and promotor regions, suggesting their importance in the modulation gene expression. Both genomic and epigenomic outliers were found in genomic regions enriched for genes with biological functions related to nervous system, immunity, behaviour, hormonal and stress responses. Interestingly, comparisons across the three pairs of city-forest populations suggested little parallelism in both genetic and epigenetic responses. Our results confirm, at both the genetic and epigenetic levels, hypotheses of polygenic and largely non-parallel mechanisms of rapid adaptation in new environments such as urbanized areas.
Life histories as mosaics: Plastic and genetic components differ among traits that underpin life‐history strategies

Life-history variation reflects phenotypic variation across suites of traits. Differences among life-history strategies result from genetic differentiation, phenotypic plasticity, and genotype-by-environment interactions. If the relative strength and direction of these components differed among traits underlying a strategy, life histories might not evolve as a cohesive unit. We tested this hypothesis on the high- and low-predation ecotypes of Trinidadian guppies, defined by distinct life-history strategies. Using common garden experiments, we assessed how strongly 36 traits were determined by ancestral habitat (i.e., ecotype) or food availability, a key environmental difference between ecotypes. Our dataset was large (1178 individuals) and included six putatively independent origins of the derived ecotype. Traits could be confidently assigned to four groups, defined by highly significant effects of only food (13 traits), only habitat (6), both (6), or neither (11), revealing substantial variation among traits in levels of genetic and environmental control. Ecotype-food (i.e., genotype-by-environment) interactions were negligible. The directions of plastic and genetic effects were usually aligned. This suggests that life histories are mosaics with unequal rates of phenotypic and evolutionary change. Broadly speaking of “life-history evolution” masks a complex interplay of genes and environment on the multiple traits that underpin life-history strategies.
Relatively Shorter Muscle Lengths Increase the Metabolic Rate of Cyclic Force Production

During animal locomotion, force-producing leg muscles are almost exclusively responsible for the whole-body’s metabolic energy expenditure. Animals can change the length of these leg muscles by altering body posture (e.g., joint angles), kinetics (e.g., body weight), or the structural properties of their biological tissues (e.g., tendon stiffness). Currently, it is uncertain whether relative muscle fascicle operating length has a measurable effect on the metabolic energy expenditure of cyclic locomotion-like contractions. To address this uncertainty, we measured the metabolic energy expenditure of human participants as they cyclically produce two distinct ankle moments at three separate ankle angles (90°, 105°, 120°) on a fixed-position dynamometer exclusively using their soleus. Overall, increasing participant ankle angle from 90° to 120° (more plantar flexion) reduced minimum soleus fascicle length by 17% (both moment levels, p<0.001) and increased metabolic energy expenditure by an average of 208% (both p<0.001). Across both moment levels, the increased metabolic energy expenditure was not driven by greater fascicle positive mechanical work (higher moment level, p=0.591), fascicle force rate (both p≥0.235), or active muscle volume (both p≥0.122); but it was correlated with average relative soleus fascicle length (r=-179, p=0.002) and activation (r=0.51, p<0.001). Therefore, the metabolic energy expended during locomotion can likely be reduced by lengthening active muscles that operate on the ascending-limb of their force-length relationship.
Human monoclonal antibodies against Staphylococcus aureus surface antigens recognize in vitro biofilm and in vivo implant infections

Implant-associated Staphylococcus aureus infections are difficult to treat because of biofilm formation. Bacteria in a biofilm are often insensitive to antibiotics and host immunity. Monoclonal antibodies (mAbs) could provide an alternative approach to improve the diagnosis and/or treatment of biofilm-related infections. Here we show that mAbs targeting common surface components of S. aureus can recognize clinically relevant biofilm types. We identify two groups of antibodies: one group that uniquely binds S. aureus in biofilm state and one that recognizes S. aureus in both biofilm and planktonic state. In a mouse model, we show that mAb 4497 (recognizing wall teichoic acid (WTA)) specifically localizes to biofilm-infected implants. In conclusion, we demonstrate the capacity of several human mAbs to detect S. aureus biofilms in vitro and in vivo. This is an important first step to develop mAbs for imaging or treating S. aureus biofilms.
The Same Ultra-Rapid Parallel Brain Dynamics Underpin the Production and Perception of Speech

The temporal dynamics by which linguistic information becomes available is one of the key properties to understand how language is organised in the brain. An unresolved debate between different brain language models is whether words, the building blocks of language, are activated in a sequential or parallel manner. In this study we approached this issue from a novel perspective by directly comparing the time course of word component activation in speech production versus perception. In an overt object naming task and a passive listening task we analysed with mixed linear models at the single-trial level the event-related brain potentials elicited by the same lexico-semantic and phonological word knowledge in the two language modalities. Results revealed that both word components manifested simultaneously as early as 75 ms after stimulus onset in production and perception; differences between the language modalities only became apparent after 300 ms of processing. The data provide evidence for ultra-rapid parallel dynamics of language processing and are interpreted within a neural assembly framework where words recruit the same integrated cell assemblies across production and perception. These word assemblies ignite early on in parallel and only later on reverberate in a behaviour-specific manner.
Dynamics and modulation of the human snoRNome

Background: Small nucleolar RNAs (snoRNAs) are mid-size non-coding RNAs required for ribosomal RNA modification, implying a ubiquitous tissue distribution linked to ribosome synthesis. However, increasing numbers of studies identify extra-ribosomal roles of snoRNAs in modulating gene expression, suggesting more complex snoRNA expression patterns. Therefore, there is a great need for mapping the snoRNome in different human tissues as the blueprint for snoRNA functions. Results: We used a low structure bias RNA-Seq approach to accurately quantify snoRNAs and compare them to the entire transcriptome in seven healthy human tissues (breast, ovary, prostate, testis, skeletal muscle, liver and brain). We identified 475 expressed snoRNAs categorized in two abundance classes that differ significantly in their function, conservation level and correlation with their host gene: 390 snoRNAs are uniformly expressed and 85 are enriched in the brain or reproductive tissues. Most tissue-enriched snoRNAs are embedded in lncRNAs and display strong correlation of abundance with them, whereas uniformly expressed snoRNAs are mostly embedded in protein-coding host genes and are mainly nonor anticorrelated with them. 59% of the non-correlated or anticorrelated protein-coding host gene/snoRNA pairs feature dual-initiation promoters, as opposed to only 16% of the correlated non-coding host gene/snoRNA pairs. Conclusions: Our results demonstrate that snoRNAs are not a single homogeneous group of housekeeping genes but include highly regulated tissue-enriched RNAs. Indeed, our work indicates that the architecture of snoRNA host genes varies to uncouple the host and snoRNA expressions in order to meet the different snoRNA abundance levels and functional needs of human tissues.
A Multiscale, Systems-Level, Neuropharmacological Model of Cortico-Basal Ganglia System for Arm Reaching Under Normal, Parkinsonian, and Levodopa Medication Conditions

The root cause of Parkinson’s disease (PD) is the death of dopaminergic neurons in Substantia Nigra pars compacta (SNc). The exact cause of this cell death is still not known. Loss of SNc cells manifest as the cardinal symptoms of PD, including tremor, rigidity, bradykinesia, and postural imbalance. To investigate the PD condition in detail and understand the link between loss of cells in SNc and PD symptoms, it is important to have an integrated multiscale computational model that can replicate the symptoms at the behavioural level by evoking the key cellular and molecular underlying mechanisms that contribute to the pathology. In line with this objective, we present a multiscale integrated model of cortico-basal ganglia motor circuitry for arm reaching task, incorporating a detailed biophysical model of SNc dopaminergic neuron. Earlier researchers have shown that fluctuations in dopamine (DA) signals are analogous to reward/punishment signals, thereby prompting application of concepts from reinforcement learning (RL) to modelling the basal ganglia system. In our model, we replace the abstract representations of reward with the realistic variable of extracellular DA released by a network of SNc cells and incorporate it with the RL-based behavioural model, which simulates the arm reaching task. Our results showed that as SNc cell loss increases, the percentage success rate to reach the target decreases, and average time to reach the target increases. With levodopa (L-DOPA) medication, both the success rate and the average time to reach the target improved significantly. The proposed model also exhibits how differential dopaminergic axonal degeneration in basal ganglia results in various cardinal symptoms of PD as manifest in reaching movements. From the model results, we were able to show the side effects of L-DOPA mediation, such as wearing off and peak dosage dyskinesias. Moreover, from the results, we were able to predict the optimum dosage for varying degrees of cell loss and L-DOPA medication. The proposed model has a potential clinical application where drug dosage can be optimized as per patient characteristics. We conclude that our model presents a realistic and efficient way of simulating the PD pathology conditions and the effect of levodopa medication, thereby giving a reliable indicator towards the optimization of the drug dosage.
During natural viewing, neural processing of visual targets continues throughout saccades

Relatively little is known about visual processing during free-viewing visual search in realistic dynamic environments. Free-viewing is characterized by frequent saccades. During saccades, visual processing is thought to be inhibited, yet we know that the pre-saccadic visual content can modulate post-saccadic processing. To better understand these processes in a realistic setting, we study here saccades and neural responses elicited by the appearance of visual targets in a realistic virtual environment. While subjects were being driven through a 3D virtual town they were asked to discriminate between targets that appear on the road. We found that the presence of a target enhances early occipital as well as late frontocentral saccade-related responses. The earlier potential, shortly after 125ms post-saccade onset, was enhanced for targets that appeared in peripheral vision as compared to central vision, suggesting that fast peripheral processing initiated before saccade onset. The later potential, at 195ms post-saccade onset, was strongly modulated by the visibility of the target with a spatial distribution reminiscent of the classic P300 response. Together these results suggest that, during natural viewing, neural processing of the pre-saccadic visual stimulus continues throughout the saccade, apparently unencumbered by saccadic inhibition.
Analysis of the Volatile Chemical Constituents of Agrimonla pilosa Ledeb with Gas Chromatography-Mass Spectrometry and Heuristic Evolving Latent Projections

Analysis of the volatile components in Agrimonia pilosa Ledeb with heuristic evolving latent projections (HELP) was presented. After extracted with water distillation method, the volatile components were detected by GCMS. Then the qualitative and quantitative analysis of the volatile components was completed with HELP resolving two-dimensional original data into mass spectra and chromatograms. 62 of 83 separated constituents in the total ion chromatogram of the volatile components were identified and quantified, accounting for about 86.49% of the total content. The obtained information can provide foundation for further study of Agrimonia pilosa Ledeb. This developed method can also be used for quality control of Agrimonia pilosa Ledeb samples.
Autocrine regulation of adult neurogenesis by the endocannabinoid 2-arachidonoylglycerol (2-AG)

The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). Specifically, deleting cannabinoid receptors on NSPCs or the constitutive deletion of the endocannabinoid 2-arachidonoylglycerol (2-AG) producing enzyme diacylglycerol lipase alpha (DAGLa) disrupts adult neurogenesis. However, it is not known which cells are the producers of 2-AG relevant to neurogenesis. In this paper, we investigated the cellular source of endocannabinoids in the subgranular zone (SGZ) of the hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete DAGLa either in neurons or astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice with a deletion of Dagla in neurons (Syn-Dagla KO), although they are the main source for the endocannabinoids in the brain. In contrast, mice with a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) showed a strongly impaired neurogenesis with significantly reduced proliferation and survival of newborn cells. These results identify Dagla in NSPCs in the SGZ of dentate gyrus or in astrocytes, as the cellular source for 2-AG in adult hippocampal neurogenesis. In summary, 2-AG produced by progenitor cells or astrocytes in the SGZ regulates adult hippocampal neurogenesis. Summary DAGLa in neuronal progenitor cells in the SGZ of dentate gyrus is identified as the cellular source for 2-AG in adult hippocampal neurogenesis.