Miracle-dz/UniFAR-FTUs huggingface dataset:
Explicit expression of mesophyll conductance in the traditional leaf photosynthesis–transpiration coupled model and its physiological significances

Almost all terrestrial biosphere models (TBMs) still assume infinite mesophyll conductance (gm) to estimate photosynthesis and transpiration. This assumption has caused low accuracy of TBMs to predict leaf gas exchange under certain conditions. Here, we developed a photosynthesis–transpiration coupled model that explicitly considers gm and designed an optimized parameterization solution through evaluating four different gm estimation methods in 19 C3 species at 31 experimental treatments. Temperature responses of the maximum carboxylation rate (Vcmax) and the electron transport rate (Jmax) estimated using the Bayesian retrieval algorithm and the Sharkey online calculator and gm temperature response estimated using the chlorophyll fluorescence–gas exchange method and anatomy method predicted leaf gas exchange better. The gm temperature response exhibited activation energy (ΔHa) of 63.13 ± 36.89 kJ mol−1 and entropy (ΔS) of 654.49 ± 11.36 J K−1 mol−1. The gm optimal temperature (Topt_gm) explained 58% of variations in photosynthesis optimal temperature (ToptA). The gm explicit expression has equally important effects on photosynthesis and transpiration estimations. Results advanced understandings of better representation of plant photosynthesis and transpiration in TBMs.
A lack of repeatability creates the illusion of a trade-off between basal and plastic cold tolerance

The thermotolerance-plasticity trade-off hypothesis predicts that ectotherms with greater basal thermal tolerance have a lower acclimation capacity. This hypothesis has been tested at both high and low temperatures but the results often conflict. If basal tolerance constrains plasticity (e.g. through shared mechanisms that create physiological constraints), it should be evident at the level of the individual, provided the trait measured is repeatable. Here, we used chill-coma onset temperature and chill-coma recovery time (CCO and CCRT; non-lethal thermal limits) to quantify cold tolerance of Drosophila melanogaster across two trials (pre- and post-acclimation). Cold acclimation improved cold tolerance, as expected, but individual measurements of CCO and CCRT in non-acclimated flies were not (or only slightly) repeatable. Surprisingly, however, there was still a strong correlation between basal tolerance and plasticity in cold-acclimated flies. We argue that this relationship is a statistical artefact (specifically, a manifestation of regression to the mean; RTM) and does not reflect a true trade-off or physiological constraint. Thermal tolerance trade-off patterns in previous studies that used similar methodology are thus likely to be impacted by RTM. Moving forward, controlling and/or correcting for RTM effects is critical to determining whether such a trade-off or physiological constraint truly exists.
The mutation effect reaction norm (MERN) highlights environmentally dependent mutation effects and genetic interactions

Measuring the fitness effects of mutations and epistasis remain central yet provocative concepts in evolutionary and population genetics. In addition to the baseline complexity that arises from the notion that genetic information can interact in a nonlinear way, recent studies have revealed that interactions can change as a function of environmental context. Here I propose the fusion of measurements of the effect of mutations and physiological epistasis with the reaction norm, a central abstraction used to depict genotype by environment interactions. In doing so, I formalize the notion of a “mutation effect reaction norm” (MERN) as an instrument through which one can analyze or depict the phenotypic consequences of interactions between mutations across environmental contexts. I demonstrate its utility through a discussion of the signature of mutations that undermine reverse evolution of antimicrobial resistance. In closing, I argue that the mutation effect reaction norm may help us resolve the dynamism of evolution across fitness seascapes through specific insight into how mutation effects and interactions are modulated by environmental context.
Assessing the relationships between neurological and psychiatric diseases with astrocyte subtypes and psychotropic medications

Astrocytes have many important functions in the brain, but their roles in CNS disorders and their responses to psychotropic medications are still being elucidated. In this study, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, neurological and psychiatric diseases, and psychotropic medications. We also carried out qPCR analyses and “look-up” studies to further assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified differential gene enrichment of different astrocyte subtypes in CNS disorders. The “common” astrocyte subtype was the most frequently enriched across disorders, but the highest level of enrichment was found in depression, supporting a role for astrocytes in this disorder. We also identified common enrichment of metabolic and signal transduction-related biological processes in astrocyte subtypes and CNS disorders. However, enrichment of different psychotropic medications, including antipsychotics, antidepressants, and mood stabilizers, was limited in astrocyte subtypes. These results were confirmed by “look-up” studies and qPCR analysis, which also reported little effect of common psychotropic medications on astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in CNS disorders and offers insights into targeting astrocytes therapeutically.
Steady-state measures of visual suppression

In the early visual system, suppression occurs between neurons representing different stimulus properties. This includes features such as orientation (cross-orientation suppression), eye-of-origin (interocular suppression) and spatial location (surround suppression), which are thought to involve distinct anatomical pathways. We asked if these separate routes to suppression can be differentiated by their pattern of gain control on the contrast response function measured in human participants using steady-state electroencephalography. Changes in contrast gain shift the contrast response function laterally, whereas changes in response gain scale the function vertically. We used a Bayesian hierarchical model to summarise the evidence for each type of gain control. A computational meta-analysis of 16 previous studies found the most evidence for contrast gain effects with overlaid masks, but no clear evidence favouring either response gain or contrast gain for other mask types. We then conducted two new experiments, comparing suppression from four mask types (monocular and dichoptic overlay masks, and aligned and orthogonal surround masks) on responses to sine wave grating patches flickering at 5Hz. At the occipital pole, there was strong evidence for contrast gain effects in all four mask types at the first harmonic frequency (5Hz). Suppression generally became stronger at more lateral electrode sites, but there was little evidence of response gain effects. At the second harmonic frequency (10Hz) suppression was stronger overall, and involved both contrast and response gain effects. Although suppression from different mask types involves distinct anatomical pathways, gain control processes appear to serve a common purpose, which we suggest might be to suppress less reliable inputs.
Transiently increased intercommunity regulation characterizes concerted cell phenotypic transition

Phenotype transition takes place in many biological processes such as differentiation and reprogramming. A fundamental question is how cells coordinate switching of expressions of clusters of genes. Through analyzing single cell RNA sequencing data in the framework of transition path theory, we studied how such a genome-wide expression program switching proceeds in five different cell transition processes. For each process we reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulation network (GRN) along the reaction coordinate. In all processes we observed common pattern that the overall effective number and strength of regulation between different communities increase first and then decrease. The change accompanies with similar change of the GRN frustration, defined as overall conflict between the regulation received by genes and their expression states, and GRN heterogeneity. While studies suggest that biological networks are modularized to contain perturbation effects locally, our analyses reveal a general principle that during a cell phenotypic transition, intercommunity interactions increase to concertedly coordinate global gene expression reprogramming, and canalize to specific cell phenotype as Waddington visioned.
The genes controlling normal function of citrate and spermine secretion is lost in aggressive prostate cancer and prostate model systems

Background Secretion of the metabolites citrate and spermine into prostate lumen is a unique hallmark for normal prostate epithelial cells. However, the identity of the genes controlling citrate and spermine secretion remains mostly unknown despite their obvious relevance for progression to aggressive prostate cancer. Materials & Methods In this study, we have correlated simultaneous measurement of citrate/spermine and transcriptomics data. We have refined these gene correlations in 12 prostate cancer cohorts containing 2915 tissue samples to create a novel gene signature of 150 genes connected with citrate and spermine secretion. We further explored the signature in public data, interrogating over 18 000 samples from various tissues and model systems, including 3826 samples from prostate and prostate cancer. Results In prostate cancer, the expression of this gene signature is gradually lost in tissue from normal epithelial cells through PIN, low grade (Gleason <= 7), high grade cancer (Gleason >= 8) and metastatic lesions. The accuracy of the signature is validated by its unique enrichment in prostate compared to other tissues, and its strong enrichment in epithelial tissue compartments compared to stroma. Several zinc-binding proteins that are not previously investigated in the prostate are present in the gene signature, suggesting new mechanisms for controlling zinc homeostasis in citrate/spermine secretion. However, the absence of the gene signature in all common prostate normal and cancer cell-lines, as well as prostate organoids, underlines the challenge to study the role of these genes during prostate cancer progression in model systems. Conclusions A large collection of transcriptomics data integrated with metabolomics identifies the genes related to citrate and spermine secretion in the prostate, and show that the expression of these genes gradually decreases on the path towards aggressive prostate cancer. In addition, the study questions the relevance of currently available model systems to study metabolism in prostate cancer development.
Systemic impact of the expression of the mitochondrial alternative oxidase on Drosophila development

Despite the beneficial effects of xenotopically expressing the mitochondrial alternative oxidase AOX from Ciona intestinalis in mammalian and insect models, important detrimental outcomes have also been reported, raising concerns regarding its potential deployment as a therapeutic enzyme for human mitochondrial diseases. Because of its non-protonmotive terminal oxidase activity, AOX can bypass the cytochrome segment of the respiratory chain whilst not contributing to mitochondrial ATP synthesis. We have previously shown that pupal lethality occurs when AOX-expressing Drosophila larvae are cultured on a low-nutrient diet, indicating that AOX can perturb normal metabolism during development. Here, combined omics analyses revealed multiple correlates of this diet-dependent lethality, including a general alteration of larval amino acid and lipid metabolism, functional and morphological changes to the larval digestive tract, and a drastic decrease in larval biomass accumulation. Pupae at the pre-lethality stage presented a general downregulation of mitochondrial metabolism and a signature of starvation and deregulated signaling. AOX-induced lethality was partially rescued when the low-nutrient diet was supplemented with tryptophan and/or methionine, but not with proline and/or glutamate, strongly suggesting perturbation of one-carbon metabolism. The developmental dependence on tryptophan and/or methionine, associated with elevated levels of lactate dehydrogenase, 2-hydroxyglutarate, choline-containing metabolites and breakdown products of membrane phospholipids, indicates that AOX expression promotes tissue proliferation and larval growth, but this is ultimately limited by energy dissipation due to partial mitochondrial uncoupling. We speculate that the combination of dietary interventions and AOX expression might, nevertheless, be useful for the metabolic regulation of proliferative tissues, such as tumors.
LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein

The interactions between severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to COVID-19. The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary ACE2 receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was restricted to SARS-CoV-2, suggesting LRRC15 represents a novel class of spike binding interaction. We localized the interaction to the C-terminus of the S1 domain, and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19. In brief We present evidence from genome-wide screening that the spike protein of SARS-CoV-2 interacts with human cells expressing LRRC15. The interaction is distinct from previously known classes of spike attachment factors, and appears to have emerged recently within the coronavirus family. Although not sufficient for cell invasion, this interaction can modulate viral infection. Our data point to an unappreciated host factor for SARS-CoV-2, with potential relevance to COVID-19. Highlights - Two systematic cell-based screens for SARS-CoV-2 spike protein binding identify LRRC15 as a human host factor - Interaction with LRRC15 is reproducible in different human cell lines and independent of known glycan or ACE2 binding pathways - The C-terminal S1 domain of SARS-CoV-2 spike binds LRRC15 with sub-micromolar affinity, while related coronavirus spikes do not - LRRC15 is expressed in tissues with high ACE2 levels and may modulate infection
Towards a combined therapy for spinal muscular atrophy based on opposing effects of an antisense oligonucleotide on chromatin and splicing

Spinal Muscular Atrophy (SMA) is a motor-neuron disease caused by loss-of-function mutations of the SMN1 gene. Humans have a paralog, SMN2, whose exon 7 is predominantly skipped, and so it cannot fully compensate for the lack of SMN1. Nusinersen (Spinraza) is a splicing-correcting antisense oligonucleotide drug (ASO) approved for clinical use. Nusinersen targets a splicing silencer located in SMN2 intron 7 pre-mRNA and, by blocking the binding of the splicing repressors hnRNPA1 and A2, it promotes higher E7 inclusion, increasing SMN protein levels. We show here that, by promoting transcriptional elongation, histone deacetylase (HDAC) inhibitors cooperate with a nusinersen-like ASO to upregulate E7 inclusion. Surprisingly, the ASO also elicits the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to RNA polymerase II elongation that acts negatively on E7 inclusion. By removing the roadblock, HDAC inhibition counteracts the undesired chromatin effects of the ASO, resulting in higher E7 inclusion. Combined systemic administration of the nusinersen-like ASO and HDAC inhibitors in neonate SMA mice had strong synergistic effects on SMN expression, growth, survival, and neuromuscular function. Thus, we suggest that HDAC inhibitors have the potential to increase the clinical efficacy of nusinersen, and perhaps other splicing-modulatory ASO drugs, without large pleiotropic effects, as assessed by genome-wide analyses.
Normative and mechanistic model of an adaptive circuit for efficient encoding and feature extraction

One major question in neuroscience is how to relate connectomes to neural activity, circuit function, and learning. We offer an answer in the peripheral olfactory circuit of the Drosophila larva, composed of olfactory receptor neurons (ORNs) connected through feedback loops with interconnected inhibitory local neurons (LNs). We combine structural and activity data and, using a holistic normative framework based on similarity-matching, we propose a biologically plausible mechanistic model of the circuit. Our model predicts the ORN → LN synaptic weights found in the connectome and demonstrate that they reflect correlations in ORN activity patterns. Additionally, our model explains the relation between ORN → LN and LN – LN synaptic weight and the arising of different LN types. This global synaptic organization can autonomously arise through Hebbian plasticity, and thus allows the circuit to adapt to different environments in an unsupervised manner. Functionally, we propose LNs extract redundant input correlations and dampen them in ORNs, thus partially whitening and normalizing the stimulus representations in ORNs. Our work proposes a comprehensive framework to combine structure, activity, function, and learning, and uncovers a general and potent circuit motif that can learn and extract significant input features and render stimulus representations more efficient. Significance The brain represents information with patterns of neural activity. At the periphery, due to the properties of the external world and of encoding neurons, these patterns contain correlations, which are detrimental for stimulus discrimination. We study the peripheral olfactory neural circuit of the Drosophila larva, that preprocesses neural representations before relaying them to higher brain areas. A comprehensive understanding of this preprocessing is, however, lacking. Here, we propose a mechanistic and normative framework describing the function of the circuit and predict the circuit’s synaptic organization based on the circuit’s input neural activity. We show how the circuit can autonomously adapt to different environments, extracts stimulus features, and decorrelate and normalize input representations, which facilitates odor discrimination downstream.
Alkaliphilus flagellatus sp. nov., Butyricicoccus intestinisimiae sp. nov., Clostridium mobile sp. nov., Clostridium simiarum sp. nov., Dysosmobacter acutus sp. nov., Paenibacillus brevis sp. nov., Peptoniphilus ovalis sp. nov. and Tissierella simiarum sp. nov., isolated from monkey faeces

Non-human primates harbor diverse microbiomes in their guts. As a part of China Microbiome Initiatives, we cultivated and characterized the gut microbiome of cynomolgus monkeys (Macaca fascicularis). In this report, we communicate the characterization and taxonomy of 8 bacterial strains that were obtained from fecal samples of captive cynomolgus monkeys. The results revealed that they represented 8 novel bacterial species. The proposed names of the 8 novel species are Alkaliphilus flagellate (type strain MSJ-5T =CGMCC 1.45007T=KCTC 15974T), Butyricicoccus intestinisimiae MSJd-7T (type strain MSJd-7T =CGMCC 1.45013T =KCTC 25112T), Clostridium mobile (type strain MSJ-11T =CGMCC 1.45009T=KCTC 25065T), Clostridium simiarum (type strain MSJ-4T =CGMCC 1.45006T =KCTC 15975T), Dysosmobacter acutus (type strain MSJ-2T =CGMCC 1.32896T=KCTC 15976T), Paenibacillus brevis MSJ-6T (type strain MSJ-6T =CGMCC 1.45008T=KCTC 15973T), Peptoniphilus ovalis (type strain MSJ-1T =CGMCC 1.31770T=KCTC 15977T), and Tissierella simiarum (type strain MSJ-40T =CGMCC 1.45012T=KCTC 25071T).
Fabrication and delivery of mechano-actived microcapsules containing osteogenic factors in a large animal model of osteochondral injury

Chondral and osteochondral repair strategies are limited by adverse bony changes that occur after injury. Bone resorption can cause entire scaffolds, engineered tissues, or even endogenous repair tissues to subside below the cartilage surface. To address this translational issue, we fabricated poly(D,L-lactide-co-glycolide) (PLGA) microcapsules containing the pro-osteogenic agents triiodothyronine and ß-glycerophosphate, and delivered these microcapsules in a large animal model of osteochondral injury to preserve bone structure. We demonstrate that developed microcapsules ruptured in vitro under increasing mechanical loads, and readily sink within a liquid solution, allowing for gravity-based positioning onto the osteochondral surface. In a large animal, these mechano-active microcapsules (MAMCs) were assessed through two different delivery strategies. Intra-articular injection of control MAMCs enabled fluorescent quantification of MAMC rupture and cargo release in a synovial joint setting over time in vivo. This joint-wide injection also confirmed that the MAMCs do not elicit an inflammatory response. In the contralateral hindlimbs, chondral defects were created, MAMCs were locally administered, and nanofracture (Nfx), a clinically utilized method to promote cartilage repair, was performed. The NFx holes enabled marrow-derived stromal cells to enter the defect area and served as repeatable bone injury sites to monitor over time. Animals were evaluated 1 and 2 weeks after injection and surgery. Analysis of injected MAMCs showed that bioactive cargo was released in a controlled fashion over 2 weeks. A bone fluorochrome label injected at the time of surgery displayed maintenance of mineral labeling in the therapeutic group, but resorption in both control groups. Alkaline phosphatase (AP) staining at the osteochondral interface revealed higher AP activity in defects treated with therapeutic MAMCs. Overall, this study establishes a new micro-fluidically generated delivery platform that releases therapeutic factors in an articulating joint, and reduces this to practice in the delivery of therapeutics that preserve bone structure after osteochondral injury.