Browse Articles

Effect of intracameral air injection during Ahmed glaucoma valve implantation on hypertensive phase

Design of an integrated model with temporal graph attention and transformer-augmented RNNs for enhanced anomaly detection

Developmental defects in ectodermal appendages caused by missense mutation in edaradd gene in the nfr mangrove killifish kryptolebias marmoratus

Abstract The mangrove killifish, Kryptolebias marmoratus, can reproduce with self-fertilisation, offering a unique and useful genetic tool for generation of genetic mutants and quick identification of mutated genes. From an ENU-mutated mangrove killifish line R228, we have isolated a novel mutant line, no-fin-ray/nfr in which homozygous mutant of adult fish fin ray development is largely reduced. Illumina RNAseq with 3 embryos each from mutants, siblings and the parental WT strain Hon9 (only 9 embryos as total) identified a mutation in the edaradd in a highly conserved C-terminal death domain. Edaradd is known as a cytoplasmic accessory protein for the Ectodysplasin A (EDA) signalling pathway. To confirm the crucial role of edaradd during fin development, CRISPR RNAs were designed to suppress the gene in another killifish species, Arabian killifish. Indeed, Arabian killifish edaradd crispants showed a potent reduction of the fin development with 100% frequency. Furthermore, EDA crispants also showed identical phenotypes to that of edaradd crispants, confirming the fin defect in the mutants/crispants is caused by the signalling pathway of the EDA in the killifish species. These data demonstrate a powerful genetic approach using isogenic self-fertilising mangrove killifish as a tool for identifying mutants and their mutations, and revealed the crucial role of edaradd for the first time in the fish fin development.

Author Correction: The role of mineralogical and textural complexity in the damage evolution of brittle rocks

CT-based scoring system for diagnosing eosinophilic solid and cystic renal cell carcinoma versus clear cell renal cell carcinoma

Association between life’s essential 8 and bone mineral density among adults aged 20–59 years

Genome assembly and population analysis of tetraploid marama bean reveal two distinct genome types

Using roof borehole electrical resistivity tomography to monitor roof water infiltration in a mine work face

Action potential–independent spontaneous microdomain Ca ²⁺ transients–mediated continuous neurotransmission regulates hyperalgesia

Neurotransmitters and neuromodulators can be released via either action potential (AP)–evoked transient or AP-independent continuous neurotransmission. The elevated AP-evoked neurotransmission in the primary sensory neurons plays crucial roles in hyperalgesia. However, whether and how the AP-independent continuous neurotransmission contributes to hyperalgesia remains largely unknown. Here, we show that primary sensory dorsal root ganglion (DRG) neurons exhibit frequent spontaneous microdomain Ca 2+ (smCa) activities independent of APs across the cell bodies and axons, which are mediated by the spontaneous opening of TRPA1 channels and trigger continuous neurotransmission via the cyclic adenosine monophosphate-protein kinase A signaling pathway. More importantly, the frequency of smCa activity and its triggered continuous neurotransmission in DRG neurons increased dramatically in mice experiencing inflammatory pain, inhibition of which alleviates hyperalgesia. Collectively, this work revealed the AP-independent continuous neurotransmission triggered by smCa activities in DRG neurons, which may serve as a unique mechanism underlying the nociceptive sensitization in hyperalgesia and offer a potential target for the treatment of chronic pain.

An evolutionarily conserved cation channel tunes the sensitivity of gustatory neurons to ephaptic inhibition in <i>Drosophila</i>

In ephaptic coupling, physically adjacent neurons influence one another’s activity via the electric fields they generate. To date, the molecular mechanisms that mediate and modulate ephaptic coupling’s effects remain poorly understood. Here, we show that the hyperpolarization-activated cyclic nucleotide–gated (HCN) channel lateralizes the potentially mutual ephaptic inhibition between Drosophila gustatory receptor neurons (GRNs). While sweet-sensing GRNs (sGRNs) engage in ephaptic suppression of the adjacent bitter-sensing GRNs (bGRNs), HCN expression in sGRNs enables them to resist ephaptic suppression from the bGRNs. This one-sided ephaptic inhibition confers sweetness dominance, facilitating ingestion of bitter-laced sweets. The role of fly HCN in this process can be replaced by human HCN2. Furthermore, unlike the mechanism in olfaction, gustatory ephaptic inhibition is independent of sensillum potential changes, suggesting that the compartmentalized arrangement of neighboring GRNs is dispensable for gustatory ephaptic inhibition. These findings indicate a role for the gating of ephaptic coding to ensure the intake of the essential nutrient despite bitter contaminants present in the feeding niche of Drosophila , and propose that studies in Drosophila gustation could reveal ephaptic principles conserved across diverse animals.

Precision data-driven modeling of cortical dynamics reveals person-specific mechanisms underpinning brain electrophysiology

Task-free brain activity affords unique insight into the functional structure of brain network dynamics and has been used to identify neural markers of individual differences. In this work, we present an algorithmic optimization framework that directly inverts and parameterizes brain-wide dynamical-systems models involving hundreds of interacting neural populations, from single-subject M/EEG time-series recordings. This technique provides a powerful neurocomputational tool for interrogating mechanisms underlying individual brain dynamics (“precision brain models”) and making quantitative predictions. We extensively validate the models’ performance in forecasting future brain activity and predicting individual variability in key M/EEG metrics. Last, we demonstrate the power of our technique in resolving individual differences in the generation of alpha and beta-frequency oscillations. We characterize subjects based upon model attractor topology and a dynamical-systems mechanism by which these topologies generate individual variation in the expression of alpha vs. beta rhythms. We trace these phenomena back to global variation in excitatory–inhibitory balance, highlighting the explanatory power of our framework to generate mechanistic insights.

Conformity to continuous and discrete ordered traits

Models of conformity and anticonformity have typically focused on cultural traits with unordered variants, such as baby names, strategies (cooperate/defect), or the presence/absence of an innovation. There have been fewer studies of conformity to cultural traits with ordered variants, such as level of cooperation (low, medium, high) or proportion of time spent on a task (0% to 100%). In these studies of ordered cultural traits, conformity is defined as a preference for the mean trait value in a population even if no members of the population have variants near this mean; e.g., 50% of the population has variant 0 and 50% has variant 1, producing a mean of 0.5. Here, we introduce models of conformity to ordered traits, which can be either discrete or continuous. In these models, conformists prefer to adopt more popular cultural variants even if these variants are far from the population mean. To measure a variant’s “popularity” in cases where no two individuals share precisely the same variant on a continuum, we introduce a metric called k -dispersal; this takes into account a variant’s distance to its k closest neighbors, with more “popular” variants having lower distances to their neighbors. We demonstrate through simulations that conformity to ordered traits need not produce a homogeneous population, as has previously been claimed. Under some combinations of parameter values, conformity sustains substantial trait variation over many generations. Furthermore, anticonformity may produce a high level of polarization.

A solution to the pervasive problem of response bias in self-reports

Self-reports are used ubiquitously to probe people’s thoughts, feelings, and behaviors and inform medical decisions, enterprise operations, and government policy and legislation. Despite their pervasive use, self-report measures such as Likert scales have a profound problem: Standard analytic approaches do not control for the confounding effects of idiosyncratic response biases. Here, we present a model-based solution to this problem. Our model disentangles response bias from latent constructs of interest to obtain less biased scores of the latent states of respondents. Inspired by Thurstonian approaches in the psychophysics literature, the model requires nothing further than standard Likert scale design assumptions. The model uses a data-driven approach to control for response biases, without the need to prespecify bias types or response strategies. We demonstrate the model’s ability to uncover more precise estimates of latent state associations, outperforming bias-affected standard scoring techniques, and garner insights into previously undetected codependencies between certain latent states and particular forms of response bias. The model is thus a tool which outperforms standard scoring methods and generates insights into, and controls for, the potentially confounding effects of response bias on self-report Likert scale data.

Nitrous oxide production via enzymatic nitroxyl from the nitrifying archaeon <i>Nitrosopumilus maritimus</i>

Ammonia oxidizing archaea (AOA) are among the most abundant microorganisms on earth and are known to be a major source of nitrous oxide (N 2 O) emissions, although biochemical origins of this N 2 O remain unknown. Enzymological details of AOA nitrogen metabolism are broadly unavailable. We report the recombinant expression, purification, and characterization of a multicopper oxidase, Nmar_1354, from the AOA Nitrosopumilus maritimus . We show that Nmar_1354 selectively produces nitroxyl (HNO) by coupling the oxidation of the obligate nitrification intermediate hydroxylamine (NH 2 OH) to dioxygen (O 2 ) reduction. This HNO undergoes several downstream reactions, although the major fates are production of N 2 via reaction with NH 2 OH and dimerization with itself to yield N 2 O. These results afford one plausible enzymatic origin for N 2 O release by AOA. Moreover, these results reveal a physiologically relevant enzymatic reaction for producing HNO, an enigmatic nitrogen oxide speculated to be operative in cellular signaling and in energy transduction.

Stimulating the regenerative capacity of the human retina with proneural transcription factors in 3D cultures

Retinal diseases often lead to degeneration of specific retinal cell types with currently limited therapeutic options to replace the lost neurons. Previous studies have reported that overexpression of ASCL1 or combinations of proneural factors in Müller glia (MG) induce regeneration of functional neurons in the adult mouse retina. Recently, we applied the same strategy in dissociated cultures of fetal human MG and although we stimulated neurogenesis from MG, our effect in 2D cultures was modest and our analysis of newborn neurons was limited. In this study, we aimed to improve our MG reprogramming strategy in a more intact retinal environment. For this purpose, we used an in vitro culture system of human fetal retinal tissue and adult human postmortem retina. To stimulate reprogramming, we used lentiviral vectors to deliver constructs with a glial-specific promoter (HES1) driving ASCL1 alone or in combination with additional developmental transcription factors (TFs) such as ATOH1 and NEUROD1 . Combining IHC, scRNA-seq, and electrophysiology, we show that human MG can generate new neurons even in adults. This work constitutes a key step toward a future clinical application of this regenerative medicine approach for retinal degenerative disorders.

The population dynamics of clustered consumer–resource spatial patterns: Insights from the demographics of a Turing mechanism

In ecology, Alan Turing’s proposed activation–inhibition mechanism has been abstracted as corresponding to several ecological interaction types to explain pattern formation in ecosystems. Consumer–resource interactions have strong theoretical arguments linking them to both the Turing mechanism and pattern formation, but there is little empirical support to demonstrate these claims. Here, we connect several lines of evidence to support the proposition that consumer–resource interactions can create empirically observed spatial patterns through a mechanism similar to Turing’s theory. We propose the existence of a fine-scale demographic spatial pattern (DSP), in which the youngest resources are located at the periphery and oldest in the center of clusters. We find evidence of a DSP in the spatially clustered distribution of arboreal ant nests, whose large-scale spatial patterning has previously been hypothesized to be driven by ant parasitoids. Through a combination of field surveys and analysis of demographic trends, we demonstrate how the DSP structures the interactions between the ant and its parasitoid. To explore the implications of DSP for consumer–resource pattern forming systems generally, we use a spatially explicit consumer–resource model to show how relative diffusion rates of the system shape multiscale spatial patterns that structure the demographic trends of the resource population in predictable ways. This work provides both empirical support for consumer–resource spatial patterns as well as a multiscale approach to understand their spatially explicit population dynamics.

Plant BCL-DOMAIN HOMOLOG proteins play a conserved role in SWI/SNF complex stability

The SWItch/Sucrose Non-Fermenting (SWI/SNF) complexes are evolutionarily conserved, ATP-dependent chromatin remodelers crucial for multiple nuclear functions in eukaryotes. Recently, plant BCL-DOMAIN HOMOLOG (BDH) proteins were identified as shared subunits of all plant SWI/SNF complexes, significantly impacting chromatin accessibility and various developmental processes in Arabidopsis. In this study, we performed a comprehensive characterization of bdh mutants, revealing the role of BDH in hypocotyl cell elongation. Through detailed analysis of BDH domains, we identified a plant-specific N-terminal domain that facilitates the interaction between BDH and the rest of the complex. Additionally, we uncovered the critical role of the BDH β-hairpin domain, which is phylogenetically related to mammalian BCL7 SWI/SNF subunits. While phylogenetic analyses did not identify BDH/BCL7 orthologs in fungi, structure prediction modeling demonstrated strong similarities between the SWI/SNF catalytic modules of plants, animals, and fungi and revealed the yeast Rtt102 protein as a structural homolog of BDH and BCL7. This finding is supported by the ability of Rtt102 to interact with the Arabidopsis catalytic module subunit ARP7 and partially rescue the bdh mutant phenotypes. Further experiments revealed that BDH promotes the stability of the ARP4-ARP7 heterodimer, leading to the partial destabilization of ARP4 in the SWI/SNF complexes. In summary, our study unveils the molecular function of BDH proteins in plant SWI/SNF complexes and suggests that β-hairpin-containing proteins are evolutionarily conserved subunits crucial for ARP heterodimer stability and SWI/SNF activity across eukaryotes.

Crucial role of the cGAS N terminus in mediating flowable and functional cGAS–DNA condensate formation via DNA interactions

The DNA-sensing protein cGAS plays a pivotal role in the innate immune response and pathogenesis of various diseases. DNA triggers liquid–liquid phase separation (LLPS) and enhances the enzymatic activity of cGAS. However, the regulatory mechanisms of the disordered N terminus remain unclear. Here, we showed that cGAS Nterm , the N-terminal intrinsic disordered region (IDR) of cGAS, modulates the material properties, specifically the flowability, of the condensed phase of cGAS and is required for full enzymatic activity. Full-length cGAS and cGAS Nterm form liquid droplets in the presence of DNA, while the cGAS catalytic domain forms gel-like solid aggregates with compromised enzymatic activity. Multiple key amino acids responsible for the cGAS Nterm –DNA interaction were identified by NMR spectroscopy as well as other biophysical methods and proven to be critical for the functional LLPS of cGAS both in vitro and in vivo. Interestingly, cGAS Nterm acts in trans to transform the solid aggregates of the cGAS catalytic domain into liquid droplets, subsequently restoring its enzymatic activity. Together, our findings highlight the importance of the IDR of cGAS in LLPS upon DNA stimulation and, more importantly, in modulating the fluidity and permeability of the droplets formed by full-length cGAS, which is crucial for its intact enzymatic activity.

Discrepancies between subjective and objective sleep assessments revealed by in-home electroencephalography during real-world sleep

Sleep insufficiency and sleep disorders pose serious health challenges. This study aimed to determine the potential discrepancy between subjective and objective sleep assessments, including the latter made by physicians, by analyzing a 421-participant dataset in Japan comprising multiple nights of in-home sleep electroencephalogram (EEG) data and questionnaire responses on sleep habits or subjective experiences. We employed logistic regression models to examine which subjective and objective sleep parameters physicians are paying attention to when assessing sleep insufficiency, insomnia, sleep quality, and sleep apnea. Questionnaire responses, including subjective sleep assessments, exhibited poor performance predicting physicians’ assessments, whereas objective data demonstrated good predictive performance, indicating a discrepancy between subjective and objective sleep assessments. Although the in-home sleep EEG measurements had minimal first night effects, incorporating measurements over multiple nights can improve the detection of objective insomnia. Moreover, we found that participants with severe sleep insufficiency overestimated their sleep duration, whereas those with subjective insomnia but without objective insomnia underestimated it. Additionally, subjective sleep quality reflected sleep efficiency but not the frequency of short awakenings or objective sleep depth. In particular, the effects of apnea on objective sleep quality were not subjectively perceived. Collectively, our findings suggest that subjective sleep assessments alone are insufficient for evaluating sleep health and that health checkups and advice based on sleep EEG measurements may be useful in improving sleep habits and for early detection of sleep disorders.

Fungal evasion of <i>Drosophila</i> immunity involves blocking the cathepsin-mediated cleavage maturation of the danger-sensing protease

Entomopathogenic fungi play a critical role in regulating insect populations, and representative species from the Metarhizium and Beauveria genera have been developed as eco-friendly biocontrol agents for managing agricultural insect pests. Relative to the advances in understanding antifungal immune responses in Drosophila , knowledge of how fungi evade insect immune defenses remains limited. In this study, we report the identification and characterization of a virulence-required effector Fkp1 in Metarhizium robertsii . Library screening and protein pull-down analysis unveiled that Fkp1 targets the cathepsin protease CtsK1 to inhibit its cleavage maturation of the danger-sensing serine protease Persephone (Psh), thereby facilitating fungal evasion of the Drosophila immune defenses. The Fkp1 -like gene is also required in Beauveria bassiana for insect infection. Transgenic expression of Fkp1 in Drosophila suppressed hemolymph cysteine protease activity and down-regulated the expression of antifungal genes. Fkp1 can also mask the Psh cleavage site without interfering with its ability to bait fungal subtilisin proteases. Given the evident compensatory relationship, our data indicate that the protease cascade is more crucial than the molecular pattern pathway in defending flies against fungal infections. This work reveals that Metarhizium fungi have evolved distinct effectors to block the dual recognition pathways of flies for immune evasion and sheds lights on the effector mechanisms mediating microbe–animal interactions.