Browse Articles

Construction and optimization of ecological security patterns in Chinese black soil areas considering ecological importance and vulnerability

Metagenomic analysis of human, animal, and environmental samples identifies potential emerging pathogens, profiles antibiotic resistance genes, and reveals horizontal gene transfer dynamics

Prescribed burning has negligible effects on the plant-soil system in Pinus sylvestris L. forests of the European Alps

A paper-based loop-mediated isothermal amplification assay for highly pathogenic avian influenza

Deciphering the impact of sepsis phenotypes on improving clinical outcome predictions: a multicenter retrospective analysis based on critical care in China

Abstract Sepsis is a clinically heterogeneous disease with high mortality. It is crucial to develop relevant therapeutic strategies for different sepsis phenotypes, but the impact of phenotypes on patients’ clinical outcomes is unclear. This study aimed to identify potential sepsis phenotypes using readily available clinical parameters and assess their predictive value for 28-day clinical outcomes by logistic regression analysis. In this retrospective analysis, researchers extracted clinical data from adult patients admitted to the First Affiliated Hospital of Anhui Medical University between April and August 2022 and from the 2014–2015 eICU Collaborative Study database. K-Means clustering was utilized to identify and refine sepsis phenotypes, and their predictive performance was subsequently evaluated. Logistic regression models were trained independently for each phenotype and five-fold cross-validation was used to predict clinical outcomes. Predictive accuracy was then compared to traditional non-clustered prediction methods using model assessment scores. The study cohort consisted of 250 patients from the First Affiliated Hospital of Anhui Medical University, allocated in a 7:3 ratio for training and testing, respectively, and an external validation cohort of 3100 patients from the eICU Cooperative Research Database. The results of the phenotype-based prediction model demonstrated an improvement in F1 score from 0.74 to 0.82 and AUC from 0.74(95%CI 0.71–0.80) to 0.84(95%CI 0.82–0.87), and these results also highlight the superiority of clinical outcome prediction with the help of sepsis phenotypes over traditional prediction methods. Phenotype-based prediction of 28-day clinical outcomes in sepsis demonstrated significant advantages over traditional models, highlighting the impact of phenotype-driven modeling on clinical outcomes in sepsis.

Monomers and short oligomers of human RAD52 promote single-strand annealing

Genome maintenance and stability rely on the repair of DNA double-strand breaks. Breaks can be repaired via the single-strand-annealing pathway mediated by the protein RAD52. RAD52 oligomerizes to rings that are thought to promote annealing. However, rings have only been observed at micromolar concentrations at which annealing activity is impaired. Thus, it is unclear which oligomeric form is responsible for annealing. We combined single-molecule mass photometry with biochemical assays to determine the in vitro oligomeric states of human RAD52. We found that RAD52 was mostly monomeric at lower nanomolar concentrations. With increasing concentration, RAD52 oligomerized and formed rings with a variable stoichiometry from heptamers to tridecamers consistent with an oligomerization model of noncooperative assembly coupled with preferential cyclization. Under conditions where hardly any rings were present, RAD52 already promoted single-strand annealing in vitro. Our findings indicate that in vitro single-strand annealing can be mediated by monomers and short oligomers of RAD52. The oligomerization model suggests that ring formation is similar to a phase transition whereby rings are a reservoir to replenish the monomer and short oligomer pool. This pool has a nearly constant concentration which may be optimal for annealing and would be independent, for example, of the amount of DNA damage, protein upregulation, or the cell cycle.

DNA bending mediated by ORC is essential for replication licensing in budding yeast

In eukaryotes, the origin recognition complex (ORC) promotes the assembly of minichromosome maintenance 2 to 7 complexes into a head-to-head double hexamer at origin DNA in a process known as replication licensing. In this study, we present a series of cryoelectron microscopy structures of yeast ORC mutants in complex with origin DNA. We show that Orc6, the smallest subunit of ORC, utilizes its transcription factor II B-B domain to orchestrate the sequential binding of ORC to origin DNA. In addition, Orc6 plays the role of a scaffold by stabilizing the basic patch (BP) of Orc5 for ORC to capture and bend origin DNA. Importantly, disrupting DNA bending through mutating three key residues in Orc5-BP impairs ORC’s ability to promote replication initiation at two points during the pre-RC assembly process. This study dissects the multifaceted role of Orc6 in orchestrating ORC’s activities on DNA and underscores the vital role of DNA bending by ORC in replication licensing.

MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis

The posttranslational modification (PTM) of innate immune sensor proteins by ubiquitin or ubiquitin-like proteins is crucial for regulating antiviral host responses. The cytoplasmic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5) undergoes several PTMs including ISGylation within its first caspase activation and recruitment domain (CARD), which promotes MDA5 signaling. However, the relevance of MDA5 ISGylation for antiviral immunity in an infected organism has been elusive. Here, we generated knock-in mice (MDA5 K23R/K43R ) in which the two major ISGylation sites, K23 and K43, in MDA5, were mutated. Primary cells derived from MDA5 K23R/K43R mice exhibited abrogated endogenous MDA5 ISGylation and an impaired ability of MDA5 to form oligomeric assemblies, leading to blunted cytokine responses to MDA5 RNA-agonist stimulation or infection with encephalomyocarditis virus (EMCV) or West Nile virus. Phenocopying MDA5 −/− mice, the MDA5 K23R/K43R mice infected with EMCV displayed increased myocardial injury and mortality, elevated viral titers, and an ablated induction of cytokines and chemokines compared to WT mice. Molecular studies identified human HERC5 (and its functional murine homolog HERC6) as the primary E3 ligases responsible for MDA5 ISGylation and activation. Taken together, these findings establish the importance of CARD ISGylation for MDA5-mediated RNA virus restriction, promoting potential avenues for immunomodulatory drug design for antiviral or anti-inflammatory applications.

Academic achievement helps coordination on mutually advantageous outcomes

This study examines the relationship between academic achievement and strategic ability to coordinate among middle school students. We designed an experimental framework using repeated asymmetric Battle of the Sexes and Hawk–Dove games, to explore how cognitive and social skills related to academic success influence behavior. A total of 132 students participated, divided into groups of high and low academic achievers based on their performance at school. Our results show that, on average, high achievers coordinate better on equilibrium outcomes with simple but effective strategies and obtain higher payoffs compared to low achievers. However, we notice also substantial heterogeneity within groups. Finally, performance in pairs with one high and one low achiever is intermediate but closer to the level of high achievers, suggesting potential peer learning effects and the educational value of mixed groups to promote guidance and joint improvements. These findings suggest that academic success may reflect broader cognitive abilities–such as strategic thinking, anticipation of others’ choices, and cooperation–crucial for navigating real-world interactions in complex environments.

Colony pattern multistability emerges from a bistable switch

Microbial colony development hinges upon a myriad of factors, including mechanical, biochemical, and environmental niches, which collectively shape spatial patterns governed by intricate gene regulatory networks. The inherent complexity of this phenomenon necessitates innovative approaches to comprehend and compare the mechanisms driving pattern formation. Here, we unveil the multistability of bacterial colony patterns, where bacterial colony patterns can stabilize into multiple distinct types including ring-like patterns and sector-like patterns on hard agar, orchestrated by a simple synthetic bistable switch. Utilizing quantitative imaging and spatially resolved transcriptome approaches, we explore the deterministic process of a ring-like colony pattern formation from a single cell. This process is primarily driven by bifurcation events programmed by the gene regulatory network and microenvironmental cues. Additionally, we observe a noise-induced process amplified by the founder effect, leading to patterns of symmetry-break during range expansion. The degrees of asymmetry are profoundly influenced by the initial conditions of single progenitor cells during the nascent stages of colony development. These findings underscore how the process of range expansion enables individual cells, exposed to a uniform growth-promoting environment, to exhibit inherent capabilities in generating emergent, self-organized behavior.

The histone variant H2A.W restricts heterochromatic crossovers in <i>Arabidopsis</i>

Meiotic crossovers rearrange allele combinations and create offspring diversity. Crossovers occur nonrandomly along chromosomes, predominantly in distal euchromatin and less in pericentromeric heterochromatin marked with histone H3 lysine 9 dimethylation (H3K9me2) and the H2A variant H2A.W in Arabidopsis thaliana . Loss of H3K9me2 increases heterochromatic crossovers, but how H2A.W affects crossover formation in pericentromeric regions is unknown. Here, we report that H2A.W is required to restrict heterochromatic crossovers in Arabidopsis . Using meiosis-specific microRNA-induced gene silencing (meiMIGS) and fluorescence-tagged recombination reporters, we show that meiotic knockdown of H2A.W.6 , H2A.W.7 , and H2A.W.12 ( meiMIGS-H2A.W.6/7/12 ) increases pericentromeric crossovers. High-resolution genomic maps of crossovers show that meiMIGS-H2A.W.6/7/12 enhances heterochromatic crossovers, similar to meiMIGS plants silencing the H3K9me2 pathway. Consistently, genome-wide crossover maps show that the mutants h2a.w.6 , h2a.w.7 , h2a.w.6 h2a.w.7 , and h2a.w.6 h2a.w.7 h2a.w.12, but not h2a.w.12, exhibit a similar increase in heterochromatic crossovers to meiMIGS-H2A.W.6/7/12 , demonstrating that H2A.W.6 and H2A.W.7 limit heterochromatic crossovers. Profiling of genome-wide nucleosome density using micrococcal nuclease sequencing reveals that h2a.w mutants with increased heterochromatic crossovers have increased heterochromatin accessibility, with lower H3K9me2 levels during meiosis. Our findings shed light on the role of H2A.W variants as heterochromatin compaction factors that suppress meiotic crossovers within the pericentromeric regions.

Disease resistance is more costly at younger ages: An explanation for the maintenance of juvenile susceptibility in a wild plant

High juvenile susceptibility drives infectious disease epidemics across kingdoms, yet the evolutionary mechanisms that maintain this susceptibility are unclear. We tested the hypothesis that juvenile susceptibility is maintained by high costs of resistance by quantifying the genetic correlation between host fitness and age-specific innate resistance to a fungal pathogen in a wild plant. We separately measured the resistance of 45 genetic families of the wild plant, Silene latifolia, to its endemic fungal pathogen, Microbotryum lychnidis-dioicae, at four ages in a controlled inoculation experiment. We then grew these same families in a field common garden and tracked survival and fecundity over a 2-y period and quantified the correlation between age-specific resistance and fitness in the field. We found significant fitness costs associated with disease resistance at juvenile but not at adult host stages. We then used an age-structured compartmental model to show that the magnitude of these costs is sufficient to prevent the evolution of higher juvenile resistance in models, allowing the disease to persist. Taken together, our results show that costs of resistance vary across host lifespan, providing an evolutionary explanation for the maintenance of juvenile susceptibility.

A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis

Recent sero-epidemiological studies have strengthened the hypothesis that Epstein–Barr virus (EBV) may be a causal factor in multiple sclerosis (MS). Given the complexity of the EBV–host interaction, various mechanisms may be responsible for the disease pathogenesis. Furthermore, it remains unclear whether this is a disease-specific process. Here, we showed that genes encoding EBV interactors are enriched in loci associated with MS but not with other diseases and in prioritized therapeutic targets. Analyses of MS blood and brain transcriptomes confirmed a dysregulation of MS-associated EBV interactors affecting the CD40 pathway. Such interactors were strongly enriched in binding sites for the EBV nuclear antigen 2 (EBNA2) viral transcriptional regulator, often in colocalization with CCCTC binding factor (CTCF) and RNA Polymerase II Subunit A (POLR2A). EBNA2 was expressed in the MS brain. The 1.2 EBNA2 allele downregulated the expression of the CD40 MS-associated gene analogously to the CD40 MS-risk variant. Finally, we showed that the 1.2 EBNA2 allele associates with the risk of MS. This study delineates how host and viral genetic variability converge in MS-specific pathogenetic mechanisms.

Transparency by Chinese cities reduces pollution violations and improves air quality

We provide national-scale experimental evidence from China showing that transparency by local governments improves the management of air pollution. Governments that perform better have more reasons to be transparent, making the causal relationship between transparency and policy outcomes difficult to disentangle. In 2015, we randomly assigned municipal governments in China to a high-visibility, public rating of their adherence to national requirements for transparency about their regulation of pollution. By 2016, this treatment significantly boosted transparency in treated cities relative to control cities, allowing us to observe the effect of randomly increasing transparency in the years that followed. Subsequently, high-polluting firms in treated cities cut their violations by 37% compared to similar firms in control cities. Inspections by local governments increased by about 90% in treated cities relative to control cities. Ambient air pollution decreased between 8 and 10% in treated cities relative to control cities, which likely generated significant health benefits. This study provides strong evidence that governmental transparency causes improved environmental quality, at least in a setting where the public and higher governments want to hold local governments accountable.

Breaking the mobility–stability dichotomy in organic semiconductors through adaptive surface doping

Organic semiconductors (OSCs) are pivotal for next-generation flexible electronics but are limited by an intrinsic trade-off between mobility and stability. We introduce adaptive surface doping (ASD), an innovative strategy to overcome this dichotomy in OSCs. ASD's adaptive mechanism accommodates a broad range of dopant concentrations, optimally passivating trap states as needed. This approach significantly lowers the trap energy level from 84 meV to 14 meV above the valence band edge, promoting a transition from hopping to band-like transport mechanisms. ASD boosts carrier mobility by over 60%, reaching up to 30.7 cm 2 V −1 s −1 , while extending the extrapolated operational lifetime of treated devices beyond 57.5 y. This breakthrough sets a standard in organic electronics, positioning ASD as a powerful method for simultaneously enhancing performance and stability in OSC devices.

HEATR3 recognizes membrane rupture and facilitates xenophagy in response to <i>Salmonella</i> invasion

Bacterial invasion into the cytoplasm of epithelial cells triggers the activation of the cellular autophagic machinery as a defense mechanism, a process known as xenophagy. In this study, we identified HEATR3, an LC3-interacting region (LIR)-containing protein, as a factor involved in this defense mechanism using quantitative mass spectrometry analysis. HEATR3 localizes intracellularly invading Salmonella , and HEATR3 deficiency promotes Salmonella proliferation in the cytoplasm. HEATR3 also localizes to lysosomes damaged by chemical treatment, suggesting that Salmonella recognition is facilitated by damage to the host cell membrane. HEATR3 deficiency impairs LC3 recruitment to damaged membranes and blocks the delivery of the target to the lysosome. These phenotypes were rescued by exogenous expression of wild-type HEATR3 but not by the LIR mutant, indicating the crucial role of the HEATR3–LC3 interaction in the receptor for selective autophagy. HEATR3 is delivered to lysosomes in an autophagy-dependent manner. Although HEATR3 recruitment to the damaged membrane was unaffected by ATG5 or FIP200 deficiency, it was markedly impaired by treatment with a calcium chelator, suggesting involvement upstream of the autophagic pathway. These findings suggest that HEATR3 serves as a receptor for selective autophagy and is able to identify damaged membranes, facilitate the removal of damaged lysosomes, and target invading bacteria within cells.

Unbalanced growth and land overvaluation

Historical trends suggest the decline in the importance of land as a production factor, as evidenced by the decline in the employment and gross domestic product (GDP) shares of land-intensive industries. However, land continues to be a prominent store of value, as over half of household wealth in major countries is real estate. To explain this apparent disconnection between land output and land value, in a plausible economic model with land and aggregate risk, we theoretically study the long-run behavior of land prices and identify economic conditions under which land becomes overvalued relative to the fundamentals defined by the present value of land rents. Unbalanced growth together with the elasticity of substitution between production factors plays a critical role. We establish the Land Overvaluation Theorem: When the elasticity of substitution between land and nonland factors exceeds 1 (which is natural because we can create more space by constructing taller buildings with fixed land) and technological progress is faster in nonland sectors, land overvaluation necessarily emerges. As applications of the Theorem, we present three examples: i) land overvaluation emerges along the long-run transition from the Malthusian agricultural economy to the modern knowledge- and service-based economy; ii) with aggregate uncertainty, land prices exhibit recurrent stochastic fluctuations around the trend, with expansions and contractions in the size of land overvaluation; and iii) in modern economies, land use is also changing and urban land has high value. We present a model of urban land prices and show that land overvaluation emerges in the process of urban formation characterized by unbalanced growth.

Critical dynamics predicts cognitive performance and provides a common framework for heterogeneous mechanisms impacting cognition

The brain criticality hypothesis postulates that brain dynamics are set at a phase transition where information processing is optimized. Long-range temporal correlations (TCs) characterizing the dissipation of information within a signal have been shown to be a hallmark of brain criticality. However, the experimental link between cognitive performance, criticality, and thus TCs has remained elusive due to limitations in recording length and spatial and temporal resolution. In this study, we investigate multiday invasive EEG recordings of 104 persons with epilepsy (PwE) together with an extensive cognitive test battery. We show that short TCs predict cognitive impairment. Further, we show that heterogeneous factors, including interictal epileptiform discharges (IEDs), antiseizure medications (ASMs), and intermittent periods with slow-wave activity (SWSs), all act directly to perturb critical dynamics and thus cognition. Our work suggests critical dynamics to be the setpoint to measure optimal network function, thereby providing a unifying framework for the heterogeneous mechanisms impacting cognition in conditions like epilepsy.

Stability of the cnidarian–dinoflagellate symbiosis is primarily determined by symbiont cell-cycle arrest

The cnidarian–dinoflagellate symbiosis relies on the regulation of resident symbiont populations to maintain biomass stability; however, the relative importance of host regulatory mechanisms [cell-cycle arrest (CC), apoptosis (AP), autophagy (AU), and expulsion (EX)] during symbiosis onset and maintenance is largely unknown. Here, we inoculated a symbiont-free (aposymbiotic) model cnidarian ( Exaiptasia diaphana : “Aiptasia”) with either its native symbiont Breviolum minutum or one of three non-native symbionts: Symbiodinium microadriaticum , Cladocopium goreaui, and Durusdinium trenchii . We then measured and compared host AP, host AU, symbiont EX, and symbiont cell-cycle phase for up to a year with these different symbionts and used these discrete measurements to inform comparative models of symbiont population regulation. Our models showed a general pattern, where regulation through AP and AU is reduced after onset, followed by an overshoot of the symbiont population that requires a strong regulatory response, dealt with by strong CC and increased EX. As colonization progresses into symbiosis maintenance, CC remains crucial for achieving steady-state symbiont populations, with our models estimating that CC regulates 10-fold more cells (60 to 90%) relative to the other mechanisms. Notably though, our models also revealed that D. trenchii is less tightly regulated than B. minutum , consistent with D. trenchii’s reputation as a suboptimal partner for this cnidarian. Overall, our models suggest that single regulatory mechanisms do not accurately replicate observed symbiont colonization patterns, reflecting the importance of all mechanisms working concomitantly. This ultimately sheds light on the cell biology underpinning the stability of this ecologically significant symbiosis.

RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa

Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration worldwide. It is characterized by the sequential death of rod and cone photoreceptors, the cells responsible for night and daylight vision, respectively. Although the expression of most RP genes occurs only in rods, there is a secondary degeneration of cones. One possible mechanism of cone death is metabolic dysregulation. Photoreceptors are highly metabolically active, consuming large quantities of glucose and producing substantial amounts of lactate. The retinal pigment epithelium (RPE) mediates the transport of glucose from the blood to photoreceptors and, in turn, removes lactate, which can influence the rate of consumption of glucose by the RPE. One model for metabolic dysregulation in RP suggests that following the death of rods, lactate levels are substantially diminished causing the RPE to withhold glucose, resulting in nutrient deprivation for cones. Here, we present adeno-associated viral vector-mediated delivery of monocarboxylate transporter 2 (MCT2, Slc16a7 ) into the eye, with expression limited to RPE cells, with the aim of promoting lactate uptake from the blood and encouraging the passage of glucose to cones. We demonstrate prolonged survival and function of cones in rat and mouse RP models, revealing a possible gene-agnostic therapy for preserving vision in RP. We also present the use of fluorescence lifetime imaging-based biosensors for lactate and glucose within the eye. Using this technology, we show changes to lactate and glucose levels within MCT2-expressing RPE, suggesting that cone survival is impacted by changes in RPE metabolism.