Browse Articles

Unveiling enhanced HCN sensing: a comparative DFT study on reactivity and sensitivity of X-doped biphenylene nanotubes (X = B, Al, and Ga)

Resolving competing evolutionary histories in joint ancestral state reconstruction

Ancestral state reconstruction (ASR) is a foundational tool in comparative biology, offering insights into the evolutionary history of lineages. With each new evolutionary model, our ability to estimate ancestral states with increased biological realism has improved. However, the field has primarily relied on marginal reconstructions, which focus on individual nodes. This framework is analytically tractable and appropriate for node-specific hypotheses, but it is not designed to identify the most probable sequence of evolutionary events across a tree. We argue that for researchers interested in evolutionary trajectories, joint reconstructions provide a more effective way to characterize the full history of transitions. Traditionally, joint reconstruction algorithms focused only on the single most likely sequence, but here we use conditional probabilities derived from stochastic mapping to sample the distribution of plausible ancestral histories efficiently. Furthermore, we provide tools to quantify and summarize this joint uncertainty. Through simulations and an empirical case study, we demonstrate that joint reconstructions more effectively recover simulated trait histories than node-wise marginal estimates and that the uncertainty surrounding these histories can be biologically meaningful. We apply our methods to epidemic multidrug-resistant Klebsiella pneumoniae and find that the evolution of antibiotic resistance is not a single narrative but a series of competing histories. Each of these histories exhibits distinct phenotype–genotype transitions that node-wise approaches would struggle to identify, yet have critical implications for predicting and understanding resistance evolution.

Trends and disparities in unintentional injury mortality among children under five in northern Iran: a 10-year population-based surveillance study (2013–2022)

mtHsp70 chaperone converts mitochondrial proteostasis stress into impaired protein import

Heat shock proteins 70 (Hsp70) represent a ubiquitous and conserved family of molecular chaperones involved in a variety of cellular processes. The conformational cycles of several Hsp70 chaperones, driven by ATP binding and hydrolysis, and regulated by cochaperones and substrate proteins, were analyzed in vitro in great detail. In contrast, little is known about the conformation Hsp70s adopt in their natural environments. In mitochondria, mtHsp70 is distributed between the TIM23 complex at the inner membrane, where it is involved in import of proteins from the cytosol, and a matrix-pool that is primarily involved in folding of proteins and prevention of their aggregation. Here, we used fluorescence microscopy to analyze the conformation of mtHsp70 at the single molecule level within physiologically active mitochondria. Our results revealed that the majority of mtHsp70 molecules are present in a substrate-bound state, suggesting that the mtHsp70 network functions at the limits of its capacity. To understand the biological significance of this finding, we modulated the levels of unfolded proteins in the matrix. Unfolded proteins reduced the association of mtHsp70 with the TIM23 complex and specifically impaired mtHsp70-dependent import of proteins. Our data show that unfolded proteins lead to a redistribution of mtHsp70 within mitochondria revealing how mitochondrial proteostasis stress is signaled to the cell—unfolded proteins remove mtHsp70 from the import sites, reducing the efficiency of protein import and initiating cellular programs to rescue or remove dysfunctional mitochondria. Thus, mtHsp70 acts as a mitochondrial quality control sensor that converts proteostasis stress into impaired protein import.

A GAN-physical simulation coupled framework for joint optimization of building energy prediction and spatial configuration

Lysosome-related organelles orchestrate guanine crystal formation in pigment cells

Iridosomes, the guanine crystal-forming organelles of pigment-producing iridophores, are among the most versatile, visually striking yet mechanistically uncharacterized organelles in vertebrate biology. Lysosome-related organelles (LROs) support cell type–specific functions by adapting endolysosomal pathways for specialized roles. Here, we show that iridosomes represent a subtype of LROs. Using transcriptomic profiling of zebrafish iridophores, CRISPR-Cas9-mediated gene disruption, and cryogenic transmission electron microscopy, we define the molecular program underlying iridosome biogenesis. Iridosomes have evolved unique adaptations for crystal growth while retaining core features of other LROs. Key regulators, including Rab32a, Ap3m2, and Hps5, are essential for crystal formation, with gene knockouts causing reduced crystal number, altered morphology, and distinct maturation defects. We further identify hallmark LRO features in iridosomes, including intraluminal vesicles and pH-regulated developmental transitions. Cross-species transcriptomic analysis confirms that iridosomes share an LRO signature across vertebrates, including teleost fish and reptiles, suggesting ancient evolutionary origins. These findings establish iridosomes as crystalline LROs and as a model for investigating how cells construct structurally specialized organelles through coordinated trafficking and crystallization, with implications for LRO evolution and human disease.

A complex interplay of various intracellular motifs determines G protein binding and activation of muscarinic receptors

Abstract G protein coupled receptors (GPCRs) mediate intracellular signaling by selectively activating heterotrimeric G proteins. While certain GPCRs exhibit a high specificity toward particular G protein subtypes, other GPCRs display promiscuous signaling by engaging interaction with multiple G protein families. Molecular determinants underlying the selectivity or promiscuity of the receptors remain incompletely understood. In the present study, we investigate various structural motifs within the intracellular domains of Muscarinic receptors to assess their role in both Gα subunit binding and activation. To this end, we generated chimeric receptors and applied both FRET- and BRET-based assays to monitor G protein binding and activation. Our study demonstrates that the determination of G protein coupling selectivity is not defined by single motifs or amino acids but rather by a complex interplay of various intracellular motifs affecting binding or/and subsequent activation. These results provide new insights into the structural basis of GPCR-G protein specificity.

Dopamine D1 and D2 receptors differentially control strength and dynamics of abstract decision codes in the primate prefrontal cortex

Dopamine critically modulates prefrontal circuits underlying cognitive control, but how D1-type (D1R) and D2-type (D2R) receptors influence abstract decision coding is unclear. We recorded single-neuron activity in two monkeys performing a number comparison task, in which abstract decisions about sequentially presented dot displays were dissociated from motor responses, while locally stimulating D1R or D2R via microiontophoresis. D1R stimulation suppressed, whereas D2R stimulation enhanced, the decision-coding strength of individual neurons, effects mirrored at the population level in decoding accuracy. Interestingly, dopamine receptors also bidirectionally modulated the temporal structure of population activity: D1R stimulation reduced the temporal generalizability of neuronal decision selectivity, suggesting more transient tuning and a shift toward a more dynamic coding regime. Conversely, D2R stimulation increased temporal generalizability of decision selectivity, implying more sustained tuning and a shift toward a more static coding regime. These findings suggest that D1- and D2-mediated mechanisms in the prefrontal cortex provide a receptor-specific substrate for balancing cognitive flexibility and stability in abstract decision-making. This pattern may reflect task-dependent deviations from classical dual-state models, in which D1 receptor activity stabilizes working memory representations whereas D2 receptor activity supports flexible coding—a relationship that appears reversed in the context of abstract decision formation.

Antimicrobial resistance varies with warming in active layer soil and permafrost

Abstract Although antimicrobial resistance is a contemporary public health concern, antimicrobial resistance genes (ARGs) have existed long before human use of antimicrobials, and recent attention has focused on whether permafrost thaw could release ARGs as the resistome shifts. We present a metagenomic analysis of permafrost samples from four sites in Alaska and Sweden, thawed under laboratory conditions. We used ABRicate, an alignment-based tool, and DeepARG, a deep learning tool, to identify ARGs, assessed their abundances under experimental thaw, measured taxonomic shifts, and examined metagenome-assembled genomes (MAGs) carrying ARGs. ARG abundance varied with depth, with some permafrost containing more ARGs than the seasonally thawed active layer. ARG abundance increased with soil carbon and decreased with pH across sites, suggesting site-specific influences. The majority of 164 high-quality MAGs contained ARGs, including 80 out of 105 species identified. This included bacteria from nine phyla, demonstrating widespread distribution across microbial taxa. Laboratory thaw experiments revealed that ARG abundances did not change significantly in two of the sites, but declined with thaw in the remaining two sites. Together, these findings demonstrate that ARGs are consistently present in permafrost microbiomes across multiple sites, but relative abundances generally do not increase during thaw. While ARGs that persist may pose potential risks, our results suggest that permafrost thaw may not substantially elevate environmental or public health risks.

Spatial multiomics profiling reveals ZFP36-mediated immunometabolic reprogramming in bladder cancer

Bladder cancer remains a significant therapeutic challenge due to its marked heterogeneity and capacity for immune evasion. Here, we employ spatial metabolomics and spatial transcriptomics to systematically characterize and visualize the metabolic and transcriptional landscapes of bladder cancer. Our findings identify distinct metabolic and transcriptional profiles across different tumor regions, highlighting heterogeneity and immune-associated metabolic reprogramming in BLCA. Further investigation identifies zinc finger protein 36 (ZFP36) as a potential immunotherapeutic target. Utilizing Zfp36 whole-body knockout and T cell–specific Zfp36 conditional knockout mice, we validated that Zfp36 knockout decreases the activation threshold for T cells and increases T cell infiltration in tumors. Moreover, we found that elevated ZFP36 expression is dramatically linked to worse patient outcomes. Mechanistically, ZFP36 facilitates mRNA degradation of key immune regulators, including C1QBP , thereby inhibiting T cell activation and cytotoxicity. Notably, combining Zfp36 knockout with anti-PD-1 therapy produced synergistic antitumor effects, suggesting that ZFP36 inhibition could be a promising therapeutic strategy. This integrated multiomics approach collectively uncovers immune-metabolic regulatory pathways in BLCA and points to critical molecular targets for immunotherapy.

T cells dressed up with a dual HLA-restricted TCR targeting cathepsin G drive effective AML eradication

Despite immunosensitivity, genetic heterogeneity, low mutational burden and lack of tumor-specific antigens hinder immunotherapy success for acute myeloid leukemia (AML). T cell receptors (TCRs) offer a promising route by targeting tumor-relevant extra- and intracellular antigens shared across AML subtypes; however human leukocyte antigen (HLA) restriction limits their potential. We identified a potent TCR capable of recognizing peptides of Cathepsin G (CTSG), a serine protease confined to neutrophil granules but aberrantly localized in the cytoplasm of blasts, when presented by HLA-A*24:02 and HLA-C*07:02, highly frequent alleles. Leveraging TCR gene-editing and CD8 co-receptor transduction, we engineered a robust T cell population, comprising CD4+ CD8+ T lymphocytes with enhanced functionality, without altering subset identity. T cells expressing the CTSG-TCR exhibited strong and specific cytotoxicity against primary blasts, in vitro and in vivo. Noticeably, no alterations in peripheral blood cell populations, bone marrow hematopoiesis, or extramedullary hematopoietic organs (spleen and liver) were observed, demonstrating optimal on-target/off-tumor safety profile. Moreover, the absence of off-target cross-reactivity was proved by peptide mutagenesis, highlighting the specificity of the TCR for CTSG. These results reveal the potential of dual restricted TCRs, and of CTSG-TCR T cells as powerful therapeutics for a broad AML patient population.

The role of self-efficacy and control beliefs in response to a multimodal headache intervention: results from a prospective observational study with a waiting-list comparator

Abstract Primary headache disorders, particularly migraine, rank among the leading causes of disability worldwide and impose substantial social and economic burden. Multimodal headache treatment (MMHT) combines pharmacologic, physiotherapeutic and cognitive-behavioural interventions and has shown benefit in high-burden patients, yet the psychological factors associated with sustained improvement remain unclear. Self-efficacy (SE) supports active coping, whereas the chance-related multidimensional health locus of control (CMHLC-C) reflects belief in uncontrollable outcomes. We hypothesised that these control beliefs are modifiable through intervention and that their baseline levels are associated with subsequent improvement in headache burden. Adults with primary headache disorders were enrolled in a prospective observational study and participated in a one-week MMHT at a tertiary neurological day clinic. Headache impact (HIT-6; primary endpoint), monthly headache days (MHD), and highest headache pain severity (HHPS) were measured three months before treatment (waiting-list baseline), at the start and end of MMHT, and at 3-, 6-, and 9-month follow-up. The waiting-list period served as a within-person pre-treatment comparator for spontaneous change. Baseline headache-management SE and MHLC-C subscales were tested as predictors of longitudinal HIT-6 trajectories using a generalized linear mixed model with visit as a repeated factor. Sixty-five patients were included in the analytic cohort (84.6% female; mean age 40.6 ± 13.3 years; 89.8% migraine). HIT-6 decreased from 63.2 at the waiting-list baseline to 59.0 at nine months ( p <.001). MHD was reduced from 17.9 ± 8.0 to 12.2 ± 7.5 days, and 44% experienced a ≥ 30% reduction. HHPS also decreased throughout follow-up. Mean SE increased significantly during MMHT and early follow-up, whereas CMHLC-C showed only small changes over time. The mixed model was significant (F(2,165) = 7.25, p <.001). Higher baseline SE predicted larger reductions in HIT-6 (β=−0.55, t(165) = − 2.62, p =.010), whereas greater belief in chance predicted smaller reductions (β = 0.85, t(165) = 2.80, p =.006). In this prospective observational study with a waiting-list comparator, MMHT was associated with sustained reductions in headache impact, headache frequency, and pain severity. Baseline self-efficacy and chance-related control beliefs independently predicted treatment response and may represent clinically relevant stratification targets in personalised headache care.

Chromosome-specific drift under stabilizing selection generates polygenic barriers to sex chromosome turnover

While sex chromosome systems show frequent evolutionary transitions in some clades, in many others they show long-term stability. Previous explanations of this stasis rely on evolutionary dynamics peculiar to sex chromosomes, such as the accumulation of deleterious mutations on the sex-specific chromosome or sexually antagonistic mutations on either sex chromosome. Here, I show that stabilizing selection on quantitative traits promotes stability of sex chromosome systems. The reason is that stabilizing selection, while keeping the value of the trait near its optimum, allows individual chromosomes’ contributions to the trait to drift, and this chromosome-specific drift reduces the fitness of the novel sex-determining genotypes necessarily produced during sex chromosome turnover. Given the ubiquity of stabilizing selection on quantitative traits, chromosome-specific drift could play a pivotal role in preventing the turnover of sex chromosome systems across multiple stages of their evolution. The theory generates several testable predictions for the evolution of sex chromosome systems that align well with observed phylogenetic patterns. For example, although chromosome-specific drift acts as a global impediment to sex chromosome turnover, those turnovers that do occur should be more likely to maintain the system of heterogamety than to change it. The theory further predicts a higher rate of transitions from environmental to genetic sex determination, versus the reverse. Finally, the theory shows that the evolution of sexual dimorphism in complex traits can drive long-term sex chromosome stability.

Differences between human and AI scoring: A meta-analysis of english language assessments

Abstract Despite a burgeoning body of research on using AI scoring systems in English assessments, concerns regarding their reliability persist. To fill this gap, this meta-analysis examined the AI-human scoring differences and the variables moderating these differences by synthesizing the results of 21 empirical studies with a total of 401,698 participants. Results indicate no statistically significant differences between AI and human scoring; the small effect size implies that the average systematic difference between the two was relatively modest. However, extremely high heterogeneity suggests that this overall finding masks considerable variability across study conditions. Moderator analyses reveal that AI-human scoring differences are significantly influenced by factors such as AI system type, number of human raters, agreement index employed, learner proficiency level (CEFR), and publication year. These findings suggest that while AI cannot fully replace human judgment, it can serve as a diagnostic reference tool within broader quality assurance frameworks. When significant discrepancies arise, they warrant investigation of both scoring sources. Based on these findings, this study offers evidence-based recommendations for educators on the effective use of AI scoring systems in language assessments.

Negative design enables cell-free expression and folding of designed transmembrane β-barrels

De novo design of membrane proteins (MPs) is a rapidly growing field with transformative potential for synthetic biology. Yet, progress has lagged behind that of soluble proteins, largely due to limited understanding of the fundamental principles governing MP folding, stability, and solubility—and the difficulty of integrating them into computational models. In cells, strict quality control mechanisms limit the expression of designed MPs with suboptimal properties, hindering iterative design-build-test cycles. Here, we use a cell-free expression system to bypass the cytotoxicity of failed or insoluble designs and investigate how sequence features influence the thermodynamically driven assembly of designed transmembrane β-barrels (TMBs) in synthetic membranes. We find that even small, idealized TMBs challenge classical protein design workflows: sequences optimized solely for thermodynamic stability misfold and aggregate, preventing membrane insertion. Aggregation in water emerges as key determinants of membrane association, instead of bulk hydrophobicity. By designing variants of a synthetic TMB, we demonstrate that suppressing aggregation-prone intermediates through local destabilization of β-strands (“negative design”) significantly improves membrane assembly. Strikingly, even substitutions typically considered highly destabilizing, such as prolines or polar threonines exposed to the bilayer core, can improve folding and assembly when strategically positioned, without significantly compromising thermodynamic stability. Based on these findings, we propose a framework for joint optimization of native stability and assembly pathways for future MP and nanopore design.

Optimizations on multi-mineral clayey soil to develop limestone calcined clay cement (LC3) based composite

Demystifying invasivorism as a management strategy

Prototype contrastive and adversarial alignment for heterogeneous domain adaptation

SARS-CoV-2 and MERS-CoV disrupt host protein synthesis via nsp1 with differential effects on the integrated stress response

Coronaviruses pose a serious threat to public health, driving the need for antiviral therapeutics and vaccines. Therefore, it is paramount to understand how this family of viruses evades cellular antiviral responses and establishes productive infection. The conserved coronavirus nonstructural protein 1 (nsp1) has been shown to inhibit host protein synthesis and, in some coronaviruses, promote host messenger RNA (mRNA) degradation while viral mRNAs are protected. We showed previously that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induces activation of host integrated stress response (ISR) kinases protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), which promote phosphorylation of eukaryotic initiation factor 2 (eIF2α) and consequent inhibition of host protein synthesis. In contrast, eIF2α remains unphosphorylated during Middle East respiratory syndrome coronavirus (MERS-CoV) infection. To investigate the interactions of nsp1 and the ISR kinases, we utilized recombinant SARS-CoV-2 and MERS-CoV expressing nsp1 with mutations in each of two conserved domains. Upon infection with SARS-CoV-2 nsp1 mutants, translation was shut down in wildtype (WT) and PKR knockout (KO) cells but rescued in PERK KO cells, likely due to reduced p-eIF2α. In contrast, translation was rescued during infection with the analogous MERS-CoV nsp1 mutants even in WT cells. Moreover, SARS-CoV-2 WT suppressed expression of GADD34, a negative regulator of eIF2α phosphorylation, while SARS-CoV-2 nsp1 mutants induced GADD34. In contrast, MERS-CoV WT induced GADD34. Utilizing single-molecule fluorescence in situ hybridization, we found that SARS-CoV-2 and MERS-CoV nsp1 promote host mRNA degradation during WT, but not nsp1 mutant, infection. Thus, SARS-CoV-2 and MERS-CoV differ in interactions with the ISR and nsp1 control of host protein synthesis.

Explaining EFL students’ continuance intention to use e-learning through technology acceptance, expectation confirmation, and flow theory