Browse Articles

A volumetric modulated arc therapy-based dynamic conformal arc technique with limited monitor units (VMATliMU) to reduce multileaf collimator interplay effects: A computational phantom study for stage I non-small-cell lung cancer

Volumetric modulated arc therapy (VMAT) for lung cancer involves complex multileaf collimator (MLC) motion, which increases sensitivity to interplay effects with tumour motion. Current dynamic conformal arc methods address this issue but may limit the achievable dose distribution optimisation compared with standard VMAT. This study examined the clinical utility of a VMAT technique with monitor unit limits (VMATliMU) to mimic conformal arc delivery and reduce interplay effects while maintaining plan quality. VMATliMU was implemented by applying monitor unit limitations during VMAT reoptimisation to minimise MLC encroachment into target volumes. Using mesh-type reference computational phantom CT images, treatment plans were generated for a simulated stage I lung cancer case prescribed to 45 Gy in three fractions. VMATliMU, conventional VMAT, VMAT with leaf speed limitations, dynamic conformal arc therapy, and constant dynamic conformal arc therapy were compared. Plans were optimised for multiple isodose line prescriptions (50%, 60%, 70%, 80%, and 90%) to investigate the impact of dose distribution. Evaluation parameters included MLC positional accuracy using area difference ratios, dosimetric indices, gradient metrics, and organ-at-risk doses. VMATliMU prevented MLC encroachment into the internal target volume across 60%–90% isodose lines, showing superior MLC accuracy compared with other methods. At the challenging 50% isodose line, VMATliMU had 4.5 times less intrusion than VMAT with leaf speed limits. VMAT plans had better dosimetric indices than dynamic conformal arc plans. VMATliMU reduced monitor units by 5.1%–19.2% across prescriptions. All plans met the clinical dose constraints, with the aortic arch below tolerance and acceptable lung doses. VMATliMU combines VMAT’s dosimetric benefits with the dynamic conformal arcs’s simplicity, minimising MLC encroachment while maintaining plan quality. Reduced monitor units lower low-dose exposure, treatment time, and interplay effects. VMATliMU is usable in existing planners with monitor unit limits, offering a practical solution for lung stereotactic body radiation therapy.

Comprehensive analysis of disulfidptosis-related genes in pulmonary hypertension through machine learning and immune infiltration: Spotlight on USP32 and ZNF655 as key regulators

Background Disulfidptosis, a novel cellular death manner, has yet to be fully explored within the context of pulmonary arterial hypertension (PAH). This study aims to identify genes implicated in PAH that are involved in disulfidptosis. Method Based on data from the GEO database, this study employed co-expression analysis, Weighted Gene Co-Expression Network Analysis (WGCNA), hub gene identification, and Gene Set Enrichment Analysis (GSEA) to uncover genes associated with PAH and disulfidptosis. Subsequent machine learning validation and functional GSEA further refined the identification of pivotal genes. The investigation extended to examining immune cell involvement via immune infiltration techniques and elucidates the hub genes’ roles within ceRNA networks. Result The integrative approach of co-expression analysis and WGCNA identified genes at the intersection of PAH and disulfidptosis. GSEA revealed their roles in essential biological processes and pathways, such as mRNA processing and cytoplasmic DNA sensing pathway. Prominently, USP32 and ZNF655 were identified as significant hub genes through machine learning analysis, demonstrating notable diagnostic potential across various datasets. Further, immune infiltration studies and ceRNA regulatory network construction revealed the intricate association between these genes and differential immune cell expression, alongside miRNA and lncRNA regulatory networks. Conclusions This study elucidates the contributory role of USP32 and ZNF655 in the pathogenesis of PAH, making them as critical genes within the disulfidptosis pathway.

Tuneable multidirectional mechanical attributes of novel sectionally nonlinearly functionally graded femur and cranial bone implants with triply periodic minimal surfaces

Sectionally nonlinearly functionally graded (SNFG) structures with triply periodic minimal surface (TPMS) are considered ideal for bone implants because they closely replicate the hierarchical, anisotropic, and porous architecture of natural bone. The smooth gradient in material distribution allows for optimal load transfer, reduced stress shielding, and enhanced bone ingrowth, while TPMS provides high mechanical strength-to-weight ratio and interconnected porosity for vascularization and tissue integration. Wherein, The SNFG structure contains sections with thickness that varies nonlinearly along their length in different patterns. And TPMS scaffolds are smooth, porous structures that repeat in three dimensions and have zero mean curvature, offering high surface area and tuneable properties. This study presents a novel design and numerical analysis of SNFG titanium alloy Ti6Al4V femur and cranial bone implants incorporating TPMSs. The accuracy of the numerical model is validated through experiments and force-reaction analysis in terms of elastic stiffness of the white Polylactic Acid (PLA)-based SNFG femur and cranial bone implants, demonstrating good agreement among methods, having a maximum percentage difference of 15.6%. It is found that among various TPMS topologies, the gyroid structure is the most suitable candidate for manufacturing SNFG bone implants, offering superior multidirectional mechanical performance. Interestingly, the anisotropy and magnitude of elastic stiffness can be tailored to closely match natural bone by adjusting the gradient index and trabecular part length while maintaining a yield strength higher than that of bone. Additionally, during service, the implant may be subjected to an impact that generates mechanical waves propagating through its structure. These waves transmit the force impulse and induce the propagation of mechanical stress throughout the implant body. The result indicates that increasing the gradient index reduces shear and longitudinal stress wave velocities with minimal impact on wave velocity anisotropy, a key factor in enhancing implant longevity and performance. And, TPMS implants exhibit extreme multiaxial yield strength anisotropy, but it can be accurately captured using the extended Hill’s criterion, which provides a reliable and cost-efficient method for constructing the critical yield surface of SNFG femur and cranial titanium implants, helping to prevent permanent plastic deformation during service. Overall, this work lays the foundation for futuristic optimization approach aimed at designing ideal SNFG titanium femur and cranial bone implants with TPMSs for biomedical applications.

Interprofessional education: A recognized necessity, a persistent challenge - Perspectives from a longitudinal study

Background Interprofessional Education (IPE) is widely recognized as essential for fostering collaborative healthcare practices and improving patient outcomes. Despite its acknowledged importance, there remains a notable scarcity of longitudinal research assessing medical students’ readiness for IPE across distinct educational stages, particularly within diverse global contexts like Brazil. Aim This study sought to address this gap by longitudinally mapping and analyzing the evolution of medical students’ readiness for interprofessional learning throughout their academic training at a Brazilian university. Methods Employing a quantitative longitudinal design, 53 medical students from the 2021 cohort completed the validated Readiness for Interprofessional Learning Scale (RIPLS) at three critical time points: upon university entry (2021), at the conclusion of the basic science cycle (2022), and at the end of the clinical cycle (2024). Temporal changes were assessed using repeated measures analysis of variance (ANOVA). Results Significant global differences were observed over time in the “Teamwork and collaboration” and “Patient-centered care” dimensions. Specifically, “Patient-centered care” exhibited a non-linear pattern, characterized by an initial increase followed by a subsequent decrease. In contrast, the “Professional identity” dimension demonstrated remarkable stability across all measurement points. Conclusions These findings reveal the complex and dynamic nature of interprofessional readiness development during medical education. They strongly advocate for the early introduction of IPE, coupled with sustained and adaptive interventions throughout the entire educational continuum, particularly to address fluctuations in patient-centered attitudes and to foster an interprofessional identity from the outset. This study offers crucial empirical insights for optimizing IPE strategies and preparing future physicians for collaborative practice.

Daily briefing: Different people’s brains process colours in the same way

Atomic armor for thermal stability in nanoporous structures

Nanoporous structures play a critical role in a wide range of applications, including catalysis, thermoelectrics, energy storage, gas adsorption, and thermal insulation. However, their thermal instability remains a persistent challenge. Inspired by the extraordinary resilience of tardigrades, an “atomic armor” strategy is introduced to enhance the stability of nanoporous structures. Applied to mesoporous silica at parts-per-million levels, the atomic armor provides thermal resistance exceeding that of existing stabilization techniques. Thermal treatment at 1,000 °C for 168 h results in a fivefold increase in specific surface area, 66% lower thermal conductivity, and a sixfold increase in pore volume compared to untreated samples. Surface viscosity is linked to sintering resistance, and glass transition temperature and fragility are introduced as design parameters. Machine-learned interatomic potentials and metabasin escape algorithm-assisted molecular dynamics simulations are employed to reveal that materials traditionally classified as nonglass formers can exhibit glass transition temperatures and display intrinsic fragility. Alumina is identified as having a record-high glass transition temperature. By modulating the surface viscosity of nanoparticles, this approach stabilizes nanoporous structures effectively. The proposed method offers a simple and universal posttreatment process for improving the thermal stability of nanoporous structures.

Joint models reveal human subcortical underpinnings of choice and learning behavior

Decision making and learning processes together enable adaptive strategic behavior. Animal studies demonstrated the importance of subcortical regions in these cognitive processes, but the human subcortical contributions remain poorly characterized. Here, we study choice and learning processes in the human subcortex, using a tailored ultra-high field 7T functional MRI protocol combined with joint models. Joint models provide unbiased estimates of brain–behavior relations by simultaneously including behavioral and neural data at the participant and group level. Results demonstrate relations between subcortical regions and the adjustment of decision urgency. Value-related blood-oxygenation level dependent (BOLD) differences were found with opposite BOLD polarity in different parts of the striatum. Multiple subcortical regions showed BOLD signatures of reward prediction error processing, but contrary to expectations, these did not include the dopaminergic midbrain. Combined, this study characterizes the human subcortical contributions to choice and learning, and demonstrates the feasibility and value of joint modeling in facilitating our understanding of brain–behavior relationships.

A mosquito-inspired theoretical framework for acoustic signal detection

Distortion products are tones produced through nonlinear effects of a system simultaneously detecting two or more frequencies. These combination tones are ubiquitous to vertebrate auditory systems and are generally regarded as byproducts of nonlinear signal amplification. It has previously been shown that several species of infectious-disease-carrying mosquitoes utilize these distortion products for detecting and locating potential mates. Furthermore, the mechanical tuning curve of the male mosquito flagellum was shown not to be aligned with that of its sensory neural elements. Using a generic theoretical model for acoustic sensing, we evaluate the signal-detection advantages and disadvantages that are implied by these two schemes: distortion product detection and cascading a signal through multiple layers of oscillator elements of different characteristic frequency. Last, we show that the combination of these two schemes yields a signal detector with enhanced frequency selectivity and speed of response, thus enabling the detection of transient, narrowband flight tones.

Action at a distance: The remarkable coupling of CO ₂ uptake to electron transfer in specialized cyanobacterial NDH-1 complexes

Cyanobacteria achieve highly efficient photosynthesis using a CO 2 -concentrating mechanism relying on specialized Type I (NDH-1) complexes. Among these, NDH-1 3 and NDH-1 4 catalyze redox-coupled hydration of CO 2 to bicarbonate, supporting carbon fixation in carboxysomes. The mechanism of coupling electron transfer to CO 2 -hydration by these variant NDH-1 complexes remains unknown. We engineered a Synechococcus PCC7942 strain that expresses exclusively the high flux/low affinity NDH-1 4 complex, enabling the observation of the coupling of CO 2 hydration to cyclic electron flow in isolation from the other NDH-1 isoforms normally present in cells. We found that inhibition of the CupB protein by the carbonic anhydrase inhibitor ethoxzolamide (EZ) suppressed CO 2 uptake, slowed photosystem I rereduction, and abolished proton pumping as probed by acridine orange fluorescence. These effects were absent in strains lacking Cup proteins, confirming specificity. The results demonstrate that CO 2 hydration and electron transfer through NDH-1 4 are tightly coupled via proton translocation across the thylakoid membrane. These findings provide direct evidence for the bidirectional interaction in bioenergetic coupling between the plastoquinone reduction and the CO 2 uptake at the distal Zn-site over a span of ~150 Å and support a proton-removal hypothesis involving the proton transfer pathways from the Zn-site of CO 2 hydration to an energetically coupled proton loading site evolutionarily repurposed from the ancestral proton pumping mechanism to enable energetic CO 2 uptake.

Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation

Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U- 13 C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the tricarboxylic acid cycle and switching substrate preference from glutamine to glucose. These effects were abolished by electron transport chain (ETC) inhibitors or in ρ 0 cells lacking mitochondrial DNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing of xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, potentially improving patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.

Origami frustration and its influence on energy landscapes of origami assemblies

Harnessing instabilities of multicomponent multistable structural assemblies can potentially lead to scalable and reversible functionalities, which can be enhanced by exploring frustration. For instance, standard Kresling origami cells exhibit nontunable intrinsic energy landscapes determined by their geometry and material properties, limiting their adaptability after fabrication. To overcome this limitation, we introduce frustration to enable fine-tuning of the energy landscape and resulting deformation states. By prestressing the Kresling cell by means of special springs with individual control, we induce either global or localized (i.e., crease level) frustration, which allows changing the energy barrier (cell or assembly). We investigate the mechanical behavior of frustrated Kresling assemblies, both theoretically and experimentally, under various loading and boundary conditions. Our findings reveal that changing the frustration state leads to precise control of folding sequences, enabling previously inaccessible folding paths. The proposed concept paves the way for applications in mechanical metamaterials and other fields requiring highly programmable and reconfigurable systems – e.g., prosthetic limbs.

Integrated Ising model with global inhibition for decision-making

Humans and other organisms make decisions choosing between different options, with the aim of maximizing the reward and minimizing the cost. The main theoretical framework for modeling the decision-making process has been based on the highly successful drift-diffusion model, which is a simple tool for explaining many aspects of this process. However, recent observations challenge this model. It was found that inhibitory tone increases during situations of difficult discrimination tasks, but the origin of this phenomenon is not understood. Motivated by this observation, we extend a recently developed model for directional decision-making of animals moving in real space. We introduce an integrated Ising-type model that includes global inhibition and use it to describe two-choice decision-making. This model can explain how the brain may utilize inhibition to improve its decision-making accuracy. Compared to experimental results, this model suggests that the regime of the brain’s decision-making activity is in proximity to a critical transition line between the ordered and disordered phases. Within the model, this observation can be explained by noting that this critical region has unique dynamics that give rise to advantageous properties for the decision-making process.

Ultracold cryogenic TEM with liquid helium and high stability

Cryogenic transmission electron microscopy has revolutionized structural biology and materials science. To image below liquid nitrogen temperatures, various liquid helium stages have been constructed but have proven to be complex and unstable, making high-resolution imaging challenging. This problem is even more pronounced in side-entry specimen holders common on modern transmission electron microscopes. Here, we introduce an ultracold liquid helium transmission electron microscope side-entry specimen holder, featuring continuous cryogen flow and vibration decoupling. This instrument is compatible with modern aberration-corrected microscopes and achieves sub-25 K base temperature, ± 2 mK thermal stability over many hours, and atomic resolution—setting the stage for a new era of cryogenic electron microscopy.

PD-1 expression identifies proliferating malignant CLL B cells and is a potential biomarker of response to BTK inhibitor therapy

Chronic lymphocytic leukemia (CLL) remains incurable despite treatment advances, and a major challenge is that biomarkers that predict response and resistance to current therapies are lacking. We report that activated and proliferating malignant CLL B cells in circulation express PD-1, a protein normally expressed in T cells. PD-1 expression is absent in circulating B cells from healthy controls and nonmalignant B cells from patients with CLL. Circulating PD-1 + CLL cells are found in all treatment naïve patients, regardless of immunoglobulin heavy-chain variable region gene mutation status or cytogenetic abnormalities. PD-1 + CLL cells are transcriptionally distinct compared to PD-1 − CLL cells and upregulate genes associated with cell activation, proliferation, and B cell receptor (BCR) and toll-like receptor (TLR) signaling. Indeed, ex vivo stimulation of the BCR and TLR9 readily increased PD-1 expression in CLL cells from treatment-naïve patients within 24 h, an effect that was blocked by Bruton’s tyrosine kinase inhibitors (BTKi). More importantly, patients initiating BTKi therapy experienced profound reductions in circulating PD-1 + CLL cell numbers within 1 mo, which is in line with reduction in Ki-67 + CLL cells. Elevated percentages of circulating PD-1 + CLL cells also preceded a clinical diagnosis of disease progression in patients receiving BTKi. Thus, our findings indicate that PD-1 expression is a potential biomarker to identify proliferating CLL cells in vivo and will be useful to predict response and resistance to BTKi. In addition, eliminating PD-1 + CLL cells with depleting anti-PD-1 monospecific or bispecific antibodies should be explored as a potential therapeutic strategy.

From relaxation to buckling: A continuum elastic framework connecting surface instabilities of highly compressed lipid thin films

Self-assembled thin films respond to external loads via surface instabilities that are critical to their functionality in both biology and technology. Lipid monolayers at the air–liquid interface are one such system. Tunability between out-of-plane buckling (e.g., folding) and in-plane relaxation (e.g., reorganization of lipid domains) in highly compressed lipid monolayers suggests underlying mechanistic generality. Yet, how in-plane relaxation occurs and how it is distinguished from folding remains elusive. Here, we use continuum mechanics, finite element (FE) simulations, and Langmuir trough fluorescence microscopy (FM) data to elucidate the underlying mechanisms of these elastic instability modes. Uniaxial loading of the Langmuir trough is evaluated in FE simulations, where the lipid monolayer is modeled as a thin sheet with a hyperelastic energy function developed to exhibit a relaxation mechanism. Results show that this material relaxation mechanism triggers tunable in-plane shear localization (shear banding). Furthermore, the simulation results of a heterogeneous model, built from fluorescence micrographs of lipid domains distributed in a continuous matrix, are rigorously compared with experimental data by domain organizational analyses. These analyses suggest shear bands are sufficient in inducing domain symmetry breaking that is characteristic of in-plane relaxation and, without such shear bands, domain organization remains in powder structure, characteristic of folding lipid monolayers. Our findings develop a hyperelastic model validated against experimental FM images that can connect the observed lipid monolayer instabilities of folding and in-plane relaxation, establishing a generalized framework with the potential to unify all other monolayer instability modes and characterize other thin film systems.

Long-term history of continental weathering and particle transport to the sea

Here, we explore the long-term history of chemical weathering and particle transport from the continents to the oceans by leveraging the histories of Zr/Al, Rb/Al, and Na/Al in marine sediments over the last 2000 My. We interpret these data in the context of elemental behavior in modern weathering environments and modern marine sediments. We find that from 2000 Mya to ca. 650 Mya, physical erosion was effective, where braided rivers efficiently delivered particles from land to the sea. Overall, chemical weathering was less efficient than now, although many easily weatherable minerals were as weathered as today. We suggest a dramatic change in weathering dynamics after 650 Mya when modern-like deep subduction originated. With this development, mantle dynamics, by promoting periodic vigorous subduction and intense mountain building, began to control the intensity of chemical weathering and particle transport to the oceans. Through spectral analysis of several geochemical records, we find that during times of enhanced subduction and mountain building, continents underwent periods of net erosion and less intense chemical weathering, while during periods of less intense subduction, continents accumulated particles, and chemical weathering was more intense. The evolution and proliferation of land plants changed chemical weathering intensity but had little apparent impact on the cyclic nature of particle transport and storage on the continents. These results could offer a framework to better understand the evolution of elemental cycling from the continents to the oceans over the last 2000 My.

Testis expressed 50 is essential for maintaining sperm acrosome integrity during epididymal transit

In mammals, sperm formation is completed in the seminiferous tubules within the testis, and sperm maturation occurs during the epididymal transit of the spermatozoa. Sperm morphology drastically changes when abnormal spermatozoa migrate from the testis to the epididymis. Detailed molecular mechanisms for sperm survival in the epididymis have not been determined yet. Globozoospermia is a cause of male infertility and is characterized by round-headed spermatozoa without acrosomes, an abnormal sperm nuclear membrane, and sperm midpiece defects. Testis expressed 50 ( Tex50 ) is a testis-enriched gene that is expressed in mice and humans. Using CRISPR-Cas9, we generated Tex50 knockout (KO) mice and found that the KO males were sterile due to epididymal sperm malformations and impaired sperm motility. Surprisingly, electron microscopy, sperm morphology, and globozoospermia-related protein expression and localization in the KO testis were all normal. To understand this phenotype in more detail, we created TEX50-mCherry knockin mice to determine the localization of the TEX50 protein during spermatogenesis. The mCherry signals detected a ring-shaped structure surrounding the sperm acrosome and migrated to the posterior region of the sperm head. After the acrosome reaction, most of the spermatozoa retained mCherry signals. These results indicate that the Tex50 KO globozoospermia phenotype occurs after the migration of spermatozoa from the testis to the epididymis. We found that sperm membrane protein TEX50 is a putative key molecule to survive against globozoospermia-like malformations in the epididymis. It is essential for complete sperm formation and male fertility in mice.

Ecology and sexual conflict drive the macroevolutionary dynamics of female-limited color polymorphisms in damselflies

Sexual conflict over mating has been documented in many species, both in the field and in experimental studies. In pond damselflies (family Coenagrionidae), sexual conflict maintains female-limited color polymorphisms, with one female morph typically being a male mimic. However, it is not known whether sexual conflict can also explain the evolutionary origin of novel female morphs, and if so, what ecological factors play a role in this macroevolutionary transition, by modulating the strength of the conflict. Here, we use phylogenetic comparative methods to show that female color polymorphisms are more likely to evolve in temperate regions and open landscapes, whereas region and habitat shifts are independent of female-color states. We also show that these macroecological patterns are mediated by population densities at breeding sites. Temperate and open habitats are associated with female-polymorphic lineages because they harbor higher densities of adults, promoting more frequent encounters between females and males. Finally, we found that female-limited polymorphisms typically evolve from sexually dimorphic ancestors through the addition of a male-like female morph, consistent with the hypothesis of selection for male mimicry. We conclude that female color polymorphisms evolve in a predictable fashion and are likely driven by ecological conditions that increase the rate of premating interactions and thus the intensity of sexual conflict.

Correction for Pang et al., Structural elucidation of how ARF small GTPases induce membrane tubulation for vesicle fission

Founders predict trait evolution and population performance after evolutionary rescue in the red flour beetle

Evolutionary rescue helps populations survive environmental change, but the phenotypic and demographic factors associated with rescue dynamics and its long-term effects remain unclear. We experimentally evolved 10 wild-collected populations of flour beetles from across India in a suboptimal corn resource for 70 generations (>5 y), collecting >10,000 population census points book-ended by measurements of fitness-related traits for 30 experimental lines. Despite clear ancestral trait differences, all lines showed highly parallel evolutionary rescue within 20 generations. Long-term average population size varied across source populations and was positively correlated with ancestral development rate, which increased convergently across populations and emerged as the single best predictor of population performance during and after evolutionary rescue. Notably, specific demographic events during rescue (such as the rate of population decline and recovery) were uncorrelated both with ancestral trait distributions and post-rescue adaptation. Our results support prior work showing founder traits as key predictors of adaptation, and highlight their role in long-term adaptation and trait evolution following evolutionary rescue.