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Genome architecture evolution in an invasive copepod species complex
Abstract Chromosomal fusions are hypothesized to facilitate evolutionary adaptation, but empirical evidence has been scarce. Here, we analyze chromosome-level genome sequences of three sibling species within the copepod Eurytemora affinis species complex, known for its remarkable ability to rapidly colonize new habitats. Genomes of this species complex show expansions of ion transport-related gene families, likely related to adaptation to various environmental salinities. Among three genetically distinct sibling species, we discover notable patterns of chromosomal evolution, with chromosomal fusions observed in two different sibling species. As a result of these chromosomal fusions, functionally linked ion transport-related genes located near the telomeres become joined near the newly formed centromeres, where recombination is low. Notably, for the highly invasive E. carolleeae and to a lesser extent for E. gulfia , the ancient chromosomal fusion sites, especially the centromeres, are significantly enriched with contemporary signatures of selection between saline and freshwater populations. This study uncovers intriguing patterns of genome architecture evolution with potentially important implications for mechanisms of adaptive evolution in response to rapid environmental change.
Specific resistance in wheat genotypes to leaf blotch (Zymoseptoria tritici)
A novel probe of photochemical reaction mechanisms of sulfine from vertical and adiabatic excitations: Nonadiabatic molecular dynamics simulation
By using SA3-CASSCF(14e,10o)/def2-TZVP level of theory, we have performed on-the-fly trajectory surface hoping molecular dynamic simulation to probe photochemical reaction mechanisms of the sulfine CH2SO from both vertical and adiabatic excitations to the bright S2 state. We found that there are two conical intersections (S2/S1-CI and S1/S0-CI) governing S–O dissociation, C–S rotation, and C–S–O cyclization motions. When vertically excited to the S2 state in the Franck–Condon region, the photo-reaction channel of CH2SO is all S–O dissociation that has almost completely taken place on the S2 state within about 50 fs. For adiabatic excitation (2 eV lower in energy than vertical excitation) starting from S2 state minimum, 91% sampling trajectories go back to planar CH2SO (S0-minimum) and the rest of 9% isomerize to cyclized oxathiirane CH2S(O) in excited-state lifetime about 800 fs. The results simulated using SA3-CASSCF(14e,10o)/def2-TZVP are confirmed by simulation with SA5-CASSCF(14e,10o)/def2-TZVP, including two triplet states. The present studies not only help to comprehensively understand photo-reaction mechanisms of sulfines but also are very helpful for analyzing photochemical mechanisms of substituted sulfines where E/Z isomerization can be achieved.
Mechanistic models of asymmetric hand-over-hand translocation and nucleosome navigation by CMG helicase
Abstract Faithful replication of eukaryotic chromatin requires the CMG helicase to translocate directionally along single-stranded DNA (ssDNA) while unwinding double-stranded DNA (dsDNA) and navigating nucleosomes. However, the mechanism by which CMG achieves processive translocation and deals with nucleosomal barriers remains incompletely understood. Here, using coarse-grained molecular dynamics simulations with ATP-driven conformational switching, we show that asymmetric rotational transitions among four distinct ssDNA-binding states enable CMG to achieve directional translocation and DNA unwinding. We further demonstrate that the fork protection complex (Csm3/Tof1) and RPA enhance processivity through distinct mechanisms: Csm3/Tof1 grips the parental duplex to suppress backtracking, while RPA alleviates lagging-strand clogging. Upon nucleosome encounter, Csm3/Tof1 promoted partial unwrapping of the entry DNA, but further progression is energetically restricted near the nucleosomal dyad. The histone chaperone FACT lowers this barrier and simultaneously prevents inappropriate histone transfer to the lagging strand. Our results provide mechanistic insights into how the eukaryotic replisome coordinates helicase activity, nucleosome navigation, histone chaperone function, and histone recycling during eukaryotic DNA replication.
Integrated compact duplexer for Tx/Rx SatCom on the move user terminals
Why good quality water models have a surprisingly wide range of dielectric constants
Simple water models with fixed partial charges, particularly 4-site models such as TIP4P/2005, TIP4P-FB, and OPC, have proven to be highly accurate in reproducing many experimental properties of liquid water. It is intriguing that dielectric constants of these models, together with those of popular 3-site models, such as SPC/E and TIP3P, cover a wide range of values, often very far from the experimental one. Here, we address the issue of the surprising insensitivity of the quality of a water model to its dielectric constant. We build upon our recently developed machine learning-assisted methodology for water model development to construct and analyze a large set of high-quality water models with dielectric constants varying from ∼45 to ∼75. We confirm the weak sensitivity of the water model quality on the dielectric constant in this broad range, with optimal values for classical 4-site fixed charge water models lying between 55 and 70. We also identified a set of correlations between parameters of high quality water models at a given value of the dielectric constant.
Multiplex neurodegeneration proteotoxicity platform reveals DNAJB6 promotes non-toxic FUS condensate gelation and inhibits neurotoxicity
Abstract Neurodegenerative disorders (NDDs) are a family of diseases that remain poorly treated despite their growing global health burden. To gain insight into the mechanisms and modulators of neurodegeneration, we developed a yeast-based multiplex genetic screening platform. Using this platform, 32 NDD-associated proteins are probed against a library of 132 molecular chaperones from both yeast and humans, and an unbiased set of ~900 human proteins. We identify both broadly active and specific modifiers of our various cellular models. To illustrate the translatability of this platform, we extensively characterize a potent hit from our screens, the human chaperone DNAJB6. We show that DNAJB6 modifies the toxicity and solubility of multiple amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD)-linked RNA-binding proteins (RBPs). Biophysical examination of DNAJB6 demonstrated that it co-phase separates with, and alters the behavior of FUS containing condensates by locking them into a loose gel-like state which prevents their fibrilization. Domain mapping and a deep mutational scan of DNAJB6 revealed key residues required for its activity and identified variants with enhanced activity. Finally, we show that overexpression of DNAJB6 prevents motor neuron loss and the associated microglia activation in a mouse model of FUS-ALS.
Using convolutional neural networks with late fusion to predict heart disease
Interactions-driven structural morphology and motion in two-dimensional active Brownian systems
While the structure and dynamics of spherical active Brownian particles are now relatively well understood, the influence of attractive interactions on these particles continues to present intriguing open questions. In this study, we investigate the structural morphology and particle velocity in two-dimensional systems with specific attractive interactions, informed by purely repulsive systems. This exploration is conducted through computer simulations, with variations in the Péclet number and packing fractions. Our systematic exploration reveals a novel non-monotonic evolution of structural and velocity ordering driven by attraction-activity competition, representing a fundamental departure from conventional active matter behavior. In particular, we identify a critical transition from attraction-dominated to activity-dominated mechanisms as activity intensifies, leading to complex structural reorganization and the emergence of distinct dynamical phases. Moreover, our study reveals significant correlations between topological defects, spatial structures, and particle motion, where defects serve as key mediators of the strong interdependence between structural order and velocity alignment. These findings advance fundamental understanding of non-equilibrium physics and provide novel frameworks for controlling collective behavior in active materials, highlighting the substantial impact of attractive forces in active environments beyond traditional motility-induced phase separation.
HIV-1 envelope trimer vaccine induces sex-associated differences in antibody responses: a phase 1 clinical trial
Abstract A protective vaccine will be the most powerful instrument to reduce HIV-1 infections worldwide and help bring about a lasting end to the AIDS epidemic. The single centre, randomised, open-label, uncontrolled, phase 1 ACTHIVE-001 clinical trial (NCT03961438) aims to assess the safety and immunogenicity of the ConM SOSIP.v7 native-like trimer protein vaccine, based on an HIV-1 group M consensus sequence, in HIV-negative adults. Twenty-four individuals were enrolled to receive three dosages of ConM SOSIP.v7 protein vaccine in a liposome formulation containing a high dose of the TLR4-agonist MPLA. The primary outcome is vaccine reactogenicity, whereas the main secondary outcome is binding and neutralising antibody responses. Overall, the vaccine is safe and well-tolerated. Furthermore, the vaccine elicits robust strain-specific binding and neutralising antibody responses in nearly all vaccinees. Post-hoc exploratory analyses demonstrate that female-born participants have 22- and 6-fold higher neutralisation titres after the second and third vaccination, respectively. The vaccine adjuvant induces higher levels of IL-6 secretion from in vitro cultured monocytes from female compared to male participants, providing a possible mechanistic explanation for the sex-based differences. Our study highlights the need to take sex-based differences into consideration when assessing HIV-1 vaccine candidates and adjuvants.
Sybil-resistant and privacy-preserving authentication based on short-term pseudonym for internet of vehicles
Surface chemistry of ferroelectric photocatalysts
Ferroelectrics with a switchable spontaneous polarization are considered highly promising for catalysis beyond the Sabatier principle, i.e., switching their polarization can modulate adsorption energies of reaction intermediates and accelerate catalyzed reactions. The surfaces of ferroelectrics are often described as either electron or hole doped, depending on the polarization direction, thus favoring oxidation or reduction reactions. Here, we show that the polarization of typical ferroelectrics is too weak to yield free electrons doped into the conduction band when adsorbates form on a ferroelectric surface that is not in ultra-high vacuum but in contact with, e.g., an aqueous environment. In such a situation, the charge present to cancel the depolarizing field is accommodated not in the form of free electrons in the conduction band but trapped on the electronic state of the adsorbates. This significantly reduces the oxidation capacity of negative carriers and can explain the rather weak effect of ferroelectric switching on the catalytic activity.
Mapping cell dynamics in human ex vivo hair follicles suggests pulling mechanism of hair growth
PCNP promotes hepatocellular carcinoma progression by upregulating UHRF2 to activate ErbB3/Ras/Raf pathway
Numerical simulations of electric-field-driven assembly of binary colloids into colloidal molecules and crystals
Colloidal molecules (CMs)—clusters of colloidal particles with directional interactions—offer a versatile platform for the programmable assembly of complex soft materials. While both static and dynamic CMs have been synthesized to mimic molecular geometries, assembling them from simple colloidal building blocks via controllable interactions remains a challenge. Here, we employ Brownian dynamics simulations with experimentally realizable interaction models to investigate the electric-field-directed assembly of binary colloidal mixtures. By modulating electrohydrodynamic attraction and dipolar repulsion between particles and leveraging particle size ratios, we demonstrate the formation of two-dimensional and pseudo-two-dimensional CMs with various valences and geometric shapes. This valence-assisted strategy further supports the bottom-up construction of open colloidal lattices, including square and honeycomb arrangements. It also enables the simultaneous stabilization of both square packing and triangular packing at high particle concentrations. Our findings present a reversible and tunable approach to designing colloidal architectures with programmable interactions, offering new opportunities for the development of photonic materials, reconfigurable metamaterials, and functional soft-matter systems.
Single versus combination treatment in tinnitus: an international, multicentre, parallel-arm, superiority, randomised controlled trial
Abstract Tinnitus is defined as the conscious awareness of a tonal or composite noise in the absence of a corresponding external acoustic source. This international multicentre, parallel-arm, superiority, randomised controlled trial investigated whether combination therapies are superior to single interventions in the treatment of chronic subjective tinnitus. Tinnitus patients were recruited from five clinical sites across the EU and randomly assigned using a web-based system, stratified by their hearing and distress level, to single or combination treatment of 12 weeks. Cognitive-behavioural therapy, hearing aids, app-based structured counselling, or app-based sound therapy were administered either alone or as a combination of two treatments resulting in ten treatment arms. App-based treatments were delivered without direct contact or guidance from clinicians. The primary outcome was the difference in the change from baseline to week 12 in the total score of the Tinnitus Handicap Inventory (THI) between single and combination treatments in the intention-to-treat population. All statistical analysis were performed blinded to treatment allocation. 674 patients of both sexes aged between 18 and 80 years were screened for eligibility. 461 participants (190 females) with chronic subjective tinnitus and at least mild tinnitus handicap were enroled, 230 of which were randomly assigned to single and 231 to combination treatment. Least-squares mean changes from baseline to week 12 were −11.7 for single treatment (95% confidence interval [CI], −14.4 to −9.0) and −14.9 for combination treatments (95% CI, −17.7 to −12.1), with a statistically significant group difference ( p = 0.034). Cognitive-behavioural therapy and hearing aids alone had large effect sizes, which could not be further increased by combination treatment. No serious adverse events occurred. In this trial involving patients with chronic tinnitus, all treatment arms showed improvement in THI scores from baseline to week 12. Combination treatments showed a stronger clinical effect than single treatment, however, no clear synergistic effect was observed when combining treatments. Instead, we observed a compensatory effect, where a more effective treatment offsets the clinical effects of a less effective treatment. ClinicalTrials.gov Identifier: NCT04663828.
Reach and implementation of human and AI-assisted diabetic retinopathy screening models in primary healthcare settings in India
Abstract Diabetic retinopathy (DR) is a leading cause of preventable vision loss. While DR screening is critical, evidence on the reach and implementation of different screening models in primary healthcare settings is limited. This study evaluated the reach and implementation of DRS models in northern India using the RE-AIM framework. A pragmatic three-arm observational study was conducted between February 2023 and January 2024 in Block Boothgarh, a rural block in District Mohali, Punjab, comprising 30 villages with an estimated 120,000 residents. Household line listing was performed to identify individuals aged 30 years or older with diabetes. Participants (n = 600) were equally allocated to three screening models: facility-based screening at Health and Wellness Centres (HWC) by non-ophthalmologists, community-based AI-assisted screening at home, and standard care. Reach and implementation were assessed through quantitative data, field observations, and qualitative interviews with healthcare providers. Refusal for screening was higher in facility-based screening (40%, 135/340) and lower in community-based screening (13%, 31/240). Older individuals were more likely to decline participation, with a mean age of 62.0 years for males and 60.3 years for females. Reported barriers included existing medical conditions, mobility limitations, perceived good eye health, travel distance, and transportation difficulties. Concerns regarding long-term medication adherence also reduced uptake. Technical issues, including power outages, hardware or software malfunctions, suboptimal image quality, and lack of cooperation, further declined implementation. Adaptations, including the use of backup power generators, on-site troubleshooting, and provision of transport support, mitigated these barriers and improved overall implementation fidelity. Assessing reach is essential for the success of public health interventions. Using the RE-AIM framework, this study identified key barriers and adaptive strategies in DRS, enhancing both reach and implementation within primary healthcare settings. These findings can inform the integration of DRS models into comparable resource-constrained contexts, thereby improving overall effectiveness. Clinical Trial Registry of India (CTRI) : 2022/10/046283.