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Rescuing the bacterial replisome at a nick requires recombinational repair and helicase reloading
Abstract DNA damage occurs in all cells and must be repaired to maintain genome integrity. Many DNA lesions are targeted for removal by repair systems that excise the damage, thereby generating a temporary single-strand discontinuity in the chromosome. If DNA repair has not been completed prior to a round of genome duplication, the single-strand discontinuity (nick or gap) can be converted to a double-strand break (DSB) by an oncoming replication fork. Because the genomic location of nucleobase damage is stochastic, investigating the fate of replication machinery (replisome) at DNA repair sites with single-strand discontinuities has been limited. Here we address this issue by expressing Cas9 nickases in Bacillus subtilis to create site-specific single-strand discontinuities in a bacterial chromosome. We find that a nick in either leading or lagging strand arrests DNA replication, while the fate of the replicative helicase is distinct and depends upon the strand nicked. Genetic, biochemical, and single cell analyses indicate that replisome/nick encounters generate a single-end DSB which requires recombinational repair to enable PriA-dependent replication restart. Together this work defines the physiologically relevant pathway used by B. subtilis to reinitiate DNA synthesis following replication fork inactivation at a single-strand discontinuity.
Dietary fiber modulates gut microbiota and lipid metabolism ameliorating Alzheimer’s pathology in 5xFAD mice
Coupled RecurDyn-EDEM simulation and experimental analysis of a precision fertilization device
Estimation of the epidemiological characteristics of scabies
A hybrid hash framework for post quantum secure zero knowledge identification
A deep learning model for contact angle prediction in carbonate reservoirs under smart water assisted foam injection (SWAF)
Giant electrostrain coefficient under low driving electric field in sodium potassium niobate piezoelectric ceramics with symmetrical bipolar strain
A autophagy related gene signature to predict the prognosis of pancreatic carcinoma and tumor immune microenvironment evaluation
Massive MIMO joint beamforming and power allocation via LMS with narwhal lemming optimization and fractional ResNeXt-based control
Atomic mechanisms of full-length ASC-mediated inflammasome assembly
Nonlinear 2-DOF PID controller optimized by artificial lemming algorithm for robust engine speed regulation in spark-ignition systems
Abstract Achieving precise and stable engine speed regulation in spark-ignition (SI) systems remains a challenging task because of the inherent nonlinearities, time-varying characteristics, and external disturbances of internal combustion engines (ICEs). Conventional proportional–integral–derivative (PID) controllers often fail to simultaneously ensure fast tracking and robust disturbance rejection under dynamic operating conditions. To address this limitation, a nonlinear two-degree-of-freedom (2-DOF) PID controller has been developed and optimized using the artificial lemming algorithm (ALA) which is a recent bio-inspired metaheuristic that mimics lemming population behaviors to balance exploration and exploitation adaptively through an energy-driven mechanism. The proposed controller was implemented on a detailed mathematical model of the SI engine, encompassing throttle dynamics, manifold pressure variation, combustion torque generation, and crankshaft motion. A multi-term cost function combining normalized overshoot, steady-state error, and stability coefficients was minimized to determine optimal controller gains. Extensive experiments were conducted, including statistical robustness evaluation, transient and steady-state analyses, trajectory tracking, and disturbance-rejection tests. ALA exhibited the lowest mean and standard deviation of the cost function (4.7170 and 0.1429, respectively), confirming its strong convergence stability compared to the starfish optimization algorithm, parrot optimizer, coati optimization algorithm, and dwarf mongoose optimizer. The ALA-optimized controller achieved a rise time of 0.3114 s, a settling time of 2.4313 s, an overshoot of only 0.0027%, and an extremely small steady-state error of 2.62 × 10⁻¹¹%. Furthermore, the controller demonstrated superior trajectory-tracking accuracy and exceptional disturbance-rejection capability, maintaining speed deviations below 0.5% under abrupt load torque perturbations. The results confirm that the ALA-based nonlinear 2-DOF PID controller provides a robust and energy-efficient solution for nonlinear engine speed regulation, outperforming recent metaheuristic-based approaches in both accuracy and reliability. Owing to its adaptive and scalable design, the proposed control framework is well-suited for integration into real-time embedded engine control units, hybrid powertrains, and other nonlinear dynamic systems requiring high-precision regulation under uncertainty.
Numerical investigation of cracking behaviors in rock with interrupted double cross fractures under Brazilian splitting
Abstract The stability of underground engineering in coal mines is influenced by the tensile properties of fractured rock masses. In this study, the finite element method with embedded zero-thickness cohesive elements (FEM-CZM) was employed to conduct numerical simulations of Brazilian splitting tests on specimens containing double intersecting pre-existing fractures, and the influence of fracture parameters on crack propagation characteristics was analyzed. The results indicate that the tensile stress zones are primarily distributed around the pre-existing fractures, while the compressive stress zones are mainly located at the central top and bottom of the specimen. The tips of the pre-existing fractures serve as stress concentration zones, and tensile failure is the primary cause of crack initiation. With the increase in the rock bridge inclination angle and main fracture inclination angle, both the number of cracks and the crack area show an upward trend. As the rock bridge length increases, the number of crack initiations and the crack area initially decrease slightly and then increase significantly. As the angle between main and secondary fractures increases, the number and density of cracks increase. The research findings provide a more scientific theoretical basis and design guidance for engineering stability assessment and disaster prevention.
NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms
Abstract The development of Philadelphia chromosome-negative classical myeloproliferative neoplasms (MPN) involves an inflammatory process that facilitates outgrowth of the malignant clone and correlates with clinical outcome measures. This raises the question to which extent inflammatory circuits in MPN depend on activation of innate immune sensors. Here, we investigate whether NLRP3, which precipitates inflammasome assembly upon detection of cellular stress, drives murine JAK2V617F mutant MPN. Deletion of Nlrp3 within the hematopoietic compartment completely prevents increased IL-1β and IL-18 release in MPN. NLRP3 in JAK2V617F hematopoietic cells, but not in JAK2 wild type radioresistant cells, promotes excessive platelet production via stimulation of the direct thrombopoiesis differentiation pathway, as well as granulocytosis. It also promotes expansion of the hematopoietic stem and progenitor cell compartment despite inducing pyroptosis at the same time. Importantly, NLRP3 inflammasome activation enhances bone marrow fibrosis and splenomegaly. Pharmacological blockade of NLRP3 in fully established disease leads to regression of thrombocytosis, splenomegaly and bone marrow fibrosis. These findings suggest that NLRP3 is critical for MPN development and its inhibition represents a new therapeutic intervention for MPN patients.
Gestational hypothyroxinemia causes an inflammatory environment at maternal-fetal tissues and fetal brain with impaired hippocampal dendritic spine maturation in the offspring
Environmental and socio-economic sustainability assessment of remediation alternatives for a contaminated oil refinery site in Southern China
These ‘programmable’ knots harness physics to make surgical stitches safer
Unveiling structural effects on the DC conductivity of warm dense matter via terahertz spectroscopy and ultrafast electron diffraction
Abstract Understanding how materials under far-from-equilibrium conditions conduct electricity is vital for modeling planetary interiors, fusion energy, and other high-energy-density environments. Yet direct measurements of electrical conductivity in these states are challenging, as experiments must capture changes in both electronic conditions and atomic arrangement. Here we show, using laser-heated aluminum films, how the electrical conductivity of materials driven to the warm dense matter regime is influenced by temperature and structure. By directly measuring the electrical conductivity using terahertz time-domain spectroscopy and observing the atomic arrangement using mega-electron-volt ultrafast electron diffraction studies, we separate the impact of these different contributions on the observed sharp drop in the conductivity after laser heating. This approach is broadly applicable for measuring the electrical conductivity of matter laser heated to high-energy-density conditions. Our results are used to benchmark leading theoretical models and highlight the importance of accurately treating both electron and ion dynamics.