Search Results (1,723)

Classical Major Histocompatibility Complex Class I (MHC-I) molecules are traditionally viewed as stable peptide-presenting structures expressed on the surface of all nucleated cells. Their expression by professional antigen-presenting dendritic cells (DCs) enables CD8+ T-cell activation, differentiation, and immune surveillance. However, accumulating evidence indicates that cell-surface MHC-I molecules exist in three major conformational states: (1) β2m-associated, peptide-loaded conformers that originate in the endoplasmic reticulum and pass through the Golgi apparatus after binding proteasome-generated cytosolic peptides (hereafter referred to as closed conformers); (2) β2m-free, peptide-empty conformers that arise following β2m dissociation from closed conformers either at the plasma membrane or after internalization and recycling (hereafter referred to as open conformers); and (3) β2m-associated, peptide-empty conformers that represent an intermediate state between closed and open conformers. Here, we propose a conceptual framework, supported by computational predictors of intrinsically disordered regions, in which transitions between closed and open MHC-I conformers are coupled to intracellular regulatory processes, including post-translational modifications of conserved motifs, intracellular trafficking, and signaling. Although direct experimental evidence linking these processes remains limited, we integrate independent observations into a working model that may guide future investigations into MHC-I-mediated cell–cell communication in both immune and non-immune contexts, in health and disease. For clarity, in this article we define “open conformers” as structurally competent, β2m-free, and peptide-deficient MHC-I molecules. Full article

Construction-stage bridge fires are seldom documented in detail, although they can change the behavior of an incomplete structural system. This paper records a 35 m span of a six-cell RC box girder at the Al-Sadreen intersection in Samawa, Iraq, damaged after the bottom slab and webs had been cast and before the top slab was completed. Burning timber formwork locally removed the temporary soffit support. The open-top section, therefore, shifted from the intended fixed–pin construction-stage response toward a pin–pin-like response, with sagging and vertical web cracks near the intended fixed support. A closed-form check showed that the required negative-restraint moment was about 5.3–5.9 times the cracking moment of the incomplete section. Visual inspection, Schmidt hammer, UPV, cores, and steel tests showed localized damage; 28 MPa was used as a representative residual concrete strength for the affected cast components. CSiBridge was used only for completed rehabilitated-state verification. The strengthened model gave maximum shear D/C ≈ 0.529 and flexural D/C < 1.0. Spreadsheet-guided jacking, top-slab reinforcement upgrading, sensitivity checks, and a 350-ton five-lane load test confirmed satisfactory service behavior and negligible residual response. Full article

Osteochondral defects, involving both articular cartilage and subchondral bone, can lead to joint degeneration and osteoarthritis. Recent advances in 3D-printed biphasic scaffolds offer promising opportunities to recreate physiological microenvironments for tissue regeneration. In tissue engineering, these scaffolds can be mechanically stimulated to promote targeted cartilage and bone formation. While computational models have been widely used to study mechanically induced cellular responses in monophasic scaffolds, time-dependent modelling of biphasic osteochondral systems remains relatively scarce. In this study, a fluid–structure interaction (FSI) framework coupled with a mechanoregulatory algorithm was developed to predict mechanically induced early-stage mesenchymal stem cell (MSC) differentiation in biphasic open-porous osteochondral scaffolds comprising chondral and bone layers designed for direct ink writing (DIW). In a second model, an interfacial barrier layer representing the native osteochondral interface was integrated. Dynamic compressive loading (1 Hz, $2.5\%$ strain) was applied. The simulations predicted region-specific differentiation patterns in both the chondral and subchondral bone regions. In the scaffold without a barrier layer, approximately $68.9\%$ of MSCs in the chondral layer and $93.4\%$ of MSCs in the bone layer underwent chondrogenic and osteogenic differentiation, respectively. Incorporation of the barrier layer caused only minor changes, reducing predicted cartilage and bone differentiation by approximately $1.5\%$ and $3.9\%$, respectively. Overall, this study highlights the capability of computational modelling to predict mechanobiological responses in complex osteochondral systems and support scaffold design and effective mechanical stimulation protocols. Full article

The FELIX trial is an ongoing, single-arm, open-label study without an internal control, in which adults with relapsed/refractory B-cell precursor acute lymphoblastic leukaemia receive Aucatzyl (a CAR-T cell therapy) and are followed for overall survival. Here, we combine the Toulmin form of argument with a structural causal model to assess the causal effect of Aucatzyl in the FELIX trial. Full article

Battery pack fires remain a critical safety concern for lithium-ion battery systems. This study presents a comprehensive application of Fault Tree Analysis (FTA) to identify and structure the sequences of failures that may lead to a battery pack fire. A detailed fault tree is developed for a cell–module–pack architecture equipped with a thermal management system, enabling a clear representation of failure pathways. The analysis highlights four main origins of battery pack fire. Each intermediate scenario is described through dedicated branches of the fault tree to enhance clarity and facilitate its adoption for other battery pack designs and use-cases. As most failure modes involved in battery pack fire do not have reliable probability data available or exhibit strong dependency on usage conditions, a fuzzy logic-based expert approach is employed. Probabilistic data are collected through a questionnaire, allowing the assignment of probabilities to undocumented failure events. A quantified use-case is presented for an electric vehicle, illustrating the practical application of the methodology. The objective of this work is to demonstrate a structured and adaptable methodology for applying FTA to lithium-ion battery pack fire risk analysis. The resulting fault tree, provided as open-access supplementary material, aims to support safety analysis, highlight critical protection failures, and identify current limitations in battery pack safety systems. It can also help identify critical components in order to support the development of rapid and targeted diagnostic strategies for battery packs throughout their lifetime. Full article

In this work, a fire dynamics simulator numerical model of an industrial and commercial energy storage cabinet equipped with 280 Ah lithium iron phosphate cells is established; full-process quantitative analysis of heat dissipation and the total released mass of CO and H₂ is realized; and the spatial–temporal evolution of the cabin temperature field, CO/H₂ concentration field and flame spread is systematically captured. The results show that under fully closed conditions, the local peak temperature exceeds 700 °C; additionally, CO and H₂ continuously accumulate inside the cabin, with their concentrations rising to a magnitude of 1000 ppm within 60 s after thermal runaway initiation. In contrast, the open-top structure forms an unobstructed buoyancy-driven venting channel, which guides high-temperature flue gas, CO and H₂ to efficiently discharge outward. The results indicate that the peak temperature and peak concentrations of CO and H₂ in the opened condition drop by more than 80% compared with the closed case. The designated top vent channel effectively cuts down the total residual mass of toxic and combustible gases inside the cabin and suppresses continuous heat accumulation, remarkably mitigating explosion and poisoning risks triggered by trapped heat and hazardous gas mixtures. Full article

Bio-inspired cellular metamaterials manufactured using additive manufacturing technologies provide a promising route for controlling thermal transport properties through architecture rather than through the intrinsic properties of the constituent material. This study investigates steady-state heat transfer in open-cell lattice structures comprising 20 different lattice metamaterial specimens representing various classes of cellular architecture. These include Kelvin, auxetic, BCCZ, BCC, cube, Z-cuboctahedron, diamond, FCC, FBCCXYZ, FCCZ, FBCC, G7, isostructure, octahedron, octet structure, rhombohedral dodecahedron, truncated cuboctahedron and truncated cube, all of which are made from polymer materials. The investigated architectures were inspired by functional principles observed in natural cellular systems, including cancellous bone, wood, coral skeletons, and other biological porous materials, where efficient transport processes are achieved through optimized material distribution and interconnected cellular networks. A theoretical model combining conduction through the lattice skeleton, radiative heat transfer within pores and potential convective contributions was developed using homogenization theory and representative volume element analysis. The experiment confirmed the main hypothesis of this study as described by the mathematical model. Experimental validation also confirmed that the homogenization model correctly predicts the thermal conductivity of open-cell lattice structures in highly porous materials with a porosity of around 0.95. The results demonstrate the potential of biomimetic cellular design for the development of lightweight thermal-management materials with programmable thermal transport properties. Full article

Background: Despite the circulation of evolutionarily related cold-causing coronaviruses (CCCs) in the pre-COVID era, most individuals lacked pre-existing serum IgG and/or class-switched memory B cell (B_mem) reactivity for the SARS-CoV-2 Spike (S) glycoprotein expressed by the ancestral Wuhan-Hu-1 (WH1) strain. Subsequent priming of the immune system through natural infection or prophylactic COVID-19 mRNA vaccination successfully generated robust B_mem responses against the WH1-S antigen, along with eliciting cross-reactivity for the future Omicron (BA.1) variant responsible for breakthrough infections (BTIs). However, to what extent immunological imprinting of B_mem towards the WH1-S antigen detrimentally constrains the elicitation of variant-specific antibody responses following subsequent booster vaccinations or BTIs—a phenomena referred to as “original antigenic sin”—remains an unresolved and open question. Methods: Using ImmunoSpot^®, we evaluated peripheral blood mononuclear cells (PBMCs) from defined human cohorts for IgG⁺ ASC reactivity against Spike proteins representing CCCs and SARS-CoV-2. Additionally, we developed a novel dual-label inverted FluoroSpot assay to distinguish between strain-specific and cross-reactive IgG⁺ ASCs recognizing epitopes in the receptor binding domain (RBD) of SARS-CoV-2 Omicron variants. Results: Our data demonstrate a lack of appreciable back-boosting of IgG⁺ B_mem recognizing structurally conserved epitopes shared between CCCs and SARS-CoV-2. Moreover, we found evidence for immunological imprinting and the preferential expansion of B_mem recognizing cross-reactive epitopes in the RBD following BTI. Nevertheless, Omicron strain-specific B_mem were detected in PBMC donors collected in 2025. Conclusions: Our novel inverted dual-label FluoroSpot methodology evidenced preferential expansion of cross-reactive B_mem following breakthrough SARS-CoV-2 infection and supports the influence of original antigenic sin shaping the recall response. Moreover, the inverted dual-label assay provides a highly flexible and easily implementable technique for distinguishing between strain-specific and cross-reactive B cell responses and has broad applications in translational vaccine research against pathogens that undergo antigenic drift. Full article

(1) Background: Large language models (LLMs) are increasingly used to generate morally distinct non-player characters in interactive fiction and tabletop role-playing games. However, prior work shows that reinforcement learning from human feedback (RLHF) safety training suppresses morally extreme expression. Hence, whether models can reliably generate and evaluate speech with a fixed moral–ethical alignment, within an assigned fictional persona, remains an open question. (2) Methods: To explore this issue, eight generator LLMs each produced three-turn role-play conversations for 37 Dungeons & Dragons 5th Edition deities spanning all nine cells of the 3 × 3 moral–ethical alignment grid (888 conversations by design, 885 obtained after one generator’s midexperiment deprecation). Next, eight evaluator LLMs classified each conversation on both alignment axes using structured output evaluation (6951 evaluation records), assessed across 17 analysis metrics. (3) Results: The obtained results can be summarised as follows. Moral-axis accuracy (Good/Neutral/Evil) exceeded ethical-axis accuracy (Lawful/Neutral/Chaotic) by approximately 10 percentage points on average across all 64 generator–evaluator pairs, with the pair-level gap ranging up to 32 points and reversing sign for one generator (nemotron-120b). Moreover, the alignment-cell hardness ranged 27.6-fold, from Lawful Good (0.910) to Neutral Neutral (0.033). Furthermore, a strong good-ward moral drift, consistent with RLHF suppression effects reported in prior work, was observed for nemotron-120b (0.931 of Evil-target outputs classified as Good) and was near-absent for grok-4.1-fast (0.024). Finally, deity wiki prominence did not predict per-deity accuracy after controlling for alignment cell (partial ρ < 0.20, p > 0.20). (4) Conclusions: In summary, good-ward drift, consistent with RLHF suppression of morally extreme expression, turned out to be graded and model-specific. Moreover, iconic characters override it (Cyric, Chaotic Evil: 0.947, nearly matching the top Lawful Good score). Finally, alignment-cell identity is the dominant accuracy predictor, not the deity familiarity, within the role-played persona setting studied here. Full article

Hypersonic air-breathing propulsion via the Oblique Detonation Wave Engine (ODWE) offers superior thermodynamic efficiency compared to conventional scramjets by utilizing a stationary oblique detonation wave (ODW). While fundamental research has predominantly focused on two-dimensional planar wedges, realistic applications feature axisymmetric conical configurations. Over a cone, radial Taylor–Maccoll (TM) compression decelerates the flow and, in the mixed flow regime, establishes a localized subsonic pocket near the cone surface. However, the unsteady structures, triple-point kinetics, and cellular evolution under the competing influences of stabilizing TM compression and destabilizing Prandtl–Meyer (PM) expansions induced by a finite-length cone remain poorly understood. To address this gap, high-resolution numerical simulations of axisymmetric conical ODWs on a finite cone (semi-cone angle θ = 49°) were conducted at an inflow Mach number of Ma₀ = 7.5 using OpenFOAM. The methodology solves the reactive Euler equations coupled with a single-step Arrhenius model and three levels of adaptive mesh refinement to resolve fine-scale wave structures. Numerical results reveal that the localized subsonic pocket completely obliterates the smooth ZND-like initiation zone typical of purely supersonic configurations. Within this subsonic channel, acoustic disturbances propagate upstream against the bulk flow at a relative velocity of c − u, bypassing the supersonic wave-blocking effect to continuously impinge upon the detonation front. This acoustic feedback loop disrupts shock–reaction coupling, accelerating wave front bifurcation into single triple-point, dual triple-point, and PM-affected segments. Shock polar analysis validates that upstream-facing triple points exhibit greater shock strength, driving slow upstream migration and causing adjacent triple points to collide and reform into distinct, chaotic cell morphologies. Trajectory tracking confirms that the mixed flow cells are substantially larger and more chaotic than supersonic cases, directly reflecting amplified perturbations from the subsonic pockets. These insights provide crucial design criteria for optimizing cone angles to suppress irregular modes and stabilize conical ODWs. Full article

Citrus peel is examined here as a naturally evolved protective surface, with the goal of developing a transferable quantitative framework for extracting engineering-relevant descriptors from biological protective surfaces and using them as design templates for biomimetic counterparts. A single-specimen-per-species design is adopted to map intra-fruit geometric variation across regions and magnifications; absolute descriptor values are therefore reported as ordinal indicators of inter-species ranking rather than as population means. Five citrus species (lemon, orange, mandarin, grapefruit, and bitter orange) were characterised by mechanical testing (cutting, puncture, and compression; five replicates per fruit), gravimetric peel density and thickness, and scanning electron microscopy (SEM) at 100×–10,000×. The 135-image SEM dataset was processed with an automatic-calibration pipeline performing per-image scale-bar detection, multilevel-Otsu segmentation of albedo air space, cell-bounded surface segment (CBSS) and oil-gland segmentation on flavedo, and grey-level co-occurrence matrix (GLCM) texture analysis with a directional anisotropy index $A_F$. Calibration was consistent across all images (FoV × magnification $=\mathrm{403,273}\pm 410$ $\mathsf{\mu }$m$·\times$, $\pm 0.10\%$). Principal component analysis separated flavedo and albedo at every magnification (PC1 + PC2 = 84–92%). Within this dataset, grapefruit showed the densest CBSS cover (1072 ${\mathrm{mm}}^{-2}$) together with the highest oil-gland density (2.77 ${\mathrm{mm}}^{-2}$); bitter orange showed the largest CBSS area (23.7 $\mathsf{\mu }{\mathrm{m}}^2$) and the thickest peel (13.1 mm); mandarin showed the most directionally oriented flavedo film ($A_F=0.0885$); and lemon showed the most open albedo (${\phi }_{2D}=36.2\%$). Oil-gland equivalent diameter was essentially invariant (∼45 $\mathsf{\mu }$m) across the five fruits, while gland density varied 4.4-fold. The structural metrics define a layered descriptor space—a dense isotropic surface relief versus a thick cellular bulk—that supplies two distinct bioinspired-design priors: dense surface films as a structural prior for selective-permeability membranes and layered cellular cores as a prior for impact-absorbing panels. A modified-atmosphere packaging (MAP)-compatible biomimetic film is identified as one downstream design hypothesis requiring direct gas-permeability verification on synthetic membranes. Full article

The voltage-dependent anion channel (VDAC) is the primary conduit for ion and metabolite transport across the mitochondrial outer membrane. Positioned at the interface between the cytosol and the mitochondrial compartment, VDAC is uniquely accessible to proteins on both sides of the membrane, making it an interaction hub whose biophysical properties and signaling functions are shaped by protein complexation in addition to its intrinsic pore specialization. Mammals express three isoforms—VDAC1, VDAC2, and VDAC3—sharing a conserved β-barrel scaffold with about 70% identity. However, minor differences in the sequence lead to drastic changes in VDAC isoform affinity with other proteins. Here, we review the molecular mechanisms and physiological consequences of VDAC complexation with a set of well-characterized partners: hexokinase, dimeric tubulin, α-synuclein, mitochondria-associated membrane proteins, B-cell lymphoma 2 (BCL-2) family proteins, and the translocase of the outer membrane (TOM) protein import complex. For each complex, we evaluate the available structural, biophysical, and genetic evidence for isoform specificity, highlight where mechanistic understanding is most advanced, and identify open questions. A consistent principle emerges across all complexes: functionally nonredundant isoform contributions are primarily governed by differential partner affinity and complexation, rather than by differences in pore architecture alone. This framework has direct implications for mitochondria-associated pathologies, including cancer, cardiovascular disease, and neurodegeneration, as well as for the rational design of VDAC-targeting therapeutics. Full article

The regeneration of the dentin-pulp complex remains a significant challenge in regenerative endodontics. While conventional therapeutic approaches are effective in eliminating infection and preserving dental structure, they fail to restore the biological functionality of the pulp tissue. In recent years, three-dimensional (3D) printing and biopolymer-based bioprinting have opened unprecedented opportunities in dental tissue engineering, enabling the fabrication of biomimetic scaffolds with precisely controlled structural and bioactive properties. This review synthesizes current advances in bioprinting technologies, the diversity of biomaterials and bioinks employed, and the various stem cell sources utilized in pulp regeneration. It further examines how the three-dimensional microenvironment modulates cell viability, odontogenic differentiation, and the promotion of angiogenesis and neurogenesis, emphasizing the role of scaffold composition, mechanical properties, and internal architecture in influencing regenerative outcomes. Additionally, persistent challenges are discussed, including the optimization of bioink formulations, the achievement of functional vascular integration, and long-term validation of regenerated tissues, underscoring the need for multidisciplinary strategies to facilitate clinical translation. By integrating recent evidence, this review establishes a conceptual framework for the development of personalized and predictable approaches to dentin-pulp complex reconstruction. Full article

Everolimus is approved for the treatment of advanced renal cell carcinoma after VEGF-targeted therapy, metastatic HR-positive/HER2-negative breast cancer in combination with exemestane, and other oncologic indications. However, an intravenous option has not been developed, largely due to its pronounced hydrophobicity and limited oral bioavailability of approximately 15–20%. In this study, we report the development of Sapu003, a novel intravenous Everolimus formulation enabled through the Deciparticle™ platform. A diverse library of mPEG-based block copolymers was evaluated for their ability to encapsulate Everolimus and self-assemble into stable nanoparticle structures. mPEG-Chol was ultimately selected based on its favorable biocompatibility characteristics. In addition to Everolimus, mPEG-Chol and related analogs demonstrated broad formulation compatibility with multiple hydrophobic therapeutics, including Sirolimus, Tacrolimus, Cyclosporine, as well as representative peptides and polyketides. Clinical manufacturing was conducted in a cGMP environment over a 7-day production cycle. Production was carried out under amber light using light-protective vials to reduce drug degradation. The bulk material was sterile-filtered, and subsequent fill/finish/lyophilization operations were performed under temperature-controlled conditions with high precision in fill accuracy (≥98%). After reconstitution, the final product yielding uniform Deciparticles™ that met predefined sterility and particle size criteria. Stability studies demonstrated that the formulation remained stable for at least one month at 5 °C and retained acceptable in-use stability for at least 24 h at room temperature. The process was successfully scaled beyond 10 g, supporting an ongoing Phase 1b open-label dose escalation clinical study of Sapu003 in combination with exemestane in patients with advanced mTOR-sensitive solid tumors (NCT07369505). In vivo evaluation demonstrated strong antitumor efficacy following intravenous administration (QW × 3), with tumor growth inhibition reaching 97–98% in the U-87MG glioblastoma xenograft model. No evidence of phlebitis was observed with repeated tail vein dosing. In this model, Sapu003 dosed weekly showed superior tumor suppression compared with oral Everolimus. Collectively, screening of a mPEG-block copolymer library identified mPEG-Chol as a lead excipient capable of consistently forming stable Deciparticles™ with sub-20 nm mean particle size. The resulting intravenous Everolimus formulation demonstrated scalable manufacturing, favorable stability, and potent antitumor activity in preclinical models, supporting further clinical evaluation of Sapu003 in advanced solid tumors. Full article

Field-Programmable Gate Array (FPGA) technology allows for the creation of unique hardware implementations based on mass-produced chips. The process of project prototyping for such systems using Hardware Description Languages (HDLs) remains complex, even with modern tools. The comparison of HDL coding styles, for example, a behavioral case statement against a structural binary-tree decomposition, shows that the choice is capable of affecting post-implementation timing and area. The performed study, using the open-source yosys/nextpnr toolchain, shows that the validity of such a comparison is decided by the fabric domain. Logic that falls through to generic Look-Up Table (LUT) mapping is governed by the mapper’s heuristic fixed point rather than by source intent: on the crossbar, the behavioral and structural netlists become identical in cell composition; on the priority encoder, the verdict reverses; and on the barrel shifter, the LUT area collapses, so the comparison does not isolate the coding-style variable. It was measured that the keep_hierarchy attribute restores a meaningful comparison at ~17% LUT cost (N = 8) and provides a structural invariant to the ABC mapper variant, but the behavioral result is mapper-sensitive and the N = 4 verdict reverses under the legacy -noabc9 mapper (Cohen’s d from +2.4 to −1.6). By contrast, logic that involves a dedicated primitive before LUT mapping—an adder bound to the carry chain or a multiplier bound to a DSP block—yields source-meaningful verdicts that do not reverse with a mapper. Replication on a second fabric (Lattice iCE40) confirms that this behavior is fabric- rather than vendor-specific. The main contribution of this work is the proposed first fabric-domain characterization of synthesis canonicalization as a methodological hazard for cross-HDL FPGA studies on open-source toolchains, which identifies the two-phase synthesis mechanism that delimits it and supplies a decision rule (inspect post-synthesis composition) to identify whether a given comparison is susceptible. Full article