Search Results (378)

Background: Bispecific antibodies have emerged as a promising class of therapeutics, enabling simultaneous targeting of two distinct antigens. Single-domain antibodies (sdAbs) comprising camelid variable heavy chains (VHHs) provide a compact and adaptable platform for bispecific antibody design due to their small size and ease of linkage. Methods: Here we investigate structure-activity relationship of VHH-based cytokine surrogates by combining cell signaling and functional assays with x-ray crystallography and other biophysical techniques. Results: We describe crystal structures of four unique bispecific VHHs that engage and activate the cytokine receptor pairs IL-18Rα/IL-18Rβ and IL-2Rβ/IL-2Rγ. These bispecific VHH molecules, referred to as surrogate cytokine agonists (SCAs), create unique cytokine signals that can be tuned by linker engineering. Our structural analysis reveals multiple dimeric conformations for these bispecific SCAs, where the two VHH domains can interact to form a compact structure. We demonstrate that the dimeric conformation can be enforced via engineering of a non-native disulfide bond between the VHH subunits, thus enhancing molecular thermostability. Conclusion: Our findings have important implications for the design and engineering of bispecific VHHs or sdAbs, offering a novel strategy for tuning their activity and increasing their stability. Full article

Helicobacter pylori (Hp), a Class I carcinogen infecting over 50% of the global population, is increasingly resistant to conventional antibiotics. This study presents an AI-engineered probiotic strategy targeting urease, a key Hp virulence factor. A humanized single-domain antibody (UreBAb), previously identified and selected in our laboratory, was synthesized commercially and modeled using AlphaFold2, with structural validation conducted via SAVES 6.0. Molecular docking (PyMOL/ClusPro2) and binding energy analysis (InterProSurf) identified critical urease-active residues: K40, P41, K43, E82, F84, T86, K104, I107, K108, and R109. Machine learning-guided optimization using mCSA-AB, I-Mutant, and FoldX prioritized four mutational hotspots (K43, E82, I107, R109), leading to the generation of nine antibody variants. Among them, the I107W mutant exhibited the highest activity, achieving 65.6% urease inhibition—a 24.95% improvement over the wild-type antibody (p < 0.001). Engineered Escherichia coli Nissle 1917 (EcN) expressing the I107W antibody significantly reduced gastric HP colonization by 4.42 log10 CFU in the treatment group and 3.30 log10 CFU in the prevention group (p < 0.001 and p < 0.05, respectively), while also suppressing pro-inflammatory cytokine levels. Histopathological (H&E) analysis confirmed that the I107W antibody group showed significantly enhanced mucosal repair compared to wild-type probiotic-treated mice. Notably, 16S rRNA sequencing revealed that intestinal microbiota diversity and the abundance of core microbial species remained stable across different ethnic backgrounds. By integrating AI-guided antibody engineering with targeted probiotic delivery, this platform provides a transformative and microbiota-friendly strategy to combat antibiotic-resistant Hp infections. Full article

Meeting the International Maritime Organization’s (IMO) 2050 targets for reducing greenhouse gas (GHG) emissions requires cost-effective solutions that minimize wind resistance without compromising safety, particularly for medium-sized multipurpose vessels (MPVs), which have been underrepresented in prior research. This study numerically evaluates 20 bow-mounted NaviScreen configurations using a coupled high-fidelity computational fluid dynamics (CFD) and finite element analysis (FEA) approach. Key design variables—including contact angle (35–50°), lower-edge height (1.2–2.0 m), and horn position (3.2–5.3 m)—were systematically varied. The sloped Type-15 shield reduced aerodynamic resistance by 17.1% in headwinds and 24.5% at a 30° yaw, lowering total hull resistance by up to 8.9%. Nonlinear FEA under combined dead weight, wind loads, and Korean Register (KR) green-water pressure revealed local buckling risks, which were mitigated by adding carling stiffeners and increasing plate thickness from 6 mm to 8 mm. The reinforced design satisfied KR yield limits, ABS buckling factors (>1.0), and NORSOK displacement criteria (L/100), confirming structural robustness. This dual-framework approach demonstrates the viability of NaviScreens as passive aerodynamic devices that enhance fuel efficiency and reduce GHG emissions, aligning with global efforts to address climate change by targeting not only CO2 but also other harmful emissions (e.g., NOx, SOx) regulated under MARPOL. The study delivers a validated CFD-FEA workflow to optimize performance and safety, offering shipbuilders a scalable solution for MPVs and related vessel classes to meet IMO’s GHG reduction goals. Full article

The MA₂Z₄ family represents a class of two-dimensional materials renowned for their outstanding mechanical properties and excellent environmental stability. By means of elemental substitution, we designed two novel phases of ScSi₂N₄, namely β₁ and β₂. Their dynamical, thermal, and mechanical stabilities were thoroughly verified through phonon dispersion analysis, ab initio molecular dynamics (AIMD) simulations, and calculations of mechanical parameters such as Young’s modulus and Poisson’s ratio. Electronic structure analysis using both PBE and HSE06 methods further revealed that both the β₁ and β₂ phases exhibit metallic behavior, highlighting their potential for battery-related applications. Based on these outstanding properties, the climbing image nudged elastic band (CI-NEB) method was employed to investigate the diffusion behavior of Li, Na, and K ions on the material surfaces. Both structures demonstrate extremely low diffusion energy barriers (Li: 0.38 eV, Na: 0.22 eV, K: 0.12 eV), indicating rapid ion migration—especially for K—and excellent rate performance. The lowest barrier for K ions (0.12 eV) suggests the fastest diffusion kinetics, making it particularly suitable for high-power potassium-ion batteries. The significantly lower barrier for Na ions (0.22 eV) compared with Li (0.38 eV) implies that both β₁ and β₂ phases may be more favorable for fast-charging/discharging sodium-ion battery applications. First-principles calculations were applied to determine the open-circuit voltage (OCV) of the battery materials. The β₂ phase exhibits a higher OCV in Li/Na systems, while the β₁ phase shows more prominent voltage for K. The results demonstrate that both phases possess high theoretical capacities and suitable OCVs. Full article

Advances in drug development continue to play a critical role in addressing diseases, including those with unmet medical needs. In 2024, the FDA approved 50 novel drugs, 16 of which were biologics. For context, during the first half of 2024 alone, the agency approved six biologics. By mid-2025, six additional biologics have received the green light, indicating that the pace of approvals of this class of drugs this year may be on par with 2024. This paper analyzes all biologics that received FDA authorization in 2024, examining their mechanisms, clinical trials, and expedited review pathways. Key approvals included the highest number of monoclonal antibodies (mAbs) since 2015 (13 mAbs, 6 indicated for oncology), while no antibody–drug conjugates were authorized—continuing with the trend in 2023. In addition, a new chimeric mAb has been approved since the last chimeric mAb approved in 2022, and a new mAb for Alzheimer’s disease. Nine biologics are first-in-class therapies, while ten received Orphan Drug Designation. The biologics considered herein fall into the categories of mAbs and proteins. Full article

This paper presents the first hybrid supply modulator (HSM) designed for envelope tracking power amplifiers (ET-PAs) in base station applications. The focus is on a rail-to-rail Class-AB linear amplifier (LA) optimized for high-voltage and wide-bandwidth operation. The LA is designed using 130 nm BCD technology, utilizing Laterally Diffused Metal-Oxide Semiconductor (LDMOS) transistors for high-voltage operation and incorporating shielding MOSFETs to protect the low-voltage devices. The circuit utilizes dual power supply domains (5 V and 30 V) to improve power efficiency. The proposed LA achieves a bandwidth of 100 MHz and a slew rate of +1003/−852 V/$\mathsf{\mu }\mathrm{s}$, with a quiescent power consumption of 0.89 W. Transient simulations using a 50 MHz bandwidth 5G NR envelope input demonstrate that the proposed HSM achieves a power efficiency of 83%. Consequently, the proposed HSM supports high-output (100 W) wideband 5G NR transmission with enhanced efficiency. Full article

Background/Objectives: This study aimed to determine whether the movement patterns and mental health of university teachers changed after returning to on-site class activities following the COVID-19 lockdown. Specifically, it compared levels of physical activity (PA), sedentary behavior time (SBT), active breaks (ABs), and symptoms of depression, anxiety, and stress among university teachers during online and on-site teaching periods. We also analyzed the association between movement patterns with psychological and anthropometric variables. Methods: University teachers who engaged in online teaching activities because of the COVID-19 restrictions and returned to on-site classes were included. Each teacher wore an accelerometer and answered the Depression Anxiety Stress Scales. The following parameters were assessed: SBT, light (LPA), moderate (MPA), and vigorous (VPA) (min/day); moderate–vigorous PA (MVPA) (min/week); steps/day and ABs/day. Results: Thirty-seven teachers with complete data from both phases were included. Once the on-site teaching activities resumed, LPA (9 min/day), MPA (6 min/day), total PA (20 min/day), MVPA (49 min/week), and steps/day (1100) significantly increased. While SBT showed no changes, ABs/day bouts increased. Depression and stress symptoms improved upon returning to on-site teaching activities. A positive association was identified between SBT and waist circumference (WC). There were negative associations between steps/day and MVPA with body mass index (BMI), steps/day with WC, and LPA with stress symptoms. Conclusions: Upon returning to on-site teaching activities, PA levels, steps/day, and ABs/day bouts all increased, although SBT remained elevated compared with during the lockdown. The teachers’ psychological symptoms improved. PA was associated with better health markers, while SBT was associated with increased WC. Full article

As part of the work, polymer composites dedicated to rapid prototyping were developed, especially for 3D printing using the material extrusion technique. For this purpose, a polymer matrix was selected, which was an acrylonitrile-butadiene-styrene (ABS) terpolymer and a flame retardant, which was tetrakis (2,6-dimethylphenyl)-m-phenylenebisphosphate, commercially known as PX200. The effect of the presence and amount (5, 10, 15 and 20 wt.%) of the introduced additive on the rheological properties, structural properties, flammability (limiting oxygen index, LOI; UL94) and flame retardant properties (microcone calorimeter, MLC) of ABS-based composites was investigated. In addition, the mechanism of thermal degradation and flame resistance was investigated using thermogravimetric analysis, TGA and Fourier transform infrared spectroscopy, FT-IR of the residue after the MLC test. In the first part of the work, using the author’s technological line, filaments were obtained from unfilled ABS and its composites. Samples for testing were obtained by 3D printing in Fused Deposition Modeling (FDM) technology. In order to determine the quantitative and qualitative spread of fire and the effectiveness of the phosphorus flame retardant PX200 in the produced composites, the Maximum Average Rate of Heat Emission (MARHE); Fire Growth Rate Index (FIGRA); Fire Potential Index (FPI) and Flame Retardancy Index (FRI) were determined. Based on the obtained results, it was found that the aryl biphosphate used in this work exhibits activity in the gas phase, which was confirmed by quantitative assessment using data from a microcone calorimeter and non-residues after combustion and thermolysis at 700 °C. As a result, the flammability class did not change (HB40), and the LOI slightly increased to 20% for the composite with 20% flame retardant content. Moreover, this composite was characterized by the following flammability indices: pHRR = 482.9 kW/m² (−40.3%), MARHE = 234 kW/m² (−40.7%), FIGRA = 3.1 kW/m²·s (−56.3%), FPI = 0.061 m²·s/kW (+64.9%), FRI = 2.068 (+106.8%). Full article

Compelling clinical evidence strongly indicates that anti-angiogenesis therapeutics including Bevacizumab, a humanised anti-VEGF mAb, can alleviate the resistance to immunotherapy. We explored the direct modulation of Bevacizumab on endothelial cell (EC) immune response including surface expression of adhesion and MHC molecules and EC-elicited proliferation of immune cells under inflammatory conditions. Flow cytometry showed that addition of VEGF inhibited TNF-α stimulation of expression of ICAM-1 and VCAM-1 on HUVECs, whereas Bevacizumab enhanced this TNF-α-stimulated expression. The presence of MHC Class I on HUVECs was decreased by VEGF and increased by TNF-α, respectively. Bevacizumab reversed VEGF downregulation and promoted TNF-α upregulation of MHC class I expression, suggesting that anti-VEGF treatment can boost the endothelial immunological reaction, a prerequisite for immune cell trafficking. Functionally, real-time monitoring of the proliferation of human PBMCs co-cultured on HUVEC monolayers over 3 days showed opposing effects on the proliferation of PBMCs between VEGF and TNF-α. Consistently, Bevacizumab antagonised VEGF suppression and sensitized TNF-α activation of PBMC growth over the time course. In line with these findings, Bevacizumab increased the surface expression of CD69 on VEGF-treated T cells collected from PBMCs after 3-day co-cultures with HUVECs. Furthermore, the proliferation of CD3+, CD8+ and CD4+ T cells was promoted via Bevacizumab. Collectively, this study demonstrates that targeting VEGF can enhance the immune response of ECs required for T cell recruitment. Our findings provide insights to a deeper understanding of increased vascular inflammatory response conferred by anti-VEGF treatment in addition to inhibiting angiogenesis, which supports its favourable dual role in the positive immunological synergism with immunotherapy. Full article

Malignant tumors of the digestive system are widespread and pose a serious threat to humans. Immune escape is an important factor promoting the deterioration of malignant tumors in the digestive system. Natural killer cells (NK cells) are key members of the anti-tumor and immune surveillance system, mainly exerting cytotoxic effects by binding to the activating receptor natural killer cell group 2D (NKG2D) on their cell surface with the corresponding ligands (major histocompatibility complex class I chain-related protein A/B, MICA/B) on the surface of tumor cells. Malignant tumors of epithelial origin usually highly express NKG2D ligands such as MICA, which can attract NK cells to kill tumor cells and also serve as an important basis for NK cell-based immunotherapy. Tumor cells highly express hypoxia-inducible factor-1α (HIF-1α), which promotes the expression of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs). These metalloproteinases hydrolyze MICA and other ligands on the surface of tumor cells to generate soluble molecules. These soluble ligands, when binding to NKG2D, cannot activate NK cells and also block the binding of NKG2D to MICA on the surface of tumor cells, enabling tumor cells to evade the killing effect of NK cells. Almost all organs in the digestive system originate from epithelial tissue, so the soluble ligands generated by the HIF-1α/MMPs or HIF-1α/ADAMs signaling pathways play a crucial role in evading NK cell killing. A comprehensive understanding of this immune escape process is helpful for a deeper understanding of the molecular mechanism of NK cell anti-tumor activity. This article reviews the molecular mechanisms of common digestive system malignancies evading NK cell killing, providing new insights into the mechanism of tumor immune escape. Full article

Neighbourhood variation in socioeconomic deprivation is recognised as a small but meaningful determinant of adolescent mental health, yet the mechanisms through which the effects operate remain poorly understood. This study used #BeeWell survey data collected from adolescents in Greater Manchester (England) in 2021–2023 (life satisfaction: N = 27,009; emotional difficulties: N = 26,461). Through Latent Growth Mixture Modelling, we identified four non-linear trajectories of life satisfaction (Consistently High (71.0%), Improving (8.7%), Deteriorating (6.3%), and Consistently Low (13.9%); entropy = 0.66) and three non-linear trajectories of emotional difficulties (Low/Lessening (53.7%), Sub-Clinical (38.3%), and Elevated/Worsening (8.0%); entropy = 0.61). Using a multi-level mediation framework we assessed (1) whether neighbourhood deprivation predicted trajectory class membership and (2) the extent to which effects of deprivation operate through aspects of Community Wellbeing, as measured by the Co-op Community Wellbeing Index (CWI). Greater deprivation increased the odds of following Deteriorating (OR = 1.081, [1.023, 1.12]) and Consistently Low (OR = 1.084, [1.051, 1.119]) life satisfaction trajectories and reduced the odds of following a Sub-Clinical emotional difficulties trajectory (OR = 0.975, [0.954, 0.996]). Mediation analyses revealed that the effects of deprivation on Consistently Low life satisfaction partially operate through Equality (ab = 0.016, [0.002, 0.029]) and Housing, Space, and Environment (ab = −0.026, [−0.046, −0.006]). Further indirect effects were observed for Housing, Space, and Environment, which reduced likelihood of Sub-Clinical emotional difficulties for those living in deprived neighbourhoods (ab = −0.026, [−0.045, −0.008]). The findings highlight the distinct effects of neighbourhood deprivation on affective and evaluative domains of adolescent mental health and the protective effect of housing and related environmental factors in disadvantaged contexts, advancing our understanding of the mechanisms underpinning neighbourhood effects on dual-state adolescent mental health. Full article

Objective: This study aimed to evaluate the characteristics, clinical outcomes, and resource use of patients with unresectable hepatocellular carcinoma (uHCC) treated with first-line (1L) atezolizumab plus bevacizumab (A+B) at five United States (US) institutions: the Mayo Clinic, Houston Methodist, Moffitt Cancer Center, Mays Cancer Center, and University of Arizona. Methods: Treating oncologists extracted data from medical charts of patients with uHCC who were treated with A+B after 1 January 2019. Real-world progression-free survival (rwPFS) and overall survival (OS) were assessed using the Kaplan–Meier method for the overall cohort and for a “trial-like” subgroup with characteristics similar to those in the IMbrave150 trial (Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0–1, Child–Pugh [CP] class A, albumin–bilirubin grade 1–2). Results: Of the 300 patients in the overall cohort (median age of 68 years; 12% ECOG PS ≥ 2; 73% CP A; 26% CP B; median follow-up of 8.7 months), the median rwPFS was 6.8 (95% confidence interval [CI]: 5.8, 8.4) months, and the median OS was 14.4 (95% CI: 12.3, 18.2) months. In the trial-like subgroup (n = 194), the median rwPFS was 8.8 (95% CI: 7.6, 12.1) months and the median OS was 19.5 (95% CI: 14.6, 24.7) months. A significantly lower proportion of patients with CP A compared with CP B (39.7% vs. 73.4%) experienced hospitalization within one year of A+B initiation, whereas hospitalizations due to treatment-related adverse events were similar. Conclusions: This study provides insights into the real-world effectiveness of 1L A+B in a diverse US patient cohort, with results from trial-like patients supporting the reproducible efficacy of A+B in clinical practice. Full article

Objective: Falciparum malaria is a major global health concern, affecting more than half of the world’s population and causing over half a million deaths annually. Red cell invasion is a crucial step in the parasite’s life cycle, where the parasite invade human erythrocytes to sustain infection and ensure survival. Two parasite proteins, Apical Membrane Antigen 1 (AMA-1) and Rhoptry Neck Protein 2 (RON2), are involved in tight junction formation, which is an essential step in parasite invasion of the red blood cell. Targeting the AMA-1 and RON2 interaction with inhibitors halts the formation of the tight junction, thereby preventing parasite invasion, which is detrimental to parasite survival. This study leverages machine learning (ML) to predict potential small molecule inhibitors of the AMA-1–RON2 interaction, providing putative antimalaria compounds for further chemotherapeutic exploration. Method: Data was retrieved from the PubChem database (AID 720542), comprising 364,447 inhibitors and non-inhibitors of the AMA-1–RON2 interaction. The data was processed by computing Morgan fingerprints and divided into training and testing with an 80:20 ratio, and the classes in the training data were balanced using the Synthetic Minority Oversampling Technique. Five ML models developed comprised Random Forest (RF), Gradient Boost Machines (GBMs), CatBoost (CB), AdaBoost (AB) and Support Vector Machine (SVM). The performances of the models were evaluated using accuracy, F1 score, and receiver operating characteristic—area under the curve (ROC-AUC) and validated using held-out data and a y-randomization test. An applicability domain analysis was carried out using the Tanimoto distance with a threshold set at 0.04 to ascertain the sample space where the models predict with confidence. Results: The GBMs model emerged as the best, achieving 89% accuracy and a ROC-AUC of 92%. CB and RF had accuracies of 88% and 87%, and ROC-AUC scores of 93% and 91%, respectively. Conclusions: Experimentally validated inhibitors of the AMA-1–RON2 interaction could serve as starting blocks for the next-generation antimalarial drugs. The models were deployed as a web-based application, known as PLASMOpred. Full article

Energy-efficient integrated circuits require scaled-down supply voltages, posing challenges for analog design, particularly for operational transconductance amplifiers (OTAs) essential in high-accuracy CMOS feedback systems. Below 1 V, gate-driven OTAs are limited in common-mode input range and minimum supply voltage. This work investigates CMOS Bulk-Driven (BD) sub-threshold techniques as an efficient alternative for ultra-low voltage (ULV) and ultra-low power (ULP) designs. Although BD overcomes MOS threshold voltage limitations, historical challenges like lower transconductance, latch-up, and layout complexity hindered its use. Recent advancements in CMOS processes and the need for ULP solutions have revived industrial interest in BD. Through theoretical analysis and computer simulations, we explore BD topologies for ULP OTA input stages, classifying them as tailed/tail-less and class A/AB, evaluating their effectiveness for robust analog design, while offering valuable insights for circuit designers. Full article

Treatment for relapsed/refractory multiple myeloma (RRMM) is complex, with several classes of drugs that can be combined into doublet, triplet, or quadruplet regimens. Real-world studies can help to determine the optimal treatment sequences and dosing through observed usage of drugs outside of clinical trials. Previous clinical trials have demonstrated high rates of durable responses in the treatment of patients with triple-class-exposed RRMM with regimens containing selinexor, a first-in-class, orally available selective exportin 1 inhibitor. This study analyzed real-world treatment patterns and survival outcomes using a nationwide electronic health record-derived, deidentified database of patients with RRMM treated with an eligible selinexor-containing, triplet-based regimen, including combinations with dexamethasone and pomalidomide, bortezomib, carfilzomib, or daratumumab. Patients had a real-world overall survival (rwOS) of 14.7 months (95% CI: 10.6, 20.9) and a derived progression-free survival (dPFS) of 4.7 months (95% CI: 3.4, 6.7). Patients with previous exposure to anti-CD38 monoclonal antibodies (mAbs) in the most recent regimen prior to the selinexor treatment had numerically higher survival outcomes (rwOS, 20.9; dPFS, 8.7 months). These data suggest that, in the real-world setting, the use of selinexor triplet regimens is effective in patients with RRMM, especially those with prior exposure to an anti-CD38 mAb in the immediate prior line of therapy. Full article