Abstract: An energy threshold alone does not establish a civilization’s ability to persist. Building on two Galaxies studies of Type I and Type II development, we propose additional qualifications based on stewardship, autonomous habitation, and resilience to loss of the original home world or star. Type I couples planetary energy capability with maintenance of a habitable Earth; Type II adds a self-sustaining Solar System network; Type III combines Galactic energy capability and transport with communities able to continue beyond the Sun. These qualifications complement the conventional power scale. A finite-speed expansion model couples access to stellar luminosity with gradual local construction and conditional continuity. In a stipulated exponential disk, the conventional 10³⁶ W threshold is crossed approximately 0.68, 6.7, or 67 million years after expansion begins; reaching the entire modeled disk takes 2.28, 22.8, or 228 million years. Neither result establishes autonomous habitation or stewardship, and neither is a forecast. Sufficient usable luminosity is a necessary condition for power attainment, while cumulative hazard constrains continuity. Independence from the Sun can occur before the energy threshold. The framework separates physical access, usable power, and durable civilizational viability, identifies their distinct timescales, and provides reproducible scenario calculations.

Abstract: Background/Objectives: Cisplatin induced hearing loss (CIHL) is a major global health sequela of chemotherapy, affecting over half a million cancer patients annually. We previously reported that honokiol, a multifunctional molecule compatible with cisplatin, protects against CIHL and upregulates sirtuin 3. Sirtuin family is composed of seven highly conserved while differentially expressed members which are critical enzymes for oxidative stress regulation in different cellular compartments. Therefore, this study aims to further verify the expression and upregulation of the entire sirtuin family during honokiol-mediated hearing protection against CIHL in a tumor-bearing mouse model. Methods: Adult female mice carrying mouse mammary tumor virus polyomavirus middle T agent oncogene were used. These mice developed palpable tumors automatically at the age of 70.8±10.3 days. CIHL was induced using a three-cycle (14 days/cycle) low-dose (4 mg/kg/day for 4 days per cycle, intraperitoneal injection) cisplatin treatment mimicking chemotherapy regimens. Honokiol (5-20 mg/kg) was administered one hour before cisplatin. Cochlear function was evaluated by auditory brainstem response threshold shifts and synaptic changes. Immunostaining and RT-qPCR were performed to verify the upregulation of sirtuin family members (1, 2, 3, 5, and 7) during these processes. Results: CIHL was observed at high-frequency range (24-32 kHz), which was mitigated by honokiol treatment. The optimal dose of honokiol for oto-protection and animal survival was 10 mg/kg. Fluorescence signals of sirtuins 1, 2, 3, 5, and 7 increased in cochleae from honokiol-treated mice. RT-qPCR confirmed a significant upregulation of sirtuin 3 mRNA with honokiol treatment. Conclusions: Sirtuin family upregulation was involved in honokiol-mediated hearing protection against CIHL. The dose-response curve of honokiol lays the foundation for potential translational applications for human studies.

Abstract: Solar thermal energy for drying applications offers a sustainable pathway to help reduce post-harvest losses and decarbonize low-temperature heat processes. However, the design of solar drying systems has advanced faster than the development of robust control and monitoring strategies. Nevertheless, these advances have generated extensive reviews on dryer configurations, thermal storage, modeling tools, and product-quality outcomes, dedicated syntheses of monitoring and control remain limited. This review synthesizes recent developments in control and monitoring for solar drying systems, covering distribution, integration, and mixed configurations operating in passive and active modes. A structured search of the recent literature in major scientific databases was used to identify studies that report explicit control or monitoring strategies, including rule-based and PID controllers, fuzzy and networked control schemes, automatic monitoring systems based on low-cost microcontrollers and IoT platforms, and smart sensing approaches for estimating moisture content and drying rate. The review analyses the process variables most frequently measured and controlled (air temperature, relative humidity, airflow rate, and product moisture) and how these choices affect drying time, product quality, and energy performance. Most practical solar drying applications still use basic rule-based or PID control and data logging, while advanced control and data-driven methods are largely limited to experimental systems. The sensor limitations and the standardized metrics and measurements remain key challenges. This paper concludes with recommendations and research opportunities for developing robust, scalable, and economically viable control architectures for solar drying.

Abstract: Platinum-based chemotherapy remains a key treatment for epithelial ovarian cancer, but platinum resistance is a major cause of treatment failure and mortality. Traditionally, platinum resistance has been defined by the interval between the last platinum treatment and disease progression, with progression within six months generally classified as platinum-resistant. This six-month platinum-free interval has long provided a useful framework for treatment selection. However, growing preclinical and clinical evidence suggests that this interval should not be treated as a strict biological boundary. Platinum susceptibility can change as tumors evolve, with some tumors retaining residual sensitivity while others develop stable or potentially modifiable resistance mechanisms. These mechanisms include restoration of homologous recombination, altered DNA-damage tolerance, epigenetic regulation, changes in platinum transport and detoxification, adaptive survival signaling, and alterations in cell-death pathways. Some resistance mechanisms are relatively stable, whereas others may remain biologically plastic and potentially amenable to therapeutic modification. This distinction has important implications for platinum rechallenge. Responses to platinum reintroduction in selected patients previously classified as platinum-resistant indicate that the six-month interval does not fully capture the biology of platinum responsiveness. However, renewed clinical activity after rechallenge should not automatically be interpreted as biological resensitization. True resensitization requires evidence that a defined resistance mechanism has been modified and that this alteration increases platinum susceptibility. Preclinical studies have identified multiple strategies to modify platinum-resistance pathways, but clinical translation remains limited. This perspective therefore proposes that platinum resistance should be understood as a clinically defined phenotype encompassing biologically heterogeneous states, some of which may be stable and others potentially reversible. Recognizing this distinction has implications for biomarker development, treatment selection, trial design, and interpretation of platinum rechallenge. Prospective studies incorporating longitudinal tumor profiling and functional assessments of platinum susceptibility may ultimately identify patients in whom platinum activity can be therapeutically restored.

Abstract: This preliminary proposal suggests an educational approach built on two complementary foundations: deep, intuitive understanding of a selected set of fundamental concepts taught by a human lecturer, and explicit AI-assisted self-learning by students to support lifelong independent learning using the best generally available AI tools as they evolve. These two foundations support a third capability - engineering and scientific judgment. An ‘Analog Electronic Circuits’ course is proposed as an initial test case.

Abstract: The concept of musicscape has been used to describe relationships between music, place, culture, and human experience. Building on the perceptual principles of soundscape research and the ISO 12913 series, this study explores the applicability of ISO-derived perceptual attributes within a musicscape context, using Cretan folk dances as a case study. A corpus of representative Cretan folk dance recordings was evaluated through listening tests, in which participants assessed each excerpt using the eight perceptual attributes defined in ISO 12913-2 on continuous 0–100 scales. Statistical analyses, multivariate visualization, and machine-learning techniques were employed to examine perceptual patterns among the selected dance forms. The results revealed systematic variations in listener assessments across the repertoire, with combinations of soundscape-derived attributes providing perceptual representations that distinguished the examined Cretan folk dance forms. Higher-dimensional projections further illustrated relationships among recordings based on shared perceptual characteristics. These findings indicate that soundscape-derived perceptual attributes may provide a useful perspective for examining musicscape experiences and contribute to the exploration of perceptually informed approaches for the study of relationships between sound, culture, and human experience.

Abstract: Curcumin is a plant-derived polyphenol with antioxidant, immunomodulatory, and metabolic regulatory activities, but its integrated effects on edible-tissue quality and hepatopancreatic homeostasis in abalone remain unclear. We evaluated five dietary curcumin levels (0, 0.02%, 0.04%, 0.06%, and 0.08%) in 240 green–Pacific abalone hybrids (Haliotis discus hannai ♀ × H. fulgens ♂) for 8 weeks. The 0.04% treatment increased muscle crude protein, while 0.04–0.06% increased total amino acids; all supplemented diets reduced crude lipid and free fatty acids. Curcumin improved hepatopancreatic histology, reduced Oil Red O-positive lipid deposition, increased superoxide dismutase, glutathione peroxidase, and total antioxidant capacity, and decreased malondialdehyde. Acid phosphatase, alkaline phosphatase, and lysozyme increased in all supplemented groups, whereas polyphenol oxidase peaked at 0.04%. Transcriptomic comparison of the control and 0.04% groups identified 622 differentially expressed genes (336 upregulated and 286 downregulated), with enrichment involving lysosome, phagosome, Toll/Imd, MAPK, and FoxO-associated processes. RT-qPCR confirmed increased SOD2, CAT, and HSP70 expression. Overall, 0.04% dietary curcumin produced the most consistent benefits, improving muscle nutritional quality, redox status, and hepatopancreatic health in hybrid abalone.

Abstract: Background: Short sleep and depression frequently co-occur in older adults, but whether they share a gut microbiota signature or carry largely phenotype-specific features remains unresolved. We therefore characterized fecal microbiota features shared by or specific to short sleep and depression using American Gut Project 16S rRNA data. Methods: Using American Gut Project (AGP) V4 16S rRNA data (PRJEB11419), we assigned older adults to four mutually exclusive groups: healthy controls (HC; 7-8 h sleep, no depression), short-sleep only (SSD), depression only (DP), and short-sleep plus depression (SSD + DP; exploratory). Complete age, sex, and BMI data with at least 1,000 reads yielded 1,056 participants (HC 617; SSD 255; DP 148; SSD + DP 36). We examined diversity, taxonomy, covariate-adjusted genus-level associations, and cross-validated discrimination. Scale-upgraded sensitivity analyses included 1,307 participants, 146 genera, and 20 multiply imputed data sets. Results: Richness (q = 0.001; adjusted q = 0.007), Shannon diversity (q = 0.031; adjusted q = 0.111), and Faith's diversity (q = 0.001; adjusted q = 0.007) differed across groups; adjusted richness and Faith's diversity also differed among depression-only participants (both q = 0.003). PERMANOVA showed no global separation (minimum P = 0.065). Significant genera numbered 3 in SSD, 3 in DP, and 0 in SSD + DP: SSD was associated with UCG-002 (log2FC = -1.01), UCG-003 (-0.76), and Erysipelatoclostridium (+0.69), and DP with UCG-003 (-1.21), [Ruminococcus] gnavus group (+1.06), and Lachnospiraceae UCG-010 (-0.71). Core clinical AUCs were 0.554 (95% CI 0.514-0.596) and 0.623 (0.579-0.668), rising to 0.599 (0.559-0.640) and 0.654 (0.611-0.695) with extended clinical variables; adding microbiota features lowered these to 0.566 (0.524-0.608) and 0.637 (0.593-0.680), providing no gain. Sensitivity AUCs were 0.575-0.610 and 0.643-0.675. Scale-upgraded OLS/limma confirmed 17 genera and 8 interaction genera, with AUCs of 0.585 and 0.645; additional models reached 0.622 and 0.687. A phenotype-matched constipation contrast (78 cases, 695 controls) yielded AUCs of 0.771 and 0.798. Conclusion: Short sleep and depression showed modest, largely non-overlapping microbiota signals, whereas constipation showed a clearer but still non-diagnostic signal. These findings are hypothesis-generating and do not support clinical or causal interpretation.

Abstract: The integration of living vegetation into building envelopes offers demonstrable ther-mal, ecological, and well-being benefits; however, conventional vertical greening sys-tems rely on synthetic, resource-intensive growing media requiring continuous fertiga-tion, limiting their regenerative credentials. This study presents a proof of concept for sustaining plant growth in engineered sand-clay substrates which are low-embodied-energy materials suited to building surface application using carbon nanoassemblies (CNAs) synthesised from citric acid and urea as a growth-sustaining additive. CNAs were characterised by FTIR spectroscopy, dynamic light scattering, zeta potential analysis, and fluorescence spectroscopy, confirming an amphiphilic sur-face chemistry and blue-range photoluminescence at 458 nm consistent with dual nu-tritional and optical plant growth promotion mechanisms. Five sand-to-clay substrate formulations were evaluated in a 25-day greenhouse cultivation trial using Raphanus sativus, with and without a weekly 200 mg/L CNA root drench. Unamended control plants ceased foliar growth upon depletion of endogenous seed reserves, whilst CNA-treated plants sustained continued vegetative growth across all substrate compo-sitions, achieving dry biomass increases of up to 695% relative to controls. These find-ings establish a functional basis for ecologically active soil systems capable of support-ing living building envelopes in both the regenerative retrofitting of existing buildings and the integration of biological components into new building design.

Abstract: Surgical interventions in cirrhotic patients are a relevant problem due to the high rates of perioperative morbidity and mortality. The purpose of this review is to provide up–to-date information on the current principles of extrahepatic abdominal surgery in cirrhotic patients. They are based on stratification of patients by risk groups and a multidisciplinary individual approach to the choice of treatment strategy. The implementation of these provisions includes the use of scores for predicting perioperative risk, diagnosis and possible correction of clinically significant portal hypertension, prophylaxis of infectious complications and postoperative venous thromboembolism, monitoring of coagulopathy and cardiovascular disorders, nutritional support and etiological therapy. When choosing the optimal method of surgical treatment in urgent cases, one should strive to use minimally invasive technologies. If elective operations are considered, a thorough examination of patients is necessary to determine the risk factors for adverse outcome, resolve issues of preoperative preparation, and choice of the scope and timing of the surgical intervention. It can be assumed that the thoughtful implementation of these principles in clinical practice and, in prospect, the use of robotics and artificial intelligence will improve the safety of extrahepatic abdominal surgery in cirrhotic patients.

Abstract: Scientific AI can retrieve, synthesize, and reuse claims far faster than any researcher can inspect them. The problem is that provenance is often preserved more faithfully than evidential strength. Weak, biased, or fabricated findings may therefore move through training corpora, retrieval pipelines, and knowledge graphs without the methodological context that should constrain their interpretation. We argue that machine-readable knowledge should be built around layered evidence records rather than papers or extracted sentences alone. These records should retain source text, study design, population, controls, uncertainty, causal status, independent validation, and correction history. The central challenge is not only whether AI can read more literature, but whether it can retain why one claim deserves more confidence than another.

Abstract: Recent advances in large language model (LLM)-driven agentic systems have demonstrated capabilities for automating biomedical data analysis workflows. However, existing systems are predominantly validated on synthetic benchmarks or retrospective tasks, without demonstrated production of novel, peer-reviewed biological findings. Here we describe Prompt-as-a-Protocol (PaaP), a methodology that converts natural-language research questions into structured, executable analytical protocols, coupled with an agentic Generative Research Automation (GRA) layer that executes these protocols with integrated quality assurance. We validate PaaP+GRA through two prospective case studies in distinct biomedical domains. In single-cell transcriptomics, the pipeline identified KIF3A as the sole genome-wide significant correlate of ciliation status in human striatal parvalbumin interneurons (adjusted p = 1.37 x 10^-14), while autonomously detecting and correcting a sex composition confound (p = 8.1 x 10^-44) that would have produced spurious results. In biosensor analytics, the pipeline achieved calibrated PPG-to-ECG heart rate variability classification matching gold-standard ECG performance (ROC AUC = 0.85) for stress-state discrimination relevant to alcohol use disorder relapse monitoring. Both studies have been submitted for peer review. To our knowledge, PaaP+GRA is the first prompt-to-protocol methodology validated by prospective production of novel biological findings across multiple domains, including autonomous confound detection, rather than benchmark performance alone.

Abstract: Multi-state photogrammetry records different conditions of the same physical object, but interactive use requires compatible geometry, paired appearance data and coordinated controls. We present the development and evaluation of the ODD INN system, linking offline fitting and asset preparation in Blender to geometry and material transitions in Unreal Engine 5. A summer–winter campaign aimed to scan an entire open-air museum; ten large sessions produced more than 2 TB of campaign data. Selected assets were integrated into Odmieniec, a playable environment with sliders, group controls, a freezing projectile, an expanding cold sphere and scene-wide transformations. The implementation uses one blend mask to coordinate geometric displacement, colour, normals and material properties. Evaluation combines integration tests, gameplay demonstrations, quality-assurance and rendering observations with supplementary source inspection and analysis of 199 frames from three recordings. These sequences show intermediate appearance, editable groups and repeated bidirectional changes; project reports document restoration and changes to at least five local and twenty global objects. The contribution is an implemented path from prepared observations to coordinated rendering and scoped interaction. The supplementary 2026 checks did not repeat Unreal execution. Geometric accuracy, restoration reliability and isolated transition cost remain unquantified.

Abstract: A field experiment was conducted in 2020–2022 at the Czesławice Experimental Farm (Lublin Voivodeship, Poland) to investigate the chemical properties and enzymatic activity of loess soil under oat cultivation, as well as crop productivity (grain yield and grain protein content). The first experimental factor was the farming system: (A) an organic system, without chemical plant protection products or NPK mineral fertilization (only the Humac Agro fertilizer, approved for organic farming, was applied); and (B) a conventional system, with chemical plant protection and NPK mineral fertilization at rates recommended for oat. The second factor comprised different forecrops for oat: potato, spring barley, narrow-leafed lupine, oat, and winter wheat. The organic system had a more fa-vorable effect on the soil contents of organic carbon (by 0.08 percentage points, pp), mag-nesium (by 10%), boron (by 13%), and zinc, manganese, and copper (by 5.5%, 18%, and 7%, respectively), and promoted higher soil enzymatic activity, with increases ranging from 9–14% (for alkaline phosphatase, urease, dehydrogenase) to 32–39% (for acid phos-phatase and protease). In contrast, the conventional system favored soil nitrogen, phosphorus, and potassium contents (increases of 0.02 pp, 12%, and 25%, respectively). The total sorption capacity of the soil was significantly higher under the organic system (by approximately 6%), particularly in interaction with potato as the forecrop (40.9 cmol(+) kg⁻¹). The forecrops such as potato and narrow-leafed lupine had a more beneficial effect on soil quality and oat productivity than the cereal forecrops. Oat grain yield under the organic system was, on average, only 8% lower than under the conventional system. When favorable root-crops and legume forecrops were used, the productivity of organically grown oat matched that of oat grown conventionally after cereal forecrops. Organic oat cultivation resulted in a significantly higher grain protein content.

Abstract: National freight frameworks consider volume, economic value, and network connectivity, but public data do not directly identify freight dependence at individual railroad bridges. This gap limits consistent national screening for preservation and resilience planning. This study developed a reproducible national workflow to estimate bridge-level freight exposure and identify regional concentrations of important bridges. The workflow assigned Freight Analysis Framework interzonal rail flows to a connected rail network in the contiguous United States, associated eligible bridges with routed edges, and calculated tonnage, value, and distinct origin–destination (OD) reach. These measures formed a zero-preserving, percentile-based rail-bridge freight infrastructure importance index (RB-FII) that gave equal total weight to economic scale and network reach. Tie-inclusive selection and density-based clustering identified important bridge groups, while parallel-track and component-weight sensitivity analyses tested stability. The model routed all 4,911 retained OD pairs, representing 846.80 million short tons and $370.29 billion, and linked 68,326 of 69,356 processed bridges (98.52%) to the routable network. The nominal top 1,000 cutoff yielded 1,003 bridges after retaining ties; 939 formed 32 regional clusters, and 64 remained regionally isolated. Parallel-track alternatives produced bridge-rank correlations of 0.977–0.979 and identical cluster relationships among common bridges. High-emphasis index component weight scenarios retained correlations of 0.988–0.995 with the baseline. The workflow provides an auditable national screening method for directing detailed engineering, operational, and resilience assessments toward bridges and corridors with high modeled freight dependence. The RB-FII is conditional on modeled routes and does not measure observed train routing, bridge condition, failure probability, or disruption loss.

Abstract: Motor-manual tree felling by chainsaws remains a widespread but hazardous forestry practice. This operation consists of executing a directional notch followed by a felling cut that releases a hinge. The hinge geometry (defined by its height, width, and alignment relative to the directional notch) is a critical determinant of safe felling, controlling the direction and stability of the falling tree. How the hinge's geometry might affect these aspects has not yet been studied. This study evaluates variations in hinge flexibility and bending stiffness using wooden square beams of European beech (Fagus sylvatica) and silver fir (Abies alba) in a rig reproducing the classical felling cuts, varying hinge geometry combinations. Two geometric parameters, back-cut height (S) and hinge width (C) were examined. Mechanical testing was performed using a universal testing machine, and load–deformation curves were smoothed with a Savitzky–Golay filter; the Critical Bending Angle and Yield Point were determined by using the 0.02° offset method and absorbed energy by Simpson integration. Results reveal different mechanical behavior between the two dimensions: hinge width primarily determines yield force, whereas back-cut height governs flexibility, showing a strong negative correlation with the critical bending angle. Significant species-specific differences were observed for both response variables. Hinge toughness, expressed as absorbed energy per unit hinge cross-section, was found to be independent of back-cut height and about 1.8 times higher in beech (0.39 kJ·m⁻²) than in fir (0.22 kJ·m⁻²).

Abstract: Everettian branch multiplicity is often discussed as though it were a count of wavefunction terms or decoherent alternatives. This paper argues that the relevant object is an algebra-relative packing number on physically admissible history classes. Candidate histories, already assumed to belong to a decoherent or approximately decoherent family, are first quotiented by exact physical symmetries and then compared only through distinctions visible in a specified operator system of admissible effects. The resulting effective branch packing number \( N_{\mathrm{eff}}(t;{\mathcal A},\varepsilon) \) is the maximal number of mutually \( \varepsilon \)-distinguishable symmetry classes of histories relative to \( \mathcal A \). The paper proves a sequence of structural results: an orbit-packing reduction theorem; monotonicity under refinement of the admissible operator system; metric packing bounds; polynomial and, under the natural affine-rank condition, sharp asymptotic record-compression theorems for collective linear records of identical bosonic qudits; contraction of channel distinguishability under recovery; and a logical cluster theorem for recovered channels. In particular, \( r_0 \) independent collective record directions give \( \Theta(N^{r_0}) \) record growth rather than the labeled \( d^N \) growth; and separated clusters of recovered logical channels, rather than microscopic histories, determine logical branch multiplicity. Applications include the three-qubit bit-flip code, bosonic qudit occupation sectors, and a formal orbit-record model for dipositronium annihilation histories. The framework relates decoherent histories, Quantum Darwinism, exchange symmetry, and quantum error correction without asserting literal merger of globally orthogonal branches.

Abstract: In recent years, morphology-driven welfare issues in the domestic dog have moved from the periphery to the center of public and professional attention, driven by breed-specific legislation and bans, dedicated sessions at major welfare conferences, and sustained scrutiny on social media. While these concerns are supported by a growing body of evidence linking extreme traits to chronic disease and compromised welfare, most research has asked only whether one breed or trait extreme differs from another. These approaches leave a critical question unanswered: which range of a given morphological trait is actually healthiest? Advice to “breed away from extremes” therefore lacks an evidence-based target. This review surveys common canine morphological phenotypes including body size, skull shape (brachycephaly), chondrodysplasia and chondrodystrophy, thoracic depth, tail and vertebral conformation, skin folds, and coat-color and hairlessness. For each, we summarize the associated disorders, the underlying biological mechanisms where known, and the welfare consequences. Examining these phenotypes in aggregate rather than trait by trait reveals insights that single-trait studies cannot. Shared mechanisms (e.g., accelerated growth, soft tissue/skeleton mismatch, melanocyte loss) drive multiple disorders simultaneously, and trade-offs across body systems become apparent. We argue that meaningful progress — the kind these legislative, professional, and public efforts are ultimately seeking — requires reframing canine welfare research toward optimization, namely, identifying the phenotypic range that minimizes total morbidity. Such targets are prerequisite to evidence-based breeding goals, revised breed standards, and informed public decision-making. This manuscript is signed by over 30 canine biology and welfare experts who support its content.

Abstract: Artificial intelligence is changing how cancer biology is read, searched, modeled, and turned into hypotheses. But scientific AI does not meet biology directly. Much of what it learns has already passed through English, abstracts, pathway labels, database entries, and text-mined relations. New foundation models create a second translation problem. They can learn from molecular structures, single-cell profiles, perturbation data, and clinical trajectories without first converting those relations into human-readable explanations. This could expand biological and biomedical discovery, but it also changes the burden of proof. If a model proposes a target, biomarker, stratification, or perturbation that is reproducible but only partly interpretable, what evidence should be required before researchers or clinicians act on it? We argue that interpretability is not only an engineering problem. It is a translation problem. When the internal language of a model is difficult to read, the external evidence must become stronger: clear provenance, experimental challenge, cross-population validation, reproducibility, and accountable human judgment.

Abstract: In the frame of our ongoing research on multitarget alkaloid-derived anticancer agents, relying on a modular synthetic strategy terminated by well-established sequential Sonogashira and CuAAC protocols, we synthesized a systematic selection of chalcone-vindoline hybrids incorporating 1,4-disubstituted 1,2,3-triazole as a linker. The use of the same synthetic approach led to the construction of a zidovudine-derived vindoline hybrid, which served as a negative control highlighting the essential contribution of the chalcone moiety to the antiproliferative activity. Two analogous aryl-substituted chalcone hybrids 14a,b were also prepared to assess the contribution of the vindoline fragment to the desired effect. The targeted hybrids and the references were evaluated for their antiproliferative activity against a panel of human adherent gynecological cancer cell lines (HeLa, SiHa, MCF-7, MDA-MB-231 and A2780) as well as on non-malignant fibroblasts (NIH/3T3). Vindoline hybrids 10a and 10i comprising 3,4,5- and 1,4,6-trimethoxyphenyl-substituted chalcone fragments, respectively, displayed substantial activity, featuring IC₅₀ values lower than 0.4 µM on all the investigated cancer cell lines. On the other hand, hybrids 10c–e containing monomethoxy-substituted chalcones, also featuring submicromolar IC₅₀ values on malignant cells, showed moderately lower activities against non-malignant fibroblasts (NIH/3T3), indicating a certain degree of cancer selectivity. The related ferrocene-derived hybrid (10i) and vindoline-free chalcones 14a,b were identified as antiproliferative agents with significantly decreased efficiency, while the ferrocene hybrid comprising an alternative enone sequence in the chalcone residue (11) as well as the zidovudine-derived vindoline hybrid 12 were inactive. Modeling results indicate that the vindoline hybrids bind to the inter-dimer vinca crevice of tubulin oligomers and confirm that the two segments exert a mutually stabilizing effect on the binding of the other, providing a framework for future structure optimization.