Biology and Life Sciences

Abstract: The Cancer Genome Atlas (TCGA) represents a comprehensive and widely utilized resource in cancer research, containing diverse genomic and molecular data from more than 30 human cancer types. Among these datasets, TCGA RNA sequencing (RNA-seq) data are particularly valuable and have become a routine and extensively employed resource for investigating the molecular mechanisms underlying cancer. Numerous studies are published annually based on TCGA RNA-seq data, contributing to the identification of novel diagnostic and prognostic biomarkers and providing insights into the cellular and molecular characteristics of human cancers. However, an important methodological challenge that is often overlooked is the presence of technical variability in TCGA data. TCGA samples are collected from multiple institutions and processed at different times, sequencing centers, and laboratory batches, which can introduce systematic technical variation, commonly referred to as batch effect. These effects may introduce unwanted differences that may affect biological analyses and consequently compromise the validity and reproducibility of downstream analyses. Several approaches have been developed to assess, visualize, and correct batch effect in TCGA RNA-seq data. The appropriate application of these methods can reduce unwanted technical variation while preserving biologically relevant signals, thereby improving the accuracy, robustness, and reliability of subsequent analyses. In this review, we provide an overview of batch effect associated methods in TCGA RNA-seq data, with particular emphasis on their assessment and visualization, as well as the methodological approaches available for their correction.

Abstract: The rapid evolution and global dissemination of Extended-Spectrum Beta-Lactamases (ESBLs) represent a critical threat to modern medicine. In settings like Iraq, the public health burden is compounded by fragmented healthcare systems and unregulated antibiotic usage. This scoping review and meta-analysis provides a comprehensive national baseline assessment of the prevalence, chronological trajectories, and molecular distribution profiles of clinical human ESBL-producing pathogens across Iraq. Following the PRISMA-ScR guidelines, exhaustive electronic searches were executed across major databases and local repositories. From 230 initially identified records, 64 fully quantified human clinical investigations comprising a verified national baseline of 4,625 unique bacterial isolates were structurally evaluated, while environmental, veterinary, and low-quality studies based on the Joanna Briggs Institute (JBI) framework were strictly excluded. Statistical pooling was achieved via a random-effects subgroup meta-analysis using Restricted Maximum-Likelihood (REML) weights. The nationwide pooled clinical ESBL prevalence across Iraq was established at 48.16% (95% CI: 46.72%–49.60%) under the random-effects framework, with a baseline crude proportion of 48.09% (2,224/4,625). Chronological stratification revealed significant fluctuations in selective resistance pressure, tracking at 55.29% during 2010–2014, rising to a critical peak at 57.59% during 2015–2019, before transitioning into a modern surveillance stabilization contraction of 41.33% during 2020–2024, driven by the integration of recent large-scale multi-center datasets. Escherichia coli (55.65%) and Klebsiella pneumoniae (52.02%) emerged as the dominant enterobacterial vectors. At the molecular scale, genotypic evaluation verified the absolute dominance of the bla_CTX-M family (81.93%; 1,732/2,114) over historical bla_TEM (38.22%) and bla_SHV (34.16%) variants. Crucially, complex multi-drug resistance co-detection markers were documented, with emerging Class D bla_OXA-like variants (45.66%) and mobile bla_AmpC/Class 1 integrons (35.77%) frequently integrated alongside baseline ESBL genotypes. In conclusion, Iraq harbors a critically high and fluctuating endemic ESBL burden. The absolute dominance of mobile enterobacterial genotypes combined with recent carbapenemase and AmpC co-carriage highlights an urgent need for enforced national antimicrobial stewardship, centralized molecular surveillance networks (Iraqi-AMRNet), and strict institutional infection control interventions.

Abstract: The use of new psychoactive substances (NPS), whether pure or in mixtures, has grown steadily, increasing the need for accurate confirmatory analysis in biological matrices given their chemical diversity, structural variability, and potential postmortem redistribution and degradation. Forensic interventions require comprehensive, broad-coverage screening strategies. Two complementary platforms, ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-ESI(+/-)-Orbitrap-HRMS) and gas chromatography-mass spectrometry (GC-MS), were used to screen classical psychoactive substances (CPS), NPS, and their metabolites in 25 postmortem urine samples with suspected consumption of NPS, using Platform-specific sample preparation and identification workflows. Forty-four drugs/metabolites were identified. Ketamine was the most prevalent drug (92% LC-MS, 84% GC-MS), along with its phase I metabolites norketamine, hydroxyketamine, and hydroxynorketamine. Cocaine (68% LC-MS, 12% GC-MS) and its main metabolite, benzoylecgonine (88% LC-MS, 52% GC-MS), were also frequent on both platforms, while amphetamine-type drugs, benzodiazepines, and opioids showed marked technique-dependent detection (e.g., 3,4-methylenedioxyamphetamine: 32% LC-MS, 4% GC-MS). UHPLC-ESI-Orbitrap-HRMS provided broader polarity coverage of parent drugs and metabolites; GC-MS reliably detected parent drugs and derivatizable xenobiotics. Combined use of both platforms provided complementary, high-confidence coverage for forensic toxicology urine screening; quantitative validation and larger cohorts are needed for diagnostic, impairment, and epidemiological extrapolation.

Abstract: Background: One potential risk factor for vaso-occlusive issues in sickle cell anemia (SCA) is the C677T polymorphism of the methylene tetrahydrofolate reductase gene. This study examined the relationship between hemoglobin levels, platelet counts, and platelet indices and the methylenetetrahydrofolate reductase (MTHFR C677T) gene variant in Sudanese patients with sickle cell disease (SCD). Methods: This case-control study involved 48 patients with HbSS and 48 healthy controls. Complete blood count (CBC) was measured using an automated blood counter analyzer, and allele-specific PCR was performed for the amplification of the MTHFR gene. SPSS version 20 was used to analyze the data. Results: Participants ranged in age from1-15 years and were evenly split by gender. Hemoglobin levels, MPV, PCT, PDW, and P-LCR were significantly different between patients with Sickle Cell Disease (SCD) and the control group (p < 0.05). However, there was no significant change in platelet count (p = 0.919). In the SCA group, 68.7% of the MTHFR C677T genotypes were wild-type (CC), 18.8% were homozygous mutants (TT), and 12.5% were heterozygous (CT). 14.6% were CT, 6.2% were TT, and 79.2% were CC among the controls. Patients with SCA had an odds ratio of 0.286 for MTHFR mutation, which was not statistically significant (p = 0.11). Nonetheless, SCA demonstrated a significant correlation through allele frequency analysis (p = 0.000; OR = 0.470; 95% CI: 0.223–0.990). Conclusion: SCD is associated with increased platelet indices and decreased hemoglobin levels. Although the MTHFR C677T polymorphism is more common in SCD patients, it did not show a statistically significant correlation with the disease.

Abstract: Background: Sialolithiasis is a multifactorial biomineralization disorder in which local salivary, biological, and potentially environmental factors may influence stone formation and maturation. The relationship between drinking-water mineralization and the chemical composition of salivary stones remains poorly understood. This study aimed to characterize the composition of sialoliths in an Armenian population and to explore whether long-term regional drinking-water hardness is associated with variation in their mineralization profile. Methods: Fifty submandibular sialoliths obtained from 50 patients were analyzed using atomic absorption spectroscopy, optical emission spectroscopy, flame-emission analysis, and photocolorimetric methods. Elemental concentrations were reported as oxide-equivalent weight percentages, and the organic fraction was quantified separately. The molar Ca/P ratio was calculated from CaO- and P₂O₅-equivalent concentrations. Regional drinking-water hardness data for 2018–2026 were obtained from official Armenian water-supply and regulatory sources and expressed in mmol/L. Associations with patient age, sex, geographic region, and long-term regional water hardness were evaluated using non-parametric statistical methods, with correction for multiple comparisons. Results: Calcium was the predominant individual inorganic constituent (CaO-equivalent: 31.38 ± 2.35 wt%), accompanied by P₂O₅ (15.83 ± 2.78 wt%) and a substantial organic fraction (32.09 ± 4.26 wt%). The mean molar Ca/P ratio was 2.62 ± 0.71. CaO and P₂O₅ concentrations were not significantly correlated, indicating considerable heterogeneity in calcium–phosphorus stoichiometry among stones. No significant associations were observed between major compositional parameters and patient age or sex. In contrast, CaO-equivalent content differed significantly among geographic regions (Kruskal–Wallis H = 19.88, p = 0.0058; Holm-adjusted p = 0.0409). Long-term drinking-water hardness ranged from approximately 1.04 to 9.52 mmol/L across the eight regions. At the patient-record level, greater regional water hardness was positively associated with CaO content (Spearman ρ = 0.374, p = 0.0075) and the molar Ca/P ratio (ρ = 0.364, p = 0.0093); however, these associations were attenuated after correction for multiple testing and were not statistically significant when the eight regions were analyzed as independent ecological units. Conclusions: Armenian submandibular sialoliths are chemically heterogeneous composite structures characterized by a calcium- and phosphorus-rich inorganic component and a substantial organic fraction. The significant geographic variability in calcium content and the exploratory positive relationship with regional drinking-water hardness suggest that environmental mineral exposure may contribute to variation in the biomineralization phenotype of sialoliths. However, the ecological nature of the exposure assessment and the absence of significant region-level associations preclude causal inference. Larger prospective studies integrating individual water exposure, salivary biochemistry, and phase-sensitive mineralogical analyses are warranted.

Abstract: Long-term, single-club datasets linking fitness and match performance are rare in women's handball. This retrospective study profiled fitness and game-quality indicators across 14 seasons (2010–2022, 2026; N = 45; 8–17 players/season). Anthropometric and specific-fitness values (height 173.90 ± 5.53 cm, body mass 68.28 ± 8.08 kg, jump-throw velocity 79.94 ± 6.83 km/h, countermovement jump 43.46 ± 4.84 cm, VO₂max 48.01 ± 3.61 mL/kg/min) were sub-elite. Shot efficiency (55.74 ± 6.00%) approached elite values (58.90 ± 7.60%). Backs were older, more experienced, and higher-scoring than Wings and Pivots. Universal players matched Backs' output despite being younger and less experienced. Experience correlated with goals per match (r = 0.51, p = 0.001), positive actions (r = 0.44, p = 0.005), and action balance (r = 0.47, p = 0.003). Throwing velocity and sprint/agility speed showed similar associations. Endurance, strength, and coordination/dribble deficit showed none. Fitness indicators improved across 2010–2022, but a single season after near-complete roster turnover departed markedly from this trend. Trends should not be extrapolated to a changed roster without re-testing. A small set of trainable, sport-specific qualities, not general fitness, best predicts match performance. Findings provide normative benchmarks and training priorities for coaches.

Abstract: Nucleosomes integrate diverse histone variants to organize chromatin and coordinate genome maintenance. In plants, the structural interplay between replication-associated histones and DNA damage -responsive histone variants remain poorly understood. Here, we determine cryogenic electron microscopy structures of an Arabidopsis thaliana nucleosome containing the replication-associated histones H2B.6 and H3.1 together with the DNA damage-responsive variant H2AXa.The mononucleosome structure, resolved at 2.73 Å preserves the canonical nucleosome architecture. Unexpectedly, the reconstituted mononucleosomes formed defined higher-order assemblies in the absence of linker DNA or chemical crosslinking. Two distinct nucleosome-nucleosome arrangements, parallel and right offset, were identified. The right offset closely resembles the human counterpart, whereas the parallel arrangement exhibits slight displacement of H2B structural elements at the inter-nucleosomal interface. Together these structures reveal how a distinct histone composition preserves canonical nucleosome architecture while supporting multiple defined modes of nucleosome packing, providing structural insights into conserved and divergent features of H2AX containing chromatin organization across plants and animals.

Abstract: DNA methylation (DNAm) signatures may capture molecular variation associated with cognitive phenotypes, but saliva-based scores for subjective memory are poorly characterized. We developed MMS-32, a frozen 32-CpG salivary DNAm score derived from an independent EPIC-array comparison of individuals reporting Very bad memory (n = 1,117) versus Very good memory (n = 2,400). Candidate loci were screened using Mann-Whitney U tests; MMS-32 comprises all candidate CpGs with discovery p < 1 × 10⁻⁴ and uses signed discovery mean differences as normalized weights. The frozen score was evaluated in an independent male dataset (n = 1,044). Among single-category memory responses, MMS-32 discriminated Very bad (n = 16) from Very good (n = 66) memory with AUC = 0.861 (95% bootstrap CI 0.736–0.957; p = 8.50 × 10⁻⁶). A broader Bad/Very bad versus Good/Very good contrast yielded AUC = 0.603 (p = 0.0079). Linear dependence on chronological age was negligible (R2 = 0.0022; Pearson r = −0.047, p = 0.133), and the extreme-memory association remained significant after age adjustment. MMS-32 is therefore a research-stage, memory-associated methylation signature rather than a biological-age score. Independent validation against objective (diagnosed dementia, MRI etc.) and longitudinal cognitive outcomes is required.

Abstract: Background: Colorectal cancer (CRC) exhibits significant molecular heterogeneity, leading to diverse clinical outcomes and highlighting the need for more accurate prognostic biomarkers. This study aimed to identify a novel gene signature to improve risk stratification and to explore its underlying biological relevance, particularly in relation to the tumor immune landscape. Results: A novel four-gene signature comprising SLC16A8, MAGEA1, LINC00634, and PPFIA4 was developed and validated. This signature effectively stratified patients into high- and low-risk groups with markedly different overall survival (p < 0.0001). The model demonstrated strong predictive accuracy for 1-, 3-, and 5-year survival (AUCs = 0.706, 0.735, 0.693, respectively). Importantly, multivariate Cox regression confirmed the signature as a powerful and independent prognostic factor (HR = 3.50, 95% CI = 2.10-5.80, p < 0.001). A clinically practical nomogram integrating the signature was constructed and showed excellent calibration. Furthermore, the risk score was significantly correlated with the infiltration levels of several key immune cells, suggesting that the signature reflects the host's anti-tumor immune status. Conclusions: We have successfully established and validated a novel four-gene signature that serves as an independent and powerful prognostic biomarker for CRC. This signature not only improves personalized risk stratification but also provides a potential link between the tumor's intrinsic molecular features and the surrounding immune landscape. The constructed nomogram offers a valuable tool to aid in clinical decision-making for CRC patients. Methods: Based on an integrated analysis of transcriptome data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project, we identified a pool of candidate prognostic genes. A robust prognostic signature was constructed using LASSO-Cox regression analysis. The signature's performance was comprehensively validated in the TCGA cohort, and its independence from conventional clinicopathological factors was assessed. A nomogram was developed to enhance its clinical utility. The CIBERSORT algorithm was used to investigate the association between the signature and tumor-infiltrating immune cells.

Abstract: Hand-arm-vibration (HAV) exposure harms the health of drill-operators. To find associated effects of HAV on workers’ skin and core body temperature, this study was conducted on 100 drill-operators, following ISO-5349 guidelines. Root-mean-square (rms) and time-weighted-frequency of HAV were calculated. Ingestible thermometric pills were used for core-body temperature measure-ments. Electronic thermometers were used for monitoring of skin temperature. 73.2% workers had white-finger-syndrome, and 90% reported tingling in right hand. The mean value for the frequency-weighted rms acceleration was 7.07 m/s², with standard deviation (SD) of 0.24 m/s². For vibration dose value, the mean value was 3.99 m/s2 with SD 0.52. Multivariate analysis of pre- and post-shift measurements of core-body and skin temperature proves effect of vi-bration exposure on skin temperature (reduces) and core body temperature (in-creases). Core body temperature rose from 37°C (98.6°F) to 38.5°C (101.3°F). Skin temperature dropped to ~34.0°C from ~36.4°C. Having established a rela-tion between HAV exposure and changes in physiological temperature of human body, the study adds a new dimension for the intervention to safe drill operators of all industries.

Abstract: Induced pluripotent stem cells have revolutionized biomedical research - yet the vast majority of life on Earth remains beyond their reach. Non-model species lack the annotated genomes, validated reagents, and species-specific culture infrastructure that make iPSC technology routine in humans and mice, and this infrastructure deficit, rather than any fundamental biological barrier, is what has kept the field narrow. The core pluripotency network is conserved across vertebrates; reprogramming is, in principle, achievable in any somatic cell from any species. This review consolidates current progress and future potential of iPSC technology across five domains: technical reprogramming challenges and advances; conservation applications including genetic rescue, in vitro gametogenesis, and de-extinction; medical applications within a one medicine framework; agricultural applications spanning disease resistance, climate resilience, and cultured meat; and species-specific iPSC-derived systems in ecotoxicology. Throughout, we distinguish what has been demonstrated from what remains aspirational and identify the priorities that will determine whether the iPSC revolution can be extended - rigorously and at scale - beyond model organism research.

Abstract: Dietary composition is a major driver of the ruminal and intestinal microbiomes in dairy cows and is implicated in digestive disorders such as subacute ruminal acidosis (SARA), which can be triggered by high-concentrate diets. Here, we used a longitudinal shotgun metagenomic approach to investigate the dynamics of ruminal and fecal microbiomes in seven dairy cows subjected to a controlled bidirectional dietary transition from low- to high-concentrate diets and back over two months. Samples were collected at three key stages of dietary modulation, enabling the assessment of temporal changes in microbial composition and function in relation to diet-associated physiological fluctuations. Shotgun metagenomic sequencing enabled a comprehensive characterization of community structure and functional potential across compartments and time, revealing a strong location effect with clear segregation between ruminal and fecal microbiomes, as well as diet-associated differences in diversity and composition. Our results highlight how gradual dietary concentrate transitions induce coordinated taxonomic and functional remodelling of the digestive microbiome in dairy cows and suggest that these responses may not be fully reversible over the course of a short experimental time frame.

Abstract: Purpose: To summarize current evidence on the incidence, magnitude, and possible predictors of rebound after cessation of myopia control treatments and to identify strategies that may help minimize rebound in practice. Methods: In this systematic review, we aimed to evaluate potential rebound effects following the cessation of optical, pharmacological, and low-level light therapy interventions used for myopia control. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature search was conducted, and 1027 articles published up to November 2025 were identified through the following databases: PubMed, Web of Science, Scopus, and ClinicalTrials.gov. Three investigators independently performed the selection process according to these inclusion and exclusion criteria. Results: In most studies, axial length (AL) and spherical equivalent refraction (SER) values were higher in cessation groups than in groups that continued myopia control treatment. HAL/DIMS spectacles for myopia control interventions showed weak to moderate rebound effects after treatment cessation, with a mean rebound of 0.09 ± 0.17 mm (0.06 to 0.11) in AL and −0.16 ± 0.43 D (-0.18 to -0.13) in SER. Multifocal contact lenses generally showed weak or no rebound after treatment cessation, whereas Ortho-K lenses were more frequently associated with moderate to strong rebound effects, suggesting a mean rebound of 0.05 ± 0.61 mm (-0.43 to 0.62) in AL and 0.05 ± 0.60 D (-0.22 to 0.41) in SER. Similarly, the mean rebound effect in the atropine intervention was concentration-dependent and was 0.14 ± 0.19 mm (-0.02 to 0.35) in AL and -0.23 ± 0.47 D (-0.87 to 0.43) in SER. LLLT intervention showed moderate to strong rebound effects with the mean rebound effect of 0.23 ± 0.26 mm (0.15 to 0.30) in AL and -0.48 ± 0.37 D (-0.71 to -0.25) in SER. Overall, the treatment continuation subgroup showed a mean axial length (AL) change of 0.15 ± 0.16 mm (range: −0.09 to 0.46) and a mean spherical equivalent refraction (SER) change of −0.25 ± 0.41 D (range: −0.67 to 0.38). In contrast, the treatment cessation subgroup demonstrated a mean AL change of 0.25 ± 0.26 mm (0.00 to 0.58) and a mean SER change of −0.55 ± 0.44 D (-1.15 to -0.01). Conclusion: Various myopia control interventions produce rebound effects of differing magnitude in different parameters, including AL, SE, and choroidal thickness. Spectacle lenses and contact lenses showed the lowest rebound, whereas high-dose atropine and LLLT were associated with the greatest rebound, highlighting the dose-dependent nature of this phenomenon.

Abstract: Open, provenance-aware datasets are essential for evaluating biological findings and identifying analytical decisions that alter interpretation. This Data Resource Article describes a curated multi-assay preclinical dataset derived from studies of oral hyperimmune anti-human immunodeficiency virus type 1 (HIV-1) gp120 immunoglobulin Y (IgY) administration in outbred domestic cats. The publicly deposited Figshare resource comprises 13 comma-separated-value tables, a structured Excel workbook, a machine-readable data dictionary, provenance and quality-control records, executable Python and R scripts, a manifest and cryptographic checksums. Two independent cohorts are represented. A six-cat proof-of-concept cohort (three immunised and three controls) generated serum anti-gp120 anti-anti-idiotypic antibody (Ab3) ELISA data, competitive-inhibition measurements and processed TZM-bl HIV-1 JR-FL pseudovirus neutralisation outputs, including RLU summaries, virus-only and cell-only controls, percentage neutralisation and an estimated ID50. A separate 42-cat mucosal-immunogenicity cohort (18 immunised and 24 controls) generated salivary anti-gp120 IgA classifications after eight weeks of assigned oral exposure. Exact source values were transcribed with explicit provenance, whereas unavailable primary measurements were represented by schema-defined blanks rather than imputed observations. Reanalysis reproduced complete separation in IgA positivity (18/18 versus 0/24; Fisher exact p = 2.83 × 10⁻¹²; absolute risk difference 100%) and identified decision-sensitive analytical features. Displayed Ab3 negative wells yielded a mean-plus-three-standard-deviations threshold of 0.146, compared with source thresholds of 0.32 and 0.35. Animal-level competitive-inhibition means produced p = 0.0118 by Welch’s t-test and p = 0.10 by an exact Mann-Whitney test. The resource supports immunological reuse, assay benchmarking and transparent sensitivity analysis while preserving clear boundaries between reported, processed, derived and unavailable primary measurements. It should be interpreted as an exploratory FAIR-oriented data resource rather than evidence of vaccine efficacy or broadly neutralising immunity.

Abstract: Antimicrobial resistance (AMR) is one of the most significant challenges facing human and veterinary medicine today. It reduces the effectiveness of conventional antibiotics against multidrug-resistant (MDR) pathogens. Snake venoms are complex mixtures of proteins, peptides, and enzymes that have evolved to target biological membranes and cellular processes. Over the past decade, numerous molecules derived from snake venom have shown promising antibacterial and antibiofilm activity against clinically relevant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and resistant Escherichia coli. Among the most promising compounds are phospholipases A₂ (PLA₂s), L-amino acid oxidases (LAAOs), cathelicidins, crotalicidin-derived peptides, and synthetic peptides engineered from natural venom sequences. Their antimicrobial activity primarily acts through mechanisms such as membrane disruption, induction of oxidative stress, inhibition of biofilm formation, and synergistic interactions with conventional antibiotics. However, native venom toxins often exhibit cytotoxicity, haemolytic activity, and poor pharmacokinetic properties, limiting their direct clinical application. Therefore, current research focuses on rational peptide engineering, nanotechnology-based delivery systems, and combination therapies to enhance efficacy while minimising toxicity. This mini-review summarises recent advances in snake venom-derived antimicrobial molecules, discusses their potential applications in veterinary medicine, and emphasises their importance within the One Health framework.

Abstract: Somatostatin receptor subtype 2 (SSTR2) is overexpressed in high-risk neuroblastoma stage 4 (NBS4) in patients with chromosome 17q gain, making it a potential therapeutic target. This computational study employed a multi-platform drug design workflow to identify novel SSTR2 ligands based on the selective agonist L-054,522. Using BROOD (OpenEye Scientific), 5,507 structural analogues were generated, from which 293 candidates were docked to SSTR2 (PDB: 7XN9) using FRED, HYBRID, and POSIT. Eight compounds achieved GREAT pose confidence (75-100% probability within 2.0 A of the true binding mode). Confirmatory docking with AutoDock Vina, FITTED, and Flare corroborated these results. ADMET profiling using T.E.S.T., DEEP-PK, and SwissADME indicated favourable safety profiles for all eight compounds, with no predicted mutagenicity or developmental toxicity. Retrosynthetic analysis using ChemAIRS and Spaya confirmed synthetic feasibility, with compound 8 achieving an RScore of 1.0. Compound 8 demonstrated consistent docking performance across all platforms and exhibited interaction patterns, including contacts with Asp122, Gln126, and Thr194, that align with residues previously identified as critical for SSTR2 ligand binding. Molecular dynamics simulation further supported the stability of the predicted complex, showing preservation of global structural integrity with local flexibility concentrated mainly in terminal and loop regions. Exploratory docking to CRHR1 and GALR2, two additional chromosome 17q GPCRs expressed in neuroblastoma, suggested that compound 8 may occupy these binding sites, though functional consequences remain unknown. These findings identify compound 8 as a computationally prioritised lead candidate warranting experimental evaluation through binding assays and functional studies to determine its pharmacological activity at SSTR2.

Abstract: The options for controlling agricultural plant-pathogenic bacterial diseases with antibiotics are rather limited. Applications of naturally derived antimicrobial peptides may provide an alternative. Background/Objectives: The cell-free conditioned media (CFCM) of Xenorhabdus budapestensis (EMA) and X. szentirmaii (EMC) bacteria inactivate Erwinia amylovora, the causative agent of fire blight disease in Rosaceae both in vitro and in planta. We suppose that the active ingredient compounds are fabclavines. Testing the hypothesis, inducible fabclavine-producing strains were constructed in regulatory gene (hfq) deleted mutant strains of both Xenorhabdus species. Anti-Erwinia potentials of non-induced and induced fabclavine-producing cultures were compared in vitro and in planta. Methods: To obtain the appropriate fabclavine-producing mutants, we applied the easyPACId method with minor modifications. Fabclavine production was confirmed by LC-HRMS and in vitro bioassays. The in planta experiments were designed and carried out as follows: apple blossoms in an incubator were subjected to antimicrobial and control treatments before artificial inoculations of the buds with Erwinia amylovora Ea1. Results: Cell-free medium of both induced fabclavine-producing Xenorhabdus species exerted strong antagonistic effects on Ea1 in vitro, while the non-induced ones showed substantially reduced antibacterial activity. Similarly, both induced culture media prevented fireblight symptoms in artificially infected flowers in a dose-dependent manner. The non-induced EMC was completely inactive in planta, whereas EMA exhibited some protective activity. Conclusions: The results support the hypothesis that inducible Xenorhabdus mutants producing only fabclavines can be used for protection against E. amylovora. Application perspectives are discussed from the aspects of resistance, side effects, and costs based on parallel in planta experiments with streptomycin and kasugamycin.

Abstract: Effective mass reflects the body mass mechanically coupled during impact. Acceleration-based effective-mass estimates require noise-sensitive differentiation of segment kinematics. This study introduced an impulse-based estimate (M_e,imp = J/v_pre) and evaluated its reliability, agreement with an acceleration-based estimate (M_e,acc), and sensitivity to a carried-load condition. Forty male military cadets performed five maximal front kicks onto a force plate synchronized with three-dimensional motion capture under two fixed-order conditions: barefoot without load (NL) and with 30 kg of carried equipment (WL). Reliability was assessed using intraclass correlation coefficients; condition differences using paired tests with effect sizes and FDR correction; method agreement using correlations, ICCs, and Bland–Altman analysis; and isokinetic strength interactions using body-mass-adjusted mixed-effects models. M_e,imp showed poor-to-moderate single-kick reliability but good reliability for the five-kick mean (ICC = 0.84–0.87). It was higher in WL than NL (25.95 ± 5.44 vs. 21.89 ± 5.14 kg; p < 0.001; d_z = 0.92), reflecting a 21% greater net impulse, while pre-impact foot velocity (v_pre) remained unchanged. Contact duration increased and the force–time profile became more push-like under WL. In a subsample with usable impact-phase marker trajectories (n = 20), M_e,imp and Me,acc were not significantly correlated (r = 0.10, p = 0.54) and showed negligible agreement (ICC = 0.02; Bland–Altman bias = −21.5 kg). Stronger concentric hip rotators were associated with a smaller WL–NL increase in M_e,imp (Bonferroni-adjusted p = 0.044–0.050). M_e,imp should be interpreted as a contact-integrated index of impulse-transfer capacity, reliable when averaged across repeated kicks, rather than as true inertial mass or an interchangeable substitute for Me,acc.

Abstract: Every crystal an active pharmaceutical ingredient (API) forms carries an intention, whether or not that intention was deliberately engineered: a lattice, hydrate shell, or amorphous halo that predetermines solubility, dissolution rate, physical and chemical stability, mechanical processability, and ultimately oral bioavailability long before the molecule reaches the bloodstream. This review proposes and applies a landscape-based organizing framework in which solid-state form is treated as an occupied position on a multidimensional lattice free-energy surface, and every deliberate engineering strategy polymorph and hydrate control, salt formation, cocrystallization, amorphous and co-amorphous dispersion, and particle/crystal habit engineering is positioned along two orthogonal axes: thermodynamic depth (resistance to reversion) and kinetic accessibility (ease with which the form can be reached and manufactured reproducibly). Framed this way, polymorph screening becomes a search for deep, accessible minima; salts and cocrystals become supramolecular relocations of the API onto an entirely different multicomponent landscape; amorphous dispersions become a deliberate exchange of thermodynamic depth for kinetic height, stabilized by polymeric or low-molecular-weight co-formers through the spring-and-parachute mechanism; and particle engineering becomes a second, independent landscape operating at the mesoscale rather than the molecular scale. We synthesize thirty-nine studies published since 2020 to update the mechanistic, analytical, and computational toolkit available to navigate this landscape, with particular emphasis on crystal structure prediction (CSP) using machine-learned interatomic potentials, machine-learning-guided coformer and amorphous-dispersion screening, disproportionation risk modeling for pharmaceutical salts, spherical co-crystallization for simultaneous molecular- and particle-level design, and continuous, solvent-minimized crystallization platforms aligned with ICH Q13. Original comparative figures and tables translate this landscape framework into a decision architecture Solid-State-by-Design (SSbD) intended to guide form selection from first candidate nomination through commercial manufacture, converting an API's crystal intentions from an accident of discovery-stage crystallization into a deliberately engineered design outcome. We close by identifying unresolved landscape-navigation problems: long-term prediction of amorphous recrystallization risk, extension of CSP and machine-learning tools to larger and more conformationally flexible discovery-stage molecules, and tighter integration of computational screening into candidate selection itself, rather than only after a lead has already been chosen.

Abstract:

The gastrointestinal tract is a critical system in acute radiation exposure. Severe radiation exposures can deplete epithelial stem and progenitor cells, compromise barrier integrity, alter host-microbe interactions, and drive fluid loss, inflammation, and systemic decline. Mammalian models remain essential for clinical translation, but their cost and complexity constrain sample sizes, statistical power, large-scale mechanistic discovery, and countermeasure screening. The adult Drosophila melanogaster midgut provides a complementary in vivo platform containing intestinal stem cells, absorptive enterocytes, enteroendocrine cells, epithelial junctions, an associated microbiota, and conserved innate immune and injury-response pathways. Direct irradiation studies have demonstrated DNA damage, altered stem cell proliferation and differentiation, epithelial plasticity, apoptosis, autophagy-associated responses, morphological disruption, barrier failure, microbiome changes, and reduced survival. These phenotypes can be modified by genotype, sex, diet, microbial status, antioxidant capacity, and regenerative signaling. This review evaluates the biological rationale, direct evidence, experimental assays, and countermeasure applications supporting the fly midgut as a model of gastrointestinal radiation injury. Although Drosophila has a long history of use in radiation research, our analysis indicates that the fly midgut is best positioned not as a miniature model of clinical gastrointestinal acute radiation syndrome, but as a genetically precise and scalable system for identifying conserved mechanisms and prioritizing interventions for validation in mammalian models.