Search Results (386)

Background/Objective: Genome-wide association studies (GWAS) have linked many noncoding variants to complex traits and diseases, but distinguishing as-sociation from causation remains difficult. Deep learning models—particularly CNN- and Transformer-based architectures—are widely used for this task, yet comparisons are hindered by inconsistent benchmarks and evaluation practices. We aimed to establish a standardized assessment of leading models for predicting variant effects in enhancers and for prioritizing putative causal SNPs. Methods: We evaluated state-of-the-art deep learning models under consistent training and evaluation conditions on nine datasets derived from MPRA, raQTL, and eQTL ex-periments. These datasets profile the regulatory impact of 54,859 single-nucleotide polymorphisms (SNPs) across four human cell lines. Performance was compared for two related tasks: predicting the direction and magnitude of regulatory impact in enhancers and identifying likely causal SNPs within linkage disequilibrium (LD) blocks. We addi-tionally assessed the effect of fine-tuning on Transformer-based models and the impact of certainty in experimental results. Results: CNN models such as TREDNet and SEI performed best for predicting the reg-ulatory impact of SNPs in enhancers. Hybrid CNN–Transformer models (e.g., Borzoi) performed best for causal variant prioritization within LD blocks. Fine-tuning benefits Transformers but remains insufficient to close the performance gap. Conclusions: Under a unified benchmark, CNN architectures are most reliable for esti-mating enhancer regulatory effects of SNPs, while hybrid CNN–Transformer models are superior for causal SNP identification within LD. These comparisons help guide model selection for variant-effect prediction in noncoding regions. Full article

Calcium carbonate (CaCO₃) is a dominant component of sedimentary rocks and biogenic structures, and is one of the most frequently studied inorganic compounds. It also plays a key role in preparing modern engineered materials. CaCO₃ has three well-known polymorphs, calcite, aragonite, and vaterite, and four solvatomorphs with diverse crystallographic arrangements, hydration states, reactivity, and stability. Its solvatomorphs include the variable water-containing amorphous calcium carbonate (ACC—CaCO₃·xH₂O) and the crystalline monohydrocalcite (MHC—CaCO₃·H₂O), calcium carbonate hexahydrate (ikaite—CaCO₃·6H₂O), and the recently reported hemihydrate (CCHH—CaCO₃·0.5H₂O). Here, we review the preparation, crystal structure, and properties of these solvatomorphs and discuss their mutual transformations. Full article

The field of bacterial systems biology is rapidly advancing beyond static genomic analyses, and moving toward dynamic, integrative approaches that connect genetic variation with cellular function. This review traces the progression from genome-wide association studies (GWAS) to multi-omics frameworks that incorporate transcriptomics, proteomics, and interactome mapping. We emphasize recent breakthroughs in high-resolution transcriptomics, including single-cell, spatial, and epitranscriptomic technologies, which uncover functional heterogeneity and regulatory complexity in bacterial populations. At the same time, innovations in proteomics, such as data-independent acquisition (DIA) and single-bacterium proteomics, provide quantitative insights into protein-level mechanisms. Experimental and AI-assisted strategies for mapping protein–protein interactions help to clarify the architecture of bacterial molecular networks. The integration of these omics layers through quantitative trait locus (QTL) analysis establishes mechanistic links between single-nucleotide polymorphisms and systems-level phenotypes. Despite persistent challenges such as bacterial clonality and genomic plasticity, emerging tools, including deep mutational scanning, microfluidics, high-throughput genome editing, and machine-learning approaches, are enhancing the resolution and scope of bacterial genetics. By synthesizing these advances, we describe a transformative trajectory toward predictive, systems-level models of bacterial life. This perspective opens new opportunities in antimicrobial discovery, microbial engineering, and ecological research. Full article

Biological invasions threaten biodiversity worldwide. The American blue crab Callinectes sapidus Rathbun, 1896, among the Mediterranean’s most damaging invaders, takes up the challenge to transform this threat into gain. To turn its impact into economic value and guide control efforts, we analysed separately the meat composition and exoskeleton biopolymers of adult crabs from three Moroccan protected Sites of Biological and Ecological Interest: Marchica Lagoon (S₁), Moulouya Estuary (S₂), and Al Hoceima National Park (S₃). Marchica specimens exhibited the highest protein content (21.87 ± 1.15 g 100 g⁻¹, p < 0.001) and an elevated lipid fraction, yielding nutrient-dense meat suitable for premium markets. Moulouya crabs were noted for their taste potential, with a higher concentration of fat (1.73 ± 0.09%) and carbohydrates (0.91 ± 0.1%). Al Hoceima individuals displayed markedly mineralised exoskeletons producing lean and low-fat meat, valued in dietary applications. Exoskeleton organic-to-mineral (OM/MM) ratios and proximate composition revealed three adaptive profiles, opportunistic (S₁), acclimatory (S₂), and conservative (S₃), presumably correlated to local salinity, productivity, and substrate conditions, underscoring the species’ phenotypic plasticity. X-ray diffraction confirmed the α-chitin polymorph, while FTIR analysis indicated degrees of deacetylation consistent with high-purity chitosan. These findings support the development of a site-specific circular economy framework and may contribute to the ecological resilience of Morocco’s protected coastal areas. Full article

Biologics targeting tumor necrosis factor-α (TNFi), interleukin-12/23 (IL-12/23i), and interleukin-17 cytokine or receptor (IL-17i/IL-17Ri) have transformed psoriasis management. However, interindividual variation in response underscores the need for predictive biomarkers in guiding therapy selection. Patients treated with a biologic for psoriasis were genotyped for 67 single-nucleotide polymorphisms (SNPs) previously associated with response to biologics. Odds ratios (OR) with 95% confidence intervals (CI) for associations between SNPs and response to biologics were calculated using logistic regression models with an absolute Psoriasis Area and Severity Index (PASI) ≤2 after 3 months as treatment response. A p-value < 0.05 was considered statistically significant. In total, 373 patients with 574 treatment series were included. Twelve SNPs were associated with treatment response: four uniquely with response to TNF inhibitors (TNFi), two to IL-12/23i, and five to IL-17i/IL-17Ri, while one was associated with response to both TNFi and IL-17i/IL-17Ri. Notably, IRAK3 (rs11541076) and CD84 (rs6427528) were associated with response to TNFi (OR: 2.56 [95% CI: 1.22–5.37], p = 0.012 and OR: 0.53 [95% CI: 0.30–0.91], p = 0.023) and IL-17i/IL-17Ri (OR: 2.55 [95% CI: 0.70–9.22], p = 0.15), and OR: 0.50 [95% CI: 0.25–0.98], p = 0.045), with trends toward opposite associations for IL-12/23i (OR: 0.38 [95%CI: 0.08–1.72], p = 0.21 and OR: 1.64 [95%CI: 0.68–3.93], p = 0.26). This study replicates known genetic associations with biologic response in psoriasis. Variants in IRAK3 and CD84 show potential as stratification biomarkers, although they need confirmation in independent cohorts. Full article

Pharmaceutical formulations, in addition to the medicinal substance(s), contain added excipients that make it possible to create a pharmaceutical product that exhibits required properties in terms of mechanical, physical, chemical, and microbiological stability. Additionally, these substances can act as release modifiers or improve bioavailability parameters. Literature data indicate that excipients, especially polymeric ones, can also affect the polymorphism of the active substance, resulting in drug bioavailability enhancement or reduction. This influence can be evaluated using thermal and spectroscopic methods. In the study, differential scanning calorimetry (DSC), vibrational spectroscopic studies (Fourier transform infrared spectroscopy, FTIR), Raman spectroscopy, and X-ray diffraction (XRD) assay of ibuprofen, naproxen, and naproxen sodium standards and pharmaceutical preparations containing these medicinal substances in their compositions were carried out. DSC results indicated that a sharp melting peak was observed on the DSC curves of the standards, confirming their crystalline form. DSC results obtained for pharmaceutical formulations also indicated that the enthalpy of melting is sometimes lower than calculated from the percentage of active ingredients in the formulations. In addition, the melting peak is often broadened and shifted toward lower temperatures, suggesting the influence of excipients on the polymorphism of drug substances. The FTIR and Raman spectra of pharmaceutical formulations contained all characteristics of the active substances. XRD analysis was also performed. Therefore, possible chemical interactions between the components of the preparations have been excluded. At the same time, FTIR and Raman spectroscopy results as well as XRD assay showed a reduction in the height of signals corresponding to the crystalline API form, confirming the possibility of reducing API crystallinity in pharmaceutical formulations. Full article

This review aims to provide a comprehensive overview of how oxidative stress drives inflammation, structural remodeling, and clinical expression of childhood asthma, while critically appraising emerging redox-sensitive biomarkers and antioxidant-focused preventive and therapeutic strategies. Oxidative stress arises when reactive oxygen species (ROS) and reactive nitrogen species (RNS) outpace airway defenses. This surplus provokes airway inflammation: ROS/RNS activate nuclear factor kappa-B (NF-κB) and activator protein-1 (AP-1), recruit eosinophils and neutrophils, and amplify type-2 cytokines. Normally, an antioxidant network—glutathione (GSH), enzymes such as catalase (CAT) and superoxide dismutase (SOD), and nuclear factor erythroid 2-related factor 2 (Nrf2)—maintains redox balance. Prenatal and early exposure to fine particulate matter <2.5 micrometers (µm) (PM_2.5), aeroallergens, and tobacco smoke, together with polymorphisms in glutathione S-transferase P1 (GSTP1) and CAT, overwhelm these defenses, driving epithelial damage, airway remodeling, and corticosteroid resistance—the core of childhood asthma pathogenesis. Clinically, biomarkers such as exhaled 8-isoprostane, hydrogen peroxide (H₂O₂), and fractional exhaled nitric oxide (FeNO) surge during exacerbations and predict relapses. Therapeutic avenues include Mediterranean-style diet, regular aerobic exercise, pharmacological Nrf2 activators, GSH precursors, and mitochondria-targeted antioxidants; early trials report improved lung function and fewer attacks. Ongoing translational research remains imperative to substantiate these approaches and to enable the personalization of therapy through individual redox status and genetic susceptibility, ultimately transforming the care and prognosis of pediatric asthma. Full article

Background/Objectives: Advances in understanding immune checkpoint pathways and tumor immune biology have enabled the development of immune checkpoint inhibitors (ICIs), particularly targeting the PD-1/PD-L1 axis, which has transformed cancer immunotherapy. While they have shown remarkable success in various cancer types, including melanoma, non-small cell lung cancer, and gastrointestinal malignancies, variability in patient response, immune-related adverse events (irAEs), and resistance mechanisms remain significant. This review aims to evaluate clinical pharmacology, mechanisms of action, resistance pathways, and pharmacogenomic influences shaping interindividual responses to ICIs. Methods: This comprehensive review synthesizes current literature on FDA-approved ICIs, exploring their clinical use, underlying biological mechanisms, and emerging pharmacogenomic data. It also assesses key biomarkers such as tumor mutational burden (TMB), microsatellite instability (MSI), HLA diversity, and epigenetic factors influencing ICI efficacy and safety. Results: We outline key mechanisms contributing to ICI resistance, including T cell dysfunction, altered antigen presentation, and immunosuppressive tumor microenvironment components. Furthermore, we highlight promising pharmacogenomic findings, including single-nucleotide polymorphisms (SNPs) in PD-1/PD-L1 and immune-regulatory genes, offering predictive and prognostic utility. Variability in PD-L1 expression and the role of epigenetic modifications are also addressed as challenges in treatment optimization. Conclusions: Interindividual variability in ICI response underscores the need for biomarker-driven strategies. By integrating pharmacogenomic insights with clinical pharmacology, future approaches may support more personalized and effective use of ICIs. Combination therapies and novel modalities hold promise for overcoming resistance, enhancing therapeutic efficacy, and enabling precision oncology. Full article

Cardiac arrhythmias remain a major source of morbidity and mortality, often stemming from molecular and structural abnormalities that are insufficiently addressed by current pharmacologic and interventional therapies. Gene therapy has emerged as a transformative approach, offering precise and durable interventions that directly target the arrhythmogenic substrate. Across the spectrum of inherited and acquired arrhythmias—including long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, atrial fibrillation, and post-infarction ventricular tachycardia—gene-based strategies such as allele-specific silencing, gene replacement, CRISPR-mediated editing, and suppression-and-replacement constructs are showing growing translational potential. Advances in delivery platforms, including cardiotropic viral vectors, lipid nanoparticle-encapsulated mRNA, and non-viral reprogramming tools, have further enhanced the specificity and safety of these approaches. Additionally, innovative applications such as biological pacemaker development and mutation-agnostic therapies underscore the versatility of genetic modulation. Nonetheless, significant challenges remain, including vector tropism, immune responses, payload limitations, and the translational gap between preclinical models and human electrophysiology. Integration of patient-derived cardiomyocytes, computational simulations, and large-animal studies is expected to accelerate clinical translation. This review provides a comprehensive synthesis of the mechanistic rationale, therapeutic strategies, delivery platforms, and translational frontiers of gene therapy for cardiac arrhythmias. Full article

As the most unstable crystalline form of calcium carbonate, vaterite is rarely found in nature due to being highly prone to phase transitions. However, its high specific surface area, excellent biocompatibility, and high solubility properties have led to a research boom and the following breakthroughs in the last two decades: (1) From primitive calculations and spectroscopic analyses to modern multidimensional research methods combining calculations and experiments, the crystal structure of vaterite has turned from early identifications in orthorhombic and hexagonal crystal systems to a complex polymorphic structure within the monoclinic crystal system. (2) The formation process of vaterite not only conforms to the classical crystal growth theory but also encompasses the nanoparticle aggregation theory, which incorporates the concepts of oriented nanoparticle assembly and mesoscale transformation. (3) Regardless of the conditions, the formation of vaterite depends on an excess of CO₃²⁻ relative to Ca²⁺, and its stability duration relates to preservation conditions. (4) Vaterite demonstrates significant value in biomedical applications—including bone repair scaffolds, targeted drug carriers, and antibacterial coating materials—leveraging its porous structure, high specific surface area, and exceptional biocompatibility. While it also shows utility in environmental pollutant adsorption and general coating technologies, the current research remains predominantly concentrated on its medical applications. Currently, the rapid transformation of vaterite presents the primary limitation for its industrial application. Future research should prioritize investigating its formation kinetics and stability. Full article

A review of the literature on polymorphic transformations by milling on pharmaceutical materials was carried out. The available information on 18 pharmaceutical materials was compiled. In particular, when data are available, the starting and final crystalline forms, their enantiotropic or monotropic relationship, the glass transition temperature of the compound and its melting temperature, the experimental observation of a transient or partial amorphization of compounds, and the transformation kinetics make it possible to suggest a two-step transformation mechanism. First, an amorphization occurs under milling of the starting polymorphic form. Secondly, a recrystallization of the amorphous form occurs towards the final form. The observed transformation kinetics are due to the fact that the recrystallization of the amorphous material towards the final form depends on the accidental formation of a cluster of this form during milling. Moreover, the observation of the transient amorphous form depends on the relative position of the glass transition temperature of the material with respect to the milling temperature. This mechanism seems to be independent of the enantiotropic or monotropic character of the polymorphic forms involved in the transformation. Full article

Background/Objectives: Tegoprazan (TPZ) is a potassium-competitive acid blocker (P-CAB) used to treat conditions such as gastroesophageal reflux disease, peptic ulcer, and Helicobacter pylori infection. It exists in three solid forms: amorphous, Polymorph A, and Polymorph B. This study investigates the molecular basis of polymorph selection, focusing on conformational bias and solvent-mediated phase transformations (SMPTs). Methods: The conformational energy landscapes of two TPZ tautomers were constructed using relaxed torsion scans with the OPLS4 force field and validated by nuclear Overhauser effect (NOE)-based nuclear magnetic resonance (NMR). Hydrogen-bonded dimers were analyzed using DFT-D. Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), solubility, and slurry tests were conducted using methanol, acetone, and water. Kinetic profiles were modeled with the Kolmogorov–Johnson–Mehl–Avrami (KJMA) equation. Results: Polymorph A was thermodynamically stable across all analyses. Both amorphous TPZ and Polymorph B converted to A in a solvent-dependent manner. Methanol induced direct A formation, while acetone showed a B → A transition. Crystallization was guided by solution conformers and hydrogen bonding. Conclusions: TPZ polymorph selection is governed by solution-phase conformational preferences, tautomerism, and solvent-mediated hydrogen bonding. DFT-D and NMR analyses showed that protic solvents favor the direct crystallization of stable Polymorph A, while aprotic solvents promote the transient formation of metastable Polymorph B. Elevated temperatures and humidity accelerate polymorphic transitions. This crystal structure prediction (CSP)-independent strategy offers a practical framework for rational polymorph control and the mitigation of disappearing polymorph risks in tautomeric drugs. Full article

Polypropylene (PP), with its good physical, thermal, and mechanical properties and excellent processing capabilities, has become one of the most used synthetic polymers. It is known that the overall properties of semicrystalline polymers, including PP, are governed by morphology, which is influenced by the crystallization behavior of the polymer under specific conditions. The most important industrial PP remains the isotactic one, and it has been studied extensively for its polymorphic characteristics and crystallization behavior for over half a century. Due to its regular chain structure, isotactic polypropylene (iPP) belongs to the group of polymers with a high tendency for crystallization. The rapid quenching of molten iPP fails to produce a completely amorphous polymer but leads to an intermediate crystalline order. On the other hand, slow cooling yields a material with high crystalline content. The processing conditions that occur in practice and industry are between these two extremes and, in some cases, are even very close. Therefore, the study of limits in processability and the impact of extreme preparation conditions on morphology, structure, thermal, and mechanical properties fills a gap in the current understanding of how the processing conditions of iPP can be used to design the desired properties for specific applications and is in the focus of this research. The first set of samples (Q samples) was obtained by rapid quenching, while the second was prepared by very slow cooling from the melt to room temperature (SC samples). Testing of samples was performed by optical microscopy (OM), scanning electron microscopy (SEM), wide-angle X-ray diffraction (WAXD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), dynamic dielectric spectroscopy (DDS), and mechanical measurements. Characterization revealed that slowly cooled samples exhibited a significantly higher degree of crystallinity and larger crystallites (χ ≥ 55% and L₍₁₁₀₎ ≈ 20 nm), compared to quenched samples (χ < 30%, L₍₁₁₀₎ ≤ 3 nm). Mechanical testing showed a drastic contrast: quenched samples exhibited elongation at break > 500%, while slowly cooled samples broke below 15%, reflecting their brittle behavior. For the first time, DDS is applied to investigate molecular mobility differences between processing-dependent structural forms, specifically the mesomorphic (smectic) and α-monoclinic forms. In slowly cooled samples, α relaxation exhibited both enhanced intensity and an upward temperature shift, indicating stronger structural constraints due to a much higher crystalline phase content and significantly larger crystallite size, respectively. These findings provide novel insights into the structure–property–processing relationship, which is crucial for industrial applications. Full article

This study reports the discovery and structural characterization of a novel polymorph, designated as Form III, of Alclometasone dipropionate, a corticosteroid commonly used in the treatment of inflammatory dermatoses. Form III was obtained by modifying the crystallization conditions reported in prior art and was thoroughly characterized using Powder X-ray Diffraction (PXRD), Fourier Transform Infrared (FT-IR) spectroscopy, melting-point determination, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), including its first derivative (DTG), optical microscopy, and Scanning Electron Microscopy (SEM). In parallel, pure Form II, previously observed only in mixtures with Form I, was successfully isolated and characterized using the same analytical techniques. Both forms were compared in terms of structural, thermal, and morphological properties. PXRD analysis revealed that Form III crystallizes in a triclinic system; FT-IR spectroscopy revealed unique vibrational signatures, and microscopy showed rod-like crystal morphology. The discovery of Form III expands the current understanding of the solid-state landscape of Alclometasone dipropionate and opens opportunities for the identification of new industrial purification methods for the compound. Full article

The transforming growth factor-beta (TGF-β) superfamily plays a crucial role in regulating female reproductive traits, particularly litter size, in small ruminants, such as sheep and goats. This review comprehensively examines the molecular mechanisms through which TGF-β superfamily members—including bone morphogenetic proteins (BMPs), growth differentiation factor 9 (GDF9), inhibin (INHA and INHB), and associated signaling genes—influence ovarian follicular development, ovulation rate, and ultimately, litter size. We synthesize recent findings on polymorphisms in key genes, such as BMPR1B, BMP15, GDF9, inhibins and SMADs family genes, across diverse sheep and goat breeds worldwide. The manuscript highlights how specific mutations in these genes create an intricate signaling network that modulates granulosa cell proliferation, follicular sensitivity to FSH, and the prevention of dominant follicle selection. These molecular interactions result in increased ovulation rates and larger litter sizes in prolific breeds. The gene dosage effects observed in heterozygous versus homozygous mutation carriers further illuminate the complex nature of these reproductive regulations. This improved the understanding of the genetic basis for prolificacy provides valuable insights for marker-assisted selection strategies aimed at enhancing reproductive efficiency in small ruminant breeding programs, with significant implications for improving livestock productivity and economic outcomes. Full article