Search Results (203)

Phage therapy, long overshadowed by antibiotics in Western medicine, has a well-established history in some Eastern European countries and is now being revitalized as a promising strategy against antimicrobial resistance (AMR). This resurgence of phage therapy is driven by the urgent need for innovative countermeasures to AMR, which will cause an estimated 10 million deaths annually by 2050. However, the emergence of phage-resistant variants presents challenges similar to AMR, thus necessitating a deeper understanding of phage resistance mechanisms and control strategies. The highest priority must be to prevent the emergence of phage resistance. Although phage cocktails targeting multiple receptors have demonstrated a certain level of phage resistance suppression, they cannot completely suppress resistance in clinical settings. This highlights the need for strategies beyond simple resistance suppression. Notably, recent studies examining fitness trade-offs associated with phage resistance have opened new avenues in phage therapy that offer the potential of restoring antibiotic susceptibility and attenuating pathogen virulence despite phage resistance. Thus, controlling phage resistance may rely on both its suppression and strategic redirection. This review summarizes key concepts in the control of phage resistance and explores evolutionary engineering as a means of optimizing phage therapy, with a particular focus on Pseudomonas infections. Harnessing evolutionary dynamics by intentionally breaking the spontaneous evolutionary trajectories of target bacterial pathogens could potentially reshape bacterial adaptation by acquisition of phage resistance, unlocking potential in the application of phage therapy. Full article

New theologies developed in tandem with evolutionary biology during the nineteenth century, which have been called metaphysical evolutionisms and evolutionary theologies. A subset of these theologies analyzed here were developed by thinkers who accepted biological science but rejected both biblical creationism and materialist science. Tools from the cognitive science of religion, including conceptual metaphor theory (CMT) and blending theory, also known as conceptual integration theory (CIT), can help to explain the development of these systems and their transformation between the nineteenth and the twentieth centuries. The analysis focuses on several stable and popular blends of ideas, which have continued with some alteration into the twenty-first century. The three blends evaluated here are Progressive Soul Evolution, Salvation is Evolution, and Evolution is Therapy. Major contributors to these blends are the theosophist and theologian Helena P. Blavatsky and psychologist Frederic W. H. Myers, both influenced by the spiritualist movement, particularly the ideas of the spiritualist and biologist Alfred Russel Wallace. The influence of these blends can be seen in the twentieth-century “Aquarian Frontier,” a group of 145 thinkers and organizations identified in 1975 by counterculture historian Theodore Roszak. Part of the appeal of these blends may be seen in their use of metaphors, including the Great Chain of Being and A Purposeful Life is a Journey. The application of the polysemic term evolution in a sense that does much of the theological work of salvation in Christianity can in part be explained by applying the principles of blending theory, including the vital relation “achieve a human scale,” as well as compressions of time and identity. These blends have been successful because they meet the needs of a population who are friendly towards science but disenchanted with traditional religions. The blends provide a satisfying new theology that extends beyond death for a subset of adherents, particularly in the New Age and spiritual but not religious (SBNR) movements, who combine the agency of self-directed “evolution” with the religious concepts of grace and transcendence. Full article

The Crimean–Congo hemorrhagic fever virus (CCHFV) is a single-stranded, segmented RNA virus belonging to the Nairoviridae family, and it is rapidly expanding across Africa, Asia, and southern Europe, probably favored by climate change and livestock trade. Its fatality rate in humans reaches up to 40%, and there is currently no specific treatment or vaccine available. Therefore, the development of therapies against CCHFV is essential, and their design requires understanding of the molecular evolution and genetic distribution of the virus. Motivated by these concerns, we present a comprehensive review of the molecular evolution, genetic characterization, and phylogeography of CCHFV, and we discuss their potential implications for therapeutic design. Specifically, we describe the virus’s capacity to increase its genetic diversity through numerous mutations, recombination events, and genomic reassortments, which affect fundamental viral functions such as RNA binding, host–virus interactions, viral entry, and polymerase activity. We also assess the presence of temporal heterogeneous rates of evolution and molecular adaptation among CCHFV coding regions, where purifying selection is generally predominant but diversifying selection is observed in molecular regions associated with host adaptation and transmission. We emphasize the importance of understanding the complex molecular evolution of CCHFV for the rational design of therapies and highlight the need for efforts in surveillance, evolutionary prediction, and therapeutic development. Full article

Docetaxel is a chemotherapeutic agent widely used for breast cancer treatment; however, its efficacy is often limited by drug resistance and associated toxicity. This review examines the molecular mechanisms of docetaxel resistance in breast cancer and discusses research advances and future directions for overcoming this challenge. Key resistance mechanisms include alterations in drug targets (microtubules), increased drug efflux, suppression of apoptosis, activation of survival signalling pathways, epithelial-to-mesenchymal transition (EMT), and cancer stem cell enrichment. An evolutionary perspective distinguishes between intrinsic and acquired resistance, emphasising the need for adaptive therapeutic strategies. Recent advances in genomic profiling, non-coding RNA research, novel drug combinations, and biomarker-guided therapies have also been reviewed. Emerging approaches, such as targeting the tumour microenvironment, harnessing immunotherapy, and implementing adaptive dosing schedules, have been discussed. This review emphasises the understanding of resistance as a multifactorial phenomenon that requires multipronged interventions. Research has aimed to identify predictive biomarkers, develop targeted agents to reverse resistance, and design rational combination strategies to improve patient outcomes. Progress in deciphering and targeting docetaxel resistance mechanisms holds promise for enhancing treatment responses and extending survival in patients with breast cancer. Full article

Herpes simplex virus 2 (HSV-2) remains a significant cause of morbidity and mortality in immunocompromised individuals, despite the availability of effective antivirals. Infections caused by drug-resistant isolates are an emerging concern among these patients. Understanding evolutionary aspects of HSV-2 resistance is crucial for designing improved therapeutic strategies. Here, we characterized 11 HSV-2 isolates recovered from various body sites of a single immunocompromised patient suffering from a primary HSV-2 infection unresponsive to acyclovir and foscarnet. The isolates were analyzed phenotypically and genotypically (Sanger sequencing of viral thymidine kinase and DNA polymerase genes). Viral clone isolations, deep sequencing, viral growth kinetics, and dual infection competition assays were performed retrospectively to assess viral heterogeneity and fitness. Sanger sequencing identified mixed populations of DNA polymerase mutant variants. Viral clones were plaque-purified and genotyped, revealing 17 DNA polymerase mutations (K533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789T/K, Y823C, V842M, R847C, F923L, T934A, and R964H) associated with acyclovir and foscarnet resistance. Deep-sequencing of the DNA polymerase detected drug-resistant variants ranging between 1 and 95%, although the first two isolates had a wild-type DNA polymerase. Some mutants showed reduced fitness, evidenced by (i) the frequency of variants identified by deep-sequencing not correlating with the proportion of mutants found by plaque-purification, (ii) loss of the variants upon passaging in cell culture, or (iii) reduced frequencies in competition assays. This study reveals the rapid evolution of heterogeneous drug-resistant HSV-2 populations under antiviral therapy, highlighting the need for alternative treatment options and resistance surveillance, especially in severe infections. Full article

Pseudomonas aeruginosa is a major opportunistic pathogen with high levels of antibiotic resistance. Phage therapy represents a promising alternative for the treatment of difficult infections both alone and in combination with antibiotics. Here, we isolated and characterized three novel lytic myoviruses, Cisa, Nello, and Moonstruck. Genomic analysis revealed that Cisa and Nello belong to the Pbunavirus genus, while Moonstruck is a novel Pakpunavirus species. All lacked lysogeny, virulence, or resistance-associated genes, supporting their therapeutic suitability. Phage Nello and Moonstruck were active against P. aeruginosa Pa3GrPv, isolated from a patient with lung infection candidate for phage therapy. Moonstruck exhibited superior lytic activity with ciprofloxacin sub-MIC value (0.125 µg/mL), achieving bacterial suppression for 48 h. However, to improve the lytic efficacy of the phages on the clinical isolate, phage adaptation via serial passage was investigated. The killing efficacy of Nello was enhanced, whereas Moonstruck showed a less consistent improvement, suggesting phage-specific differences in evolutionary dynamics. Sequencing of the evolved phages revealed point mutations in tail-associated genes, potentially linked to a better phage–host interaction. These results support the use of phage–antibiotic combinations and directed evolution as strategies to enhance phage efficacy against drug-resistant infections. Overall, these findings support the therapeutic potential of the newly isolated phages in treating P. aeruginosa lung infections. Full article

The circadian rhythm plays a crucial role in regulating biological processes, and its disruption is linked to various health issues. Identifying small molecules that influence the circadian period is essential for developing targeted therapies. This study explores the use of evolutionary optimization techniques to enhance the classification of these molecules. We applied a genetic algorithm to optimize feature selection and classification performance. Several tree-based learning classification algorithms (Decision Trees, Extra Trees, Random Forest, XGBoost) and a distance-based classifier (kNN) were employed. Their performance was evaluated using accuracy and F1-score, while considering their generalization ability with a validation set. The findings demonstrate that the proposed genetic algorithm improves classification accuracy and reduces overfitting compared to baseline models. Additionally, the use of variance in accuracy as a penalty factor may enhance the model’s reliability for real-world applications. Our study confirms that evolutionary optimization is an effective strategy for classifying small molecules regulating the circadian rhythm. The proposed approach not only improves predictive performance but also ensures a more robust model. Full article

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow. These disorders arise from acquired genetic driver mutations, with or without underlying genetic predispositions, resulting in the uncontrolled production of red blood cells, white blood cells, or platelets. The excessive cell production and abnormal signaling from driver mutations cause chronic inflammation and a higher risk of blood clots and vascular complications. The primary goals of MPN treatment are to induce remission, improve quality of life and survival, as well as to reduce the risk of complications such as thrombosis, vascular events, and leukemic transformation. This review provides a comprehensive update on the diagnosis and therapeutic advancements in major MPN subtypes, including chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It examines these complex diseases from a molecular and evolutionary perspective, highlighting key clinical trials’ long-term follow-up and therapies targeting driver mutations that have transformed treatment strategies. Additionally, several important advancements in addressing challenges such as anemia in myelofibrosis, along with promising emerging therapies, are also discussed. Full article

Bacterial biofilms, characterized by complex structures, molecular communication, adaptability to environmental changes, insensitivity to chemicals, and immune response, pose a big problem both in clinics and in everyday life. The increasing bacterial resistance to antibiotics also led to the exploration of lytic bacteriophages as alternatives. Nevertheless, bacteria have co-evolved with phages, developing effective antiviral strategies, notably modification or masking phage receptors as the first line of defense mechanism. This study investigates viral–host interactions between non-host-specific phages and Pseudomonas aeruginosa, assessing whether bacteria can detect phage particles and initiate protective mechanisms. Using real-time biofilm monitoring via impedance and optical density techniques, we monitored the phage effects on biofilm and planktonic populations. Three Klebsiella phages, Slopekvirus KP15, Drulisvirus KP34, and Webervirus KP36, were tested against the P. aeruginosa PAO1 population, as well as Pseudomonas Pbunavirus KTN6. The results indicated that Klebsiella phages (non-specific to P. aeruginosa), particularly podovirus KP34, accelerated biofilm formation without affecting planktonic cultures. Our hypothesis suggests that bacteria sense phage virions, regardless of specificity, triggering biofilm matrix formation to block potential phage adsorption and infection. Nevertheless, further research is needed to understand the ecological and evolutionary dynamics between phages and bacteria, which is crucial for developing novel antibiofilm therapies. Full article

Secreted viral proteins are crucial in virus–host interactions, as they modify the host microenvironment to promote infection. These secreted proteins could alter immune and inflammatory responses, allowing viruses to evade defense mechanisms such as cytotoxic T cell activation and antibody neutralization. Some secreted proteins mimic host molecules to suppress antiviral responses, making them valuable targets for antivirals and diagnostics. Notable examples include BARF1 from Epstein–Barr virus, associated with gastric cancer; vIL-10 from Epstein–Barr virus, which regulates immune responses and contributes to autoimmune diseases; NS1 from dengue virus, associated with vascular permeability and early diagnosis; and NSP4 from rotavirus as an enterotoxin, among others. The study of these proteins improves our understanding of viral pathogenesis and helps to develop innovative treatments for infectious and non-infectious diseases, taking advantage of the evolutionary adaptations of viruses. This review explores their impact on the infection cycle, disease progression, and key processes, such as cell cycle regulation, apoptosis, and cell signaling. Research on these proteins deepens our basic knowledge of virology and generates alternative methods for detecting biomarkers and creating more effective therapies, as well as implementing some emerging technologies, such as biosensors and plasmon resonance, for the diagnosis of viral diseases. Full article

As an important zoonotic pathogen, Toxoplasma gondii relies on a unique organelle known as the apicoplast, which has garnered significant attention as a potential drug target for anti-Toxoplasma therapy. To better understand the structure and function of the apicoplast, we previously constructed a membrane protein database of the apicoplast. During this process, we identified the major facilitator superfamily (MFS) transporter protein HAP12, which partially colocalizes with the apicoplast. Evolutionary analysis revealed that HAP12 is highly conserved across the Apicomplexa family and model organisms. HAP12 depletion impaired T. gondii invasion and survival but did not affect the stability of several key organelles, including the apicoplast. Moreover, depletion of HAP12 resulted in a characteristic delayed-death phenotype in the apicoplast. Mouse virulence assays confirmed that HAP12 is an essential protein for parasite survival. This study provides new insights into potential drug and vaccine targets for combating Toxoplasma infections. Full article

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70–85% of prostate cancer patients. Understanding the cellular and molecular mechanisms underlying bone metastasis is essential for developing targeted therapies. This study aimed to systematically characterize the heterogeneity and microenvironmental adaptation of prostate cancer bone metastases using single-cell transcriptomics. Methods: We integrated the largest single-cell transcriptome dataset to date, encompassing 124 samples from primary prostate tumors, various bone metastatic sites, and non-malignant tissues (e.g., benign prostatic hyperplasia, normal bone marrow). After quality control, 602,497 high-quality single-cell transcriptomes were analyzed. We employed unsupervised clustering, gene expression profiling, mutation analysis, and metabolic pathway reconstruction to characterize cancer cell subtypes and tumor microenvironmental remodeling. Results: Cancer epithelial cells dominated the tumor microenvironment but exhibited pronounced heterogeneity, posing challenges for conventional clustering methods. By integrating genetic and metabolic features, we revealed key evolutionary trajectories of epithelial cancer cells during metastasis. Notably, we identified a novel epithelial subpopulation, NEndoCs, characterized by unique differentiation patterns and distinct spatial distribution across metastatic niches. We also observed significant metabolic reprogramming and recurrent mutations linked to prostate-to-bone microenvironmental transitions. Conclusions: This study comprehensively elucidates the mutation patterns, metabolic reprogramming, and microenvironment adaptation mechanisms of bone metastasis in prostate cancer, providing key molecular targets and clinical strategies for the precise treatment of bone metastatic prostate cancer. Full article

Designing effective drug therapies requires balancing competing objectives, such as therapeutic efficacy, safety, and cost efficiency—a task that poses significant challenges for conventional optimization methods. To address this, we propose the multi-objective spider–wasp optimizer (MOSWO), a novel approach uniquely emulating the cooperative predation dynamics between spiders and wasps observed in nature. MOSWO integrates adaptive mechanisms for exploration and exploitation to resolve complex trade-offs in multiobjective drug design. Unlike existing approaches, the algorithm employs a dynamic population-partitioning strategy inspired by predator–prey interactions, enabling efficient Pareto frontier discovery. We validate MOSWO’s performance through extensive experiments on synthetic benchmarks and real-world case studies spanning antiviral and antibiotic therapies. Results demonstrate that MOSWO surpasses state-of-the-art methods (NSGA-II, MOEA/D, MOGWO, and MOPSO), achieving 11% higher hypervolume scores, 8% lower inverted generational distance scores, 9% higher spread scores, a 30% faster convergence, and superior robustness against noisy biological datasets. The framework’s adaptability to diverse therapeutic scenarios underscores its potential as a transformative tool for computational pharmacology. Full article

Familial Mediterranean Fever (FMF) is the prototype and most common autoinflammatory disease that is particularly frequent in populations originating from the Mediterranean basin. It is characterized by episodes of recurrent inflammation lasting 2–3 days. Colchicine is the mainstay therapy, which decreases the number of attacks and eventually prevents amyloidosis, the most worrisome complication of uncontrolled FMF. It is an autosomal recessive disease. The high rate of MEFV gene mutations in specific populations has been discussed as the result of an evolutionary advantage. Tel-Hashomer criteria were the first set of criteria primarily designed for adults. Recently, the Eurofever/PRINTO group has validated a new set of classification criteria for FMF, including clinical and genetic variables. Colchicine intolerance is an important problem and limits the ability to reach an effective dose. In these groups of patients, adding an alternative biological treatment (anti IL-1 agents) is recommended. Several tools such as FMF50, AIDAI, ADDI, ISSF and MASIF have been proposed to evaluate and quantify the disease activity and organ damage. Ongoing research should clarify the exact mechanisms causing FMF attacks and phenotypic variabilities between the patients; further translational research requires the implementation of proteomics and epigenetics signatures to elucidate the pathogenesis. Full article

Recent progress in material science has led to the development of new drug delivery systems that go beyond the conventional approaches and offer greater accuracy and convenience in the application of therapeutic agents. This review discusses the evolutionary role of nanocarriers, hydrogels, and bioresponsive polymers that offer enhanced drug release, target accuracy, and bioavailability. Oncology, chronic disease management, and vaccine delivery are some of the applications explored in this paper to show how these materials improve the therapeutic results, counteract multidrug resistance, and allow for sustained and localized treatments. The review also discusses the translational barriers of bringing advanced materials into the clinical setting, which include issues of biocompatibility, scalability, and regulatory approval. Methods to overcome these challenges include surface modifications to reduce immunogenicity, scalable production methods such as microfluidics, and the harmonization of regulatory systems. In addition, the convergence of artificial intelligence (AI) and machine learning (ML) is opening new frontiers in material science and personalized medicine. These technologies allow for predictive modeling and real-time adjustments to optimize drug delivery to the needs of individual patients. The use of advanced materials can also be applied to rare and underserved diseases; thus, new strategies in gene therapy, orphan drugs development, and global vaccine distribution may offer new hopes for millions of patients. Full article