Biology Direct最新文献

Prokaryote evolution is driven in large part by the incessant arms race with viruses. Genomic investments in antivirus defense can be coarsely classified into two categories, immune systems that abrogate virus reproduction resulting in clearance, and programmed cell death (PCD) systems. Prokaryotic defense systems are enormously diverse, as revealed by an avalanche of recent discoveries, but the basic ecological determinants of defense strategy remain poorly understood. Through mathematical modeling of defense against lytic virus infection, we identify two principal determinants of optimal defense strategy and, through comparative genomics, we test this model by measuring the genomic investment into immunity vs. PCD among diverse bacteria and archaea. First, as viral pressure grows, immunity becomes the preferred defense strategy. Second, as host population size grows, PCD becomes the preferred strategy. We additionally predict that, although optimal strategy typically involves investment in both PCD and immunity, investment in immunity can also result in antagonism, increasing the likelihood that a PCD-competent cell will lyse due to infection. Together, these findings indicate that, generally, PCD is preferred at low multiplicity of infection (MOI) and immunity is preferred at high MOI. Finally, we demonstrate that PCD, which is typically considered to be an altruistic trait, is in some cases neutral and can be maintained in an unstructured population over an evolutionary timescale. Our work shows that the landscape of prokaryotic antivirus defense is substantially more complex than previously suspected.

Kinesin family member 4 A (KIF4A) is a multifunctional motor protein essential for chromosome condensation, spindle dynamics, and cytokinesis. Beyond its classical mitotic functions, emerging evidence positions KIF4A as a central regulator of tumorigenesis, therapy resistance, metabolic reprogramming, and immune modulation across diverse cancer types. However, no comprehensive review has integrated its molecular mechanisms with its roles in both oncological and non-oncological diseases, nor clarified its context-dependent behavior, including paradoxical tumor-suppressive effects in cervical cancer. In this review, we synthesize current advances spanning structural biology, transcriptional and post-translational regulation, and pathway-level interactions involving PI3K/AKT, TGF-β/Smad, Hippo-YAP, metabolic remodeling, and DNA damage response networks. We summarize KIF4A's expression and functions across more than 30 malignant tumors and multiple non-neoplastic conditions-including neurodevelopmental disorders, autoimmune diseases, viral infections, fibrotic diseases, and congenital anomalies-highlighting shared molecular themes and disease-specific distinctions. A notable finding is KIF4A's context dependency: while generally oncogenic, high KIF4A expression in cervical cancer correlates with improved survival, suggesting HPV-specific transcriptional rewiring, altered phosphorylation states, or compensatory genome stabilization as potential mechanisms.We further evaluate the translational implications of KIF4A as a biomarker for diagnosis, prognosis, and treatment response, and we critically examine therapeutic strategies targeting KIF4A-ranging from small-molecule inhibitors and gene-silencing approaches to miRNA therapeutics, exosome-based delivery systems, and neoantigen-directed immunotherapy. Finally, we outline major challenges to clinical translation, including its essential roles in mitosis and neuronal integrity, the need for tumor-selective delivery platforms, and incomplete understanding of its tissue-specific functions. Collectively, this review provides a unified mechanistic and translational framework for understanding KIF4A across human diseases, identifies key knowledge gaps, and proposes future research directions to enable safe and effective targeting of this biologically indispensable protein.

Background: RNAs fold into complex structures that critically influence gene expression. A prominent class of regulatory elements resides in the 5' untranslated region (5' UTR), where internal ribosome entry sites (IRESs) promote cap-independent translation by directly engaging the ribosome. First discovered in viral genomes, IRESs have been classified into four types according to their structural compactness and factor requirements. While viral IRESs are well studied, cellular IRESs remain poorly understood: they display limited sequence conservation, reduced structural compactness, and variable dependence on auxiliary RNA-binding proteins known as IRES trans-acting factors (ITAFs). Whether their activity relies mainly on RNA structure or protein assistance remains unresolved. Here, we present a computational framework that combines in silico mutagenesis and RNA-protein interaction profiling to investigate IRES mechanisms and guide the design of synthetic elements.

Results: Using the Hepatitis C Virus (HCV) IRES as a benchmark, we performed systematic single-nucleotide mutagenesis coupled with structural predictions. Mutations were classified as synonymous or non-synonymous based on their effect on the secondary structure. The HCV IRES showed overall robustness, but the domain interacting with eIF3 was particularly sensitive, consistent with its essential role in translation initiation. Extending this approach to other viral IRES families revealed distinct profiles of resilience: Aphthoviruses retained structural integrity despite extensive sequence variation, whereas Cripaviruses displayed higher variability. We then applied the same analysis to cellular IRESs, which proved to be more structurally sensitive, suggesting stronger reliance on cofactor support. To probe this connection, we used the catRAPID approach to predict interactions with translation-related proteins. The method distinguished IRESs with known ITAF binding, such as PTBP1, and highlighted stability-promoting mutations that increased the predicted affinity for translation factors.

Conclusions: Our in silico analysis indicates that mutational tolerance mirrors IRES cofactor dependence: compact viral IRESs are structurally robust, whereas non-viral IRESs are more reliant on protein interactions. By linking structure prediction with interaction profiling, we identify variants that both stabilize IRESs and improve binding to ITAFs or translation factors. This framework provides mechanistic insight into sequence-structure-function relationships and supports the rational design of synthetic IRES elements for therapeutic and biotechnological applications.

Autophagy - the cell's built-in recycling and quality-control programme - touches every layer of cutaneous biology. In keratinocytes it sculpts the cornified envelope; in melanocytes it balances pigment synthesis and oxidative stress; in immune and appendageal cells it fine-tunes defence, repair and hair-follicle cycling. When this choreography falters, skin disorders emerge. This review journeys from basic mechanisms (ULK1 signalling, Beclin-1/VPS34 nucleation, LC3B lipidation, selective mitophagy) to their fingerprints in health and disease. We dissect how autophagy malfunctions drive psoriasis hyper-proliferation, atopic-dermatitis barrier leakiness, vitiligo depigmentation and the metabolic rewiring of melanoma. Non-melanoma cancers, infectious dermatoses, wound repair, ageing and photo-damage are mapped onto the same autophagic atlas. Therapeutically, the pathway is a double-edged sword. mTOR or caloric-restriction mimetics jump-start a protective flux; chloroquine derivatives and ULK1 blockers clip tumour survival circuits; cannabinoids, photodynamic therapy and immune-checkpoint combinations exploit context-specific toggling between induction and brake. Emerging biomarkers (LC3B-II, p62, AMBRA1) promise patient-stratified interventions. By weaving together molecular detail, pre-clinical insight and clinical translation, we show why autophagy is no longer a backstage process but a star player in dermatology - and how targeting its switches could reshape future treatment algorithms.